Дисертації з теми "Stéatose hépatique non alcoolique – complications"
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Canivet, Clémence. "Étude de deux acteurs dans le développement des complications hépatiques liées à l’obésité : la vitamine D et FNDC5/Irisine." Thesis, Université Côte d'Azur (ComUE), 2019. http://theses.univ-cotedazur.fr/2019AZUR6036.
Non-Alcoholic Fatty Liver Diseases (NAFLD) is a major public health concern with global prevalence of 25%. NAFLD is increasingly recognized as the most common chronic liver disease. The spectrum of the hepatic diseases ranges from steatosis (fatty liver) to nonalcoholic steatohepatitis (NASH) (steatosis, inflammation, liver injury) and subsequently to the activation of fibrogenic pathways, which correlates with a high risk of developing cirrhosis and hepatocellular carcinoma. The treatment of NASH is still limited because of the lack of effective pharmacological treatment as well as lack of effective and practical diagnostic tools. NAFLD is associated with obesity and metabolic syndrome and the presence of type 2 diabetes can increase the risk of liver diseases. Inversely, NAFLD is also a risk factor for many metabolic diseases, including type 2 diabetes and cardiovascular disease. The mechanisms underlying the progression of NAFLD are multifactorial and not well understood. Better understand the pathogenesis of NASH will lead to identify new potential therapeutic targets. One part of my work focused on clinical aspects in a large cohort of obese patients regarding factors that potentially regulate the development of NAFLD. We here reported that: 1) binge eating disorders were associated as expected with obesity but independently of NAFLD severity and 2) the circulating level of vitamin D, well-known to display anti-oxidant and anti-fibrotic properties, was not diminished with NAFLD severity.In parallel, we investigated the expression level and the role of a new "hepatokine", Fibronectin type III domain containing 5 (FNDC5) and its soluble form irisin in NAFLD. We reported that hepatic expression of FNDC5 increased in the presence of hepatic steatosis and liver injury without impacting the systemic level of irisin in mouse models of NAFLD and in obese patients. This local production of FNDC5 was mainly influenced by genotoxic stress and behaved as local protective factor against NAFLD by preventing hepatocyte steatosis and injury. Finally, the single nucleotide polymorphism (SNP) FNDC5 rs3480 was protective of severe steatosis independently of PNPLA3 SNP rs738409, age, female, BMI and type 2 diabetes in a cohort of 613 patients. In conclusion, our human and experimental data strongly suggest that hepatic expression of FNDC5 could dampen the development of NAFL by negatively regulating steatogenesis and hepatocyte death
Nicolas, Anthony. "Polymorphismes du gène de la t-cadhérine (CDH13), récepteur de l'adiponectine, dans les diabètes et leurs complications." Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066232/document.
T-cadherin is a receptor of adiponectin, a protein involved in the pathophysiology of diabetes. In genome-wide association studies, T-cadherin gene (CDH13) polymorphisms are associated with adiponectin concentrations. The aim of our study was to deepen the relationship between polymorphisms of CDH13, plasma adiponectin, and the risk of diabetes and its complications. We selected two polymorphisms in CDH13. Genotyping was performed in D.E.S.I.R., cohort drawn from the French general population, DIABHYCAR (subjects with type 2 diabetes) and three cohorts of patients with type 1 diabetes, GENESIS, GENEDIAB and SURGENE. In the general population, CDH13 polymorphisms were associated with body mass index, HbA1c, Fatty Liver Index, an index of hepatic steatosis, and plasma adiponectin. In a case-control study between D.E.S.I.R. and DIABHYCAR, polymorphisms were associated with the risk of type 2 diabetes. These associations with clinical phenotypes could be due to the beneficial effects of adiponectin. In subjects with type 1 diabetes from GENESIS and GENEDIAB, we observed associations between polymorphisms of CDH13 and the prevalence and the incidence of kidney disease. The analysis in the SURGENE prospective study confirmed these associations. The direction of the relationships observed in this study is in favor of a deleterious role of adiponectin in diabetic nephropathy. In conclusion, these associations may be explained by variations in adiponectin and suggest a causal relationship
Bauvin, Pierre. "Modélisation de la stéatose hépatique (NAFLD) et de ses facteurs de risque par apprentissage sur des données de santé." Thesis, Lille 2, 2020. http://www.theses.fr/2020LIL2S028.
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease which is a combination of simple, slowly progressing steatosis, and non-alcoholic steatohepatitis (NASH), an inflammatory form which accelerates its progression. It is estimated that one in four people in the world is affected by NAFLD, and its prevalence is increasing rapidly, in parallel with the prevalence of its main risk factors: overweight, obesity and type 2 diabetes.This pathology is asymptomatic up to the complications, cirrhosis and liver cancer (hepatocellular carcinoma, HCC), which leads to late diagnosis and a negative impact on the associated morbidity and mortality. Furthermore, the reference diagnosis requires a liver biopsy, an invasive examination that cannot be performed routinely. As a result, the progression of the disease is poorly known and its estimation may suffer from a selection bias, towards patients with significant risk factors, who require a biopsy in the first place. A better understanding would allow the implementation of strategies to reduce its burden.The modelling approach is appropriate to take into account all susceptible patients, without having to carry out a large-scale follow-up study using liver biopsies in patients who are mostly asymptomatic. The objectives of this thesis are to describe and quantify the progression of NAFLD, to predict the associated morbidity and mortality, and to identify the population at risk, using Markov models. To do this, it is necessary to fill in some of the progression parameters via a literature review, to characterise the initial states (population likely to develop NAFLD) and the final states (mortality due to NAFLD), in order to deduce the missing progression parameters between the onset of the disease and mortality, by back-calculation.To exhaustively characterise NAFLD mortality, we identified all patients with cirrhosis or HCC from national hospital databases, representing more than 380,000 patients. We then developed an identification algorithm to determine the etiology underlying the hepatic complication, based on all the stays of the identified patients. This algorithm requires the identification of patients with cirrhosis or HCC of alcoholic or viral origin, to obtain by elimination only NAFLD patients. Once the specific mortality data had been obtained, we estimated the population likely to develop NAFLD, defined as all individuals with overweight or type 2 diabetes, excluding the population of excessive drinkers. We estimated the prevalence and incidence of this population, and modelled its evolution with age and years, based on individual data from surveys representative of the French population.Finally, we quantified the progression of NAFLD, and the impact of risk factors, using two approaches: from the literature, and from biopsy data from more than 1,800 obese patients who were candidates for bariatric surgery, resulting in a tool for predicting the progression of NAFLD in this population. We chose to back-calculate the progression parameters corresponding to the asymptomatic states, which are the most susceptible to selection bias.We obtained a model of the progression of NAFLD, taking into account the dynamic distribution of the population among weight classes and diabetes status, and resulting in the observed statistics of NAFLD deaths. The model takes into account gender, age, year, BMI (body mass index) class, diabetes status and the presence of a genetic polymorphism (PNPLA3 rs738409, C→G) as covariates of progression. It is a tool for assessing the impact of a possible treatment or public health policy on morbidity and mortality
Decoin, Raphaël. "Impact de la stéatohépatite non alcoolique sur le remodelage myocardique et sur les complications cardiovasculaires." Electronic Thesis or Diss., Université de Lille (2022-....), 2023. https://pepite-depot.univ-lille.fr/ToutIDP/EDBSL/2023/2023ULILS066.pdf.
Cardiac remodeling is a pathophysiological phenomenon during which the cardiac muscle undergoes structural alterations at both tissue and cellular levels, leading to functional changes. The clinical implications are diverse, including the development of atrial fibrillation and heart failure. Among the numerous risk factors identified, Non-Alcoholic Fatty Liver Diseases (NAFLD) have an emerging role. This liver disease, characterized by steatosis, inflammation, and fibrosis, is associated with the development of myocardial pathologies.In this study, we hypothesize that NAFLD specifically triggers characteristic cardiac remodeling at both histological and functional levels. To explore this hypothesis, we employ a translational approach using various cohorts from the Lille University Hospital, as well as a murine model of NAFLD. Three distinct objectives have been defined: 1) demonstrate an association between atrial remodeling and NAFLD in patients; 2) propose an early diagnostic method for cardiac remodeling; 3) propose mechanistic hypotheses for the liver-heart connection through a translational methodology. Firstly, we characterized atrial cardiac remodeling in a cohort of patients indicated for atrial fibrillation ablation. Among these patients, we observed a positive association between the progression of hepatic pathology (assessed through clinical-biological scores) and, on one hand, dilation and impaired contractility of the left atrium as estimated by echocardiography, and on the other hand, the presence of areas with low extracellular voltages. This remodeling profile was also linked to a poor prognosis of ablation. In a second cohort of patients scheduled for cardiac surgery (POMI-AF), we demonstrated greater fibrosis in the atrial myocardium of patients with a high-risk NAFLD-related fibrosis compared to those without NAFLD. Next, using the same POMI-AF cohort, we showed that quantifying myocardial fat (intracardiomyocytic lipid droplets) using VARPRO MRI sequence is a robust, reliable, and feasible analysis in NAFLD-affected patients. Lastly, in a murine model of NAFLD developed in the laboratory (high-fat, sucrose, and cholesterol diet for 24 weeks), we described the presence of cardiac remodeling. Mice subjected to the NAFLD-inducing diet developed diastolic dysfunction with preserved ejection fraction, assessed by echocardiography, in comparison to the control diet group. This loss of function was associated with concentric left ventricular hypertrophy. Histologically, this hypertrophy was explained by an increase in the cross-sectional diameter of cardiomyocytes, which was also associated with diffuse interstitial fibrosisstarting from a vascular point. These observations were more pronounced with higher hepatic involvement, reinforcing the initial hypothesis. Total ventricular mRNA sequencing revealed a significantly altered transcriptional profile in NAFLD-affected mice, indicating impaired energy metabolism and a profound immune signature. Subsequently, flow cytometry analysis of immune populations revealed macrophage and dendritic cell infiltration in the myocardium, similar to what is observed in NAFLD liver. This macrophage infiltration was also evident in human biopsies from patients with advanced NAFLD.In conclusion, we demonstrate that NAFLD-associated cardiac remodeling affects both the left atrium and the left ventricle. Additionally, we have shown that quantifying cardiac lipid droplet accumulation is feasible using MRI. Finally, the myeloid infiltration observed in the myocardium of NAFLD patients and in our murine model suggests a potential link between hepatic dysimmunity and cardiac remodeling
Leclère, Pierre. "Rôle du facteur de transcription circadien Krüppel-Like Factor 10 (KLF 10) dans le développement des complications hépatiques de l’obésité." Thesis, Université Côte d'Azur (ComUE), 2019. http://theses.univ-cotedazur.fr/2019AZUR6030.
Non-alcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver diseases (NAFLDs), is a global public health problem without approved pharmacological therapy. NAFLD extend from non-pathogenic lipid accumulation, known as hepatic steatosis to hepatocellular carcinoma (HCC) through a wide spectrum of stages including NASH and fibrosis. NASH is featured by hepatic inflammation and hepatocyte cell death. Better understand NASH pathogenic cellular and molecular mechanisms is an important clinical requirement.Circadian timing system (CTS) is the main synchronizer of organismal physiology to environmental light/dark cycles. This CTS is comprised of a central pacemaker in the supra-chiasmatic nucleus of the hypothalamus and peripheral clocks localized in each single cell throughout the brain and body. Western society life style, including junk food consumption and erratic feeding, chronic jet lag, light exposure at night and shift-work, can disrupt the CTS. CTS disruption has been assessed as a risk factor for the development of chronic diseases including metabolic syndrome and cancer. The liver is the most rhythmic organ and evidence for an intricate link between CTS disruption and NAFLD development is most illustrated by (i) the genetic and environmental disruption of the CTS leads to dyslipidemia, hepatic steatosis as well as spontaneous NASH and HCC development (ii) the circadian hepatic transcriptome is rearranged in mice fed high fat diet and displaying hepatic steatosis, showing that metabolic disruption also impacts diurnal oscillation of transcripts. Krüppel-like factor 10 is a circadian transcription factor directly regulated by the circadian clock in the liver and help shaping the hepatic diurnal transcriptome and the control carbohydrate and lipid metabolism homeostasis. Beside from metabolism, this transcription factor has also been shown to regulate two NASH related processes, in very different contexts, namely inflammation and cell death. We thus aimed to evaluate the implication of circadian rhythms and the role of KLF10 during steatohepatitisHere, we show that hepatic steatosis and inflammation display diurnal rhythmicity in mice developing steatohepatitis upon feeding with a methionine and choline deficient diet (MCDD). Core clock gene oscillations remained mostly unaffected but rhythmic Klf10 expression was abolished in this model. Klf10 deficient mice (Klf10-/-) display enhanced liver injury despite the same level of hepatic steatosis and inflammation that control mice upon MCDD challenge. Specific genetic ablation of Klf10 only in hepatocytes phenocopied the phenotype of Klf10-/- mice upon MCDD. Silencing Klf10 in isolated primary hepatocytes also sensitized these cells to apoptosis along with increased caspase 3 activation in response to TNFα. We also show that the hepatic KLF10 expression correlates with liver injury (ALT activity) and the circulating keratin 18 hepatocyte death marker in a cohort of obese patients. Collectively our findings suggest that specific NASH features including steatosis and inflammation display diurnal oscillations and the associated altered circadian expression of Klf10 may aggravate liver injury through hepatocyte sensitization to cell death.Collectively, our results gathered from cellular and animal experiments as well as correlative study in Human indicate that hepatic steatosis and inflammation could be rhythmic during NASH and that KLF10 could be a hepatoprotective factor that could limit NAFLD progression
Fedchuk, Larysa. "Progression et tests diagnostiques de la stéatose hépatique non alcoolique." Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066210/document.
Non-alcoholic fatty liver disease (NAFLD) covers a spectrum ranging from isolated steatosis to non-alcoholic steatohepatitis (NASH) and is becoming one of the most frequent causes of chronic liver disease, mainly because of its close association with the worldwide epidemic of diabetes and obesity. Liver steatosis can predict the occurrence of metabolic complications associated with insulin resistance, such as diabetes and cardiovascular events. Our understanding of the natural history of NAFLD is still incomplete. Currently, the explicative model is based on a dichotomy between steatohepatitis, considered the progressive form of the disease, which can lead to cirrhosis and isolated steatosis with or without minimal inflammation, which is considered a non-progressive condition that does not impact overall survival or result in liver-related mortality and morbidity. This dichotomy largely determines the management of NAFLD patients: patients without steatohepatitis usually do not undergo specific monitoring for liver disease progression. Liver biopsy is considered the reference diagnostic method but its implementation in clinical practice remains limited due to procedure complexity, invasiveness, cost, potential complications, sampling error and inter-observer variability. Non-invasive methods of hepatic injury have become a real alternative to liver biopsy for the diagnosis of patients with chronic liver disease in the past decade. The aims of this thesis were: 1) to better understand the histological course of the disease, to better identify patients at risk of histological progression based on initial histological findings and to establish a correlation between histological changes and the course of metabolic co-morbidities often associated with NAFLD : 2) to establish factors associated with short-term variability of repeated measurements of elastometry in patients with chronic liver diseases in order to understand how this non invasive procedure can be used for patient monitoring 3) to determine the diagnostic value and limitations of several steatosis biomarkers using liver biopsy as a reference standard in a large cohort of patients with suspected NAFLD. Our study shows that a fraction of patients with isolated steatosis can unambiguously evolve towards well-defined steatohepatitis, and in some of them, bridging fibrosis. The presence of mild lobular inflammation or any amount of fibrosis substantially increases the risk of histological progression in the mid-term while those with steatosis alone are at lowest risk. Patients with disease progression experienced a deterioration of cardio-metabolic risk factors. Our data if validated by independent studies, allow for better stratification of patients at risk of disease progression. The results of this study favor a change in the practices of monitoring and risk assessment of patients with steatosis but without steatohepatitis
Delacôte, Claire. "Vers une meilleure compréhension de la maladie du foie liée à l'alcool et des facteurs influençant sa progression : approche de modélisation." Thesis, Lille 2, 2020. http://www.theses.fr/2020LIL2S029.
In France, excessive alcohol consumption is the leading cause of cirrhosis and hepatocellular carcinoma (HCC), ahead of viral hepatitis and metabolic syndrome. In 2016, there were nearly 10,500 deaths by cirrhosis or HCC, despite a significant decrease in per capita alcohol consumption since 1960 (26L in 1960, 11.7L in 2017).Alcohol drinkers are at risk of developing alcohol-related liver disease (ALD). It progresses from the initial stage of steatosis to more advanced stages of fibrosis and cirrhosis, which may lead to complications: decompensation and HCC. ALD is an asymptomatic disease prior to the onset of complications, and many patients are diagnosed late with life-threatening consequences.Implementing early actions targeting excessive alcohol drinkers could help to reduce liver morbidity and mortality through the avoidance or earlier diagnosis of complications. The evaluation of the possible benefit of such public health actions requires, on the one hand, knowledge of the different stages leading to the development of complications and, on the other hand, knowledge of the impact of risk factors on progression, in order to be able to determine the populations to target. Among the risk factors identified, the metabolic syndrome plays an important role. Thus, in order to understand the mechanisms of evolution of ALD, it is necessary to study in parallel those leading to non-alcoholic fatty liver disease (NAFLD).The natural history of ALD is still poorly described, especially for the stages preceding cirrhosis. Mathematical modeling provides a conceptual framework to overcome the ethical issues that would arise from a cohort study of the evolution of ALD.The main objective of this work is to mathematically reconstruct the natural history of ALD and to predict the associated morbidity and mortality. The secondary objectives are to estimate the incidence of this pathology and to identify the at-risk population. For this purpose, we developed a Markov model that simulates the trajectory of cohorts of individuals from the moment they start at-risk alcohol consumption until their death. It integrates the main risk factors described as associated with the progression of ALD in the literature (sex, age, overweight and obesity, amount of alcohol, genetic polymorphism). Unknown parameters of progression are estimated by a back-calculation method.Three steps were necessary to supply and calibrate this model : 1) characterize mortality by decompensated cirrhosis and HCC related to alcohol consumption or metabolic syndrome from data provided by the French National Hospital Discharge database; 2) set up a Markov model on hospitalization data of excessive consumers to estimate the progression of fibrosis; 3) implement a Markov model on survey data from the general French population to estimate the process of entry into at-risk alcohol consumption or the onset of overweight and obesity.In conclusion, this work is the first to characterize the progression of ALD in the general French population. It is based on robust epidemiological data to which new insights are provided. The developed tools could be used to test the impact of public health policies that could be implemented in populations most likely to develop liver damage
Jegatheesan, Prasanthi. "Stéatose hépatique non-alcoolique : intérêt d’un apport nutritionnel en acides aminés." Thesis, Sorbonne Paris Cité, 2015. http://www.theses.fr/2015USPCB096.
Nonalcoholic fatty liver disease (NAFLD) is a manifestation of the metabolic syndrome whose prevalence is constantly growing. Therapeutic strategies are either difficult to implement or of limited effectiveness. We studied a nutritional approach with three specific amino acids: glutamine, arginine and citrulline (Cit) for their pharmaconutrient properties. In a model of moderate fructose-induced NAFLD, citrulline alone (1 g/kg/day) improved lipid metabolism. However, the study of the kinetics of NAFLD suggested a protective effect of nitrogen supply by itself. The specific effect of Cit compared to that of nitrogen (NEAAs) has been determined in a model of 8 week fructose diet-induced NAFLD. This has confirmed the protective effect of Cit and NEAAs. However, Cit exerted a specific effect on the expression of Fas and SREBP1c and improves peripheral Arg availability, an important component of insulin sensitivity. Steatosis was associated with loss of lean mass, suggesting AA oxidation at the expense of muscle anabolism, and lipid accumulation causing steatosis and visceral fat gain; Cit and NEAAs by acting on NAFLD would prevent this effect of fructose. We then evaluated the effects of Cit in a model of more severe steatosis induced by western diet. Cit improved liver function (reduced fat and liver inflammation) and protected the liver-gut axis (restoration of Bacteroides/Prevotella group in the colonic mucosa, decreased intestinal inflammation and increased expression of claudin 1) but did not prevent all western diet-induced alterations. It would be interesting to assess the dose/effect relationship and the effectiveness of Cit in combination with other treatments. Furthermore, the cellular mechanisms remain to be elucidated
Perazzo, Pedroso Barbosa Hugo. "Marqueurs non-invasifs de stéatose et fibrose hépatique." Phd thesis, Université Pierre et Marie Curie - Paris VI, 2014. http://tel.archives-ouvertes.fr/tel-00989999.
Trak, Smayra Viviane. "La stéatose hépatique non-alcoolique et la NASH : approche diagnostique et modèles murins." Paris 7, 2011. http://www.theses.fr/2011PA077247.
Lavallard, Vanessa. "Étude de la mort hépatocytaire associée à la stéatohépatite non alcoolique : implication de l'autophagie." Nice, 2011. http://www.theses.fr/2011NICE4063.
Obesity is associated with a large spectrum of hepatic complications called non alcoholic fatty liver diseases. They evolve from steatosis (hepatic accumulation of triglycerides) to inflammation (NASH : non alcoholic steatohepatitis) which can progress to fibrosis, cirrhosis and hepatocarninoma. NASH is characterized by fatty liver, hepatic inflammation and hepatocyte death (necro-inflammation). Alcoholic liver diseases share the same spectrum of hepatic alterations. The mechanisms involved in the evolution from steatosis to inflammation and then fibrosis are complex. Among the several factors, metabolic endotoxinemia and hepatocyte death could play an important role. The increase in circulating LPS level due to the modifications of intestinal permeability activates hepatic inflammation which induces necro-inflammation and fibrosis. Hepatocyte apoptosis also increases inflammation and fibrosis. So, improving cell survival could be a therapeutic target to prevent evolution of hepatic complications. The study of this hepatocyte death in hepatic complications in obesity determined : i) Serum hepatocyte death markers levels predict hepatic inflammation. Hepatic biopsy, an invasive approach, remains the gold standard for assessment of liver inflammation? Identifying non invasive markers is a real need for clinical. Our first goal was to determine whether serum markers of hepatocyte death could predict hepatic inflammation in chronic liver diseases associated to obesity and chronic alcohol consumption. In morbidly obese and alcoholic patients, we have reported that the circulating level of apoptotic markers significantly increased with hepatic inflammation. These markers also predict hepatic fibrosis in alcoholic patients. Further, association of apoptotic hepatocyte marker with ALT and metabolic syndrome improves prediction of hepatic inflammation in morbidly obese patients. Ii) Inflammation negatively regulates the hepato-protective role of autophagy. Studies have recently reported that autophagy could play an hepato-protective role. In our second project, we have determined the role of inflammation in hepatic autophagic turnover and cell death. In mouse models of NASH (menthionine choline deficient-diet, obese mice upon LPS challenge), hepatic inflammation is associated with a decrease in autophagic flux and an increase in hepatocyte suffering. Activation (fasting) or inhibition of autophagic flux decreases or increases liver injury induced by inflammation, respectively. In mouse primary hepatocytes, autophagic flux is decreased in response to TNFα and IL1β. The inhibition of autophagic flux also enhances HepG2 cells death induced by TNFα and IL1β. In obese patients, hepatic expression level of autophagic markers is increased and correlated with ALT level. Autophagosomes and p62 accumulation suggest an alteration of autophagic flux. We have therefore shown that hepatic inflammation decreases hepatic autophagic turnover and enhances liver injury in steatotic liver associated with obesity. Iii) Autophagy is activated for cell survival after lipoapotosis in HepG2 cells. Obesity is associated with elevated free saturated fatty acids, such as palmitate, which are involved in lipotoxicity and lipoapoptosis in liver cells. Palmitate also regulates autophagy leading to either cell death or survival in other cells. The objective of the last study was to determine if palmitate regulates autophagic turnover and to evaluate its role in lipotoxicity in HepG2 cells. Palmitate induces autophagic turnover independently of TNFα and ceramides and partially dependent on JNK activation. The inhibition of autophagy enhances cell death induced by palmitate. In addition, treatment of cells with an unsaturated fatty acid (oleic acid) prevented the activation of JNK, autophagic flux partially via the JNK pathway in HepG2 cells. The induction of autophagy played a protective role but the level of activation of this compensatory effect was insufficient to completely prevent lipoapoptosis. Our studies highlight new potentially actors involved in the pathogenesis of hepatic complications in obesity
Deprince, Audrey. "Rôle de l’Apolipoprotéine F dans le métabolisme des lipides : impact sur le développement de la stéatose hépatique non alcoolique." Thesis, Université de Lille (2018-2021), 2021. https://pepite-depot.univ-lille.fr/ToutIDP/EDBSL/2021/2021LILUS063.pdf.
Non-Alcoholic Fatty Liver Disease (NAFLD) is a chronic, progressive disease which includes a spectrum of disease states ranging from isolated hepatic steatosis to steatohepatitis (or NASH). These changes in the liver have a significant impact on overall physiology and indicate higher risk of mortality from cardiovascular disease and hepatocellular carcinoma. However, the molecular mechanisms driving NAFLD evolution to NASH remain poorly understood. Through an unbiased transcriptomic analysis, we identified Apolipoprotein F (ApoF) whose expression is inversely correlated with steatosis and reduced ~ 50% in subjects with NASH. ApoF is secreted exclusively from the liver and found associated with high-density (HDL) and low-density lipoprotein (LDL) particles. Previous functional studies of ApoF have shown that ApoF favors reverse cholesterol transport in mice. These results suggest ApoF could affect NAFLD development and/or its cardiovascular complications.However, the precise role of ApoF in lipoprotein metabolism remains poorly understood. In this project, we have identified a new role for ApoF. Our results show that overexpression of APOF in mice is associated with a decrease in fasting plasma triglycerides (TG) levels by promoting both VLDL secretion and clearance of TG-rich particles via an increase in their hepatic uptake, probably through activation of the SREBP2 pathway.Subsequently, we sought to determine the impact of modulating hepatic ApoF expression on the development of NAFLD in mice fed with a high fat diet supplemented with sucrose and cholesterol, which induces NASH. Surprisingly, our results show that raising the level of hepatic APOF in the context of NAFLD may rather be deleterious. We observed an aggravation of hepatic inflammation and unfavorable changes in plasma lipids (reduced HDL-C and increased LDL-C) in mice overexpressing APOF compared to GFP after being fed the NASH-inducing diet. Similarly, total deletion of ApoF does not seem to accelerate the development of the disease. Thus, our results suggest that the decrease in hepatic APOF expression in NAFLD patients may be a compensatory mechanism to prevent a deleterious effect of ApoF activity. However, further studies are needed to confirm the role of ApoF in the development of NAFLD
Bertola, Adeline. "Rôle de l'inflammation dans le développement de la stéatohépatite non alcoolique chez les patients obèses : interrelations entre le foie et le tissu adipeux." Nice, 2009. http://www.theses.fr/2009NICE4087.
Obesity is associated with hepatic complications ranging from steatosis to nonalcoolic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma. The pathophysiological mechanisms involved in the development of NASH remain poorly understood. In obesity, production of proinflammatory cytokines by adipocytes and adipose tissue- infiltrating macrophages may play a central role in the development of these hepatic complications. Using a large scale real-time quantitative PCR technique, we identified genes related to inflammation and immune response whose expression is altered in the liver of morbidly obese patients with NASH. These results suggest that immune response may be polarized towards a Th1 phenotype in the lover of these patients. Furthermore, we have identified immune semaphorins as potential new players in NASH. Recently, adipose tissue has been identified as a new source of osteopontin. This proinflammatory cytokine plays an important role in several murine models of liver diseases. We have shown that osteopontin expression is associated with adipose tissue inflammation and hepatic steatosis in morbidly obese patients. Our results suggest that osteopontin may contribute to macrophage infiltration into adipose tissue and that its enhanced expression during steatosis may be involver in the progression of hepatic complications. We have thus identified new players involved in the development of hepatic complication of obesity in humans
Pham, Sandrine. "Rôle de LECT2 dans les maladies stéatosiques non alcooliques du foie." Thesis, Université Paris sciences et lettres, 2020. https://tel.archives-ouvertes.fr/tel-03176850.
The liver is the privileged site of metabolic regulations that must be tightly coordinated to prevent metabolic imbalance to preserve homeostasis. Alteration of these processes can promote steatosis, an essential feature of Non-Alcoholic Fatty Liver Diseases (NAFLD), representing the new global epidemic threat. During this thesis work, we demonstrated that LECT2, a liver secreted factor, is increased in both Human and mice harboring fatty liver. In a physiological context, we demonstrated that LECT2 controls liver lipogenesis through the LXR signalling pathway. At the molecular level, the absence of LECT2 induces a specific accumulation of 25-OHC oxysterol which leads to a significant increase in the activity of LXR and its target genes. From a mechanistic point of view, hepatospecific re-expression of LECT2 in Lect2-deficient mice is sufficient to specifically decrease the activity of LXR and the expression of its target genes. These results demonstrate that Lect2 behaves as a regulator of LXR signaling in the liver and illustrate that LECT2 is a key player in hepatic lipogenesis. Taken together, our results suggest that LECT2 is a key player in NAFLD, and open up new diagnostic and therapeutic perspectives for these diseases
Le, Mentec Hélène. "Impact de perturbateurs endocriniens sur la stéatose hépatique et sa progression pathologique." Electronic Thesis or Diss., Université de Rennes (2023-....), 2023. https://ged.univ-rennes1.fr/nuxeo/site/esupversions/78c59db4-86ae-460e-b535-a00dcb37c55e.
Non-alcoholic fatty liver disease (NAFLD) are the most common form of liver diseases in the world, affecting around 25% of the general population. The first stage of NAFLD is the steatosis, a benign condition defined by the accumulation of lipid droplets in liver. Around 20% of people with steatosis develop the pathological stage, steatohepatitis, characterized by cell death of hepatocytes associated with hepatic inflammation. Recently, exposure to endocrine disruptors (EDs), to which humans are continuously exposed, has been described to impact these diseases. In this context, the aim of this thesis was to develop two biological tests, based on fluorescence microscopy and using the in vivo model of the zebrafish larva, thereby allowing to estimate the impact of EDs on the induction (1st test,"Steatosis Assay on Zebrafish" - StAZ) and progression of NAFLD (2nd test, "Steatohepatitis Assay on Zebrafish" - ShAZ). The StAZ allowed us to identify DDE as a potent steatogenic compound. Looking for underlying mechanisms, it has been shown that scd1 desaturase induction by DDE was partly responsible for steatosis and membrane remodeling (fluidization of hepatic cell membranes). The ShAZ, aims at identifying EDs capable of promoting the progression to steatohepatitis by measuring characteristic markers of this pathology by microscopy (i.e. cell death, oxidative stress and inflammation). Overall, these studies should allow the identification of EDs involved in the initiation and pathological progression of NAFLD, as well as a better understanding of their modes of action, in order to allow a better regulation of EDs
Grzych, Guillaume. "Étude du profil métabolomique des patients atteints de stéatose hépatique non alcoolique (NASH) : recherche d’hypothèses physiopathologiques et de biomarqueurs." Thesis, Lille 2, 2020. http://www.theses.fr/2020LIL2S026.
NAFLD (Non-Alcoholic Fatty Liver Disease), a major public health issue, is considered thehepatic manifestation of the metabolic syndrome. NAFLD is characterized by liver injury dueto an accumulation of triglycerides in the liver which, when associated with inflammation, canprogress to steatohepatitis (NASH Non-Alcoholic Steato Hepatitis). The molecular mechanismsunderlying the pathogenesis, and particularly the transition from steatosis to NASH, are still poorly understood. A better understanding of the pathophysiology of NASH is necessary to identify potential therapeutic targets and non-invasive markers for the diagnosis and monitoring of the pathology. In this context, metabolomic approaches are promising.Metabolomics is the comprehensive analysis of metabolites in a biological medium, and it complements other "omics" techniques for the study of dynamic biological processes. The objective of this work is to use the metabolomics approach to highlight a particular profile in NASH patients in order to understand the pathophysiology and identify potential biomarkers.For this, we have used two metabolomic approaches: 1/ the targeted approach, on plasma,focusing on two classes of metabolites, amino acids and bile acids, 2/ the non-targeted approach on human plasma and livers (results are pending).In the literature, bile acids (B A) are studied as pathophysiological actors and potential biomarkers in the context of NASH. However, interpretation of many cohort studies is complicated by the close association of NASH with type 2 diabetes (T2D), insulin resistance(IR) and obesity, which are also associated with variations in BA. We therefore sought tounderstand the complex relationship between NASH and BA concentrations, as a function ofT2D status, considering IR and obesity as confounding parameters. Through analysis of BAprofiles in two cohorts (ABOS n=219, RESOLVE n=58) of well-characterized obese patients (histological analysis of liver biopsies, clinical-biological status, well-powered statistically), weshow that plasma BA concentrations are higher in NASH vs. non-NASH patients in both T2Dand non-T2D patients. These increases are dependent on the degree of IR, suggesting that NASH causes AB alterations only in the presence of advanced IR and independently of diabetes status.In the literature, plasma levels of branched-chain AA (BCAA) are associated with obesity, IR,and severity of liver damage in NAFLD. In addition, plasma BCAA concentrations differ between genders, which display different susceptibilities to development of cardiometabolicdisease. We evaluated the association between plasma BCAA concentrations and the severity stages of NAFLD, independent of gender, IR and obesity. In the RESOLVE cohort, 112 obese patients were divided into four groups based on NAFLD severity and matched for gender, BMI,IR, and HbA1c. As expected, a modest positive correlation was observed between BCAAconcentrations and NAFLD severity, as well as a major impact of gender on BCAAconcentrations. Subgroup analysis revealed that while plasma BCAA concentrations increased with the severity of NAFLD in females, they tended to decrease in males, suggesting an impact of gender on the metabolic component of NAFLD. Analysis of other AA in the cohort reveals plasma AA alterations involved in the methionine cycle (serine, cysteine, ...), whose molecular mechanisms are being explored in mouse models. The use of metabolomics has allowed us to better characterize the complex interactions of NASH with IR and sex on BA and AA
Loffroy, Romaric. "Particularités de l’athérosclérose du sujet non diabétique, diabétique de type 2, et/ou stéatosique non alcoolique : de la physiopathologie aux techniques d’imagerie non invasives." Thesis, Lyon 1, 2010. http://www.theses.fr/2010LYO10282/document.
Atherosclerosis is a major public health problem and is one of the major causes of death in the developed western world today. It is therefore of utmost importance that we understand the mechanisms involved in the evolution and progression of this disease and its associated complications. With the work done for this thesis, we tried to bring forth the importance of non invasive clinical imaging to study the pattern of evolution of atherosclerosis involving the carotid and/or coronary arteries. We also present the role played by imaging in prevention and early diagnosis of associated complications in non diabetic and type 2 diabetic patients, presenting with or without non alcoholic hepatic steatosis. In this study, we evaluated three different clinical research protocols used involving the clinical findings, biochemical as well as radiological examination results. The results of these protocols have been the basis for several peer reviewed international publications till date
Helmy, Nada. "Etude des mécanismes du développement de la stéatohépatite non alcoolique (NAHS) chez des patients obèses." Sorbonne Paris Cité, 2015. http://www.theses.fr/2015USPCC261.
Obesity is currently one of the major public health issues worldwide and nationally. NAFLD (non-alcoholic fatty liver disease) represents one of the major complications associated with obesity, and is considered as the hepatic manifestation of metabolic syndrome. The term NAFLD extends from simple steatosis (reversible) to steatohepatitis (NASH) having potential progression to fibrosis, cirrhosis and possibly hepatocellular carcinoma. At present, the mechanisms responsible for the establishment of NAFLD in obese patients, and its evolution towards NASH, are not well understood. The aim of my thesis was to determine if alterations in liver lipid metabolism and/or mitochondrial function, in a context of fat overload of the liver, could participate in the development of NASH. Intraoperative surgical liver biopsies were obtained from morbidly obese patients undergoing bariatric surgery, as well as non-obese controls. The long-chain fatty acid (LCFA) metabolic fluxes using [1-¹⁴C]oleate and exploration of mitochondrial respiration were performed on fresh liver tissue. The results show impaired complete LCFA oxidation in obese NASH patients (decreased ¹⁴cCO₂increased ¹⁴c acido-soluble products, decreased ketogenesis). Hepatic ¹⁴cCO₂ production negatively correlates with liver triglyceride and diacylglycerol contents, which are increased in obese NASH patients compared to other groups. Mitochondrial respiration was measured by oxygraphy using different substrates and inhibitors in liver homogenate as well as isolated mitochondria. A general reduction in mitochondrial respiration was observed between control group and all obese patients groups. However, NASH is associated with a significant decreased mitochondrial respiratiorewhen compared to other obese patients. These alterations are not associated with a change in mitochondrial mass, nor in protein expression of respiratory OXPHOS complexes
Loffroy, Romaric. "Particularités de l'athérosclérose du sujet non diabétique, diabétique de type 2, et/ou stéatosique non alcoolique : de la physiopathologie aux techniques d'imagerie non invasives." Phd thesis, Université Claude Bernard - Lyon I, 2010. http://tel.archives-ouvertes.fr/tel-00825146.
Collin, de l'Hortet Alexandra. "La dérégulation de l’axe GH/EGFR inhibe la régénération du foie dans le cadre de la stéatose hépatique." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05T003/document.
This doctoral work focused on liver regeneration in physiological conditions and during steatosis. These last decades, several studies used gene invalidation models to identify important actors during the liver regeneration. In this context, it had been observed that animals displaying a defect of growth hormone pathway had a drastic defect of liver regeneration after partial hepatectomy. Initially, we started this work by focusing on understanding how growth hormone controls liver regeneration at the molecular level. To do so, we performed partial hepatectomies on animals deleted for the growth hormone receptor gene (GHrKO). These results showed that growth hormone plays a central role in the control of liver regeneration through the expression of EGFR and the activation of Erk1/2. Secondly, we focused our attention on a pathological situation showing a defect of growth hormone signaling : hepatic steatosis. Interestingly, many mice models of hepatic steatosis also present a drastic inhibition of hepatocytes proliferation after partial hepatectomy. In Humans, non-alcoholic fatty liver disease (NAFLD) represents an important risk factor regarding liver transplantations and resections. Through quantified analysis of several parameters from obese patient biopsies, we showed the existence of a strong correlation between hepatic steatosis and decrease in EGFR expression on humans. We also performed partial hepatectomies on two models of hepatic steatosis, one being genetic (ob/ob) and the other one being induced by a methionine choline deficient diet (MCD). Kinetics of regeneration post hepatectomy led us to confirm the defect of liver regeneration in on ob/ob and MCD mice. Moreover, the study of these steatotic models allowed us to corroborate the downregulation of the growth hormone signaling and the transcriptional decrease of EGFR expression. We also underlight the importance of TGF-β, a signaling pathway inhibiting proliferation, in the liver regeneration defect observed in ob/ob mice. Indeed, many members of this pathway have been found to be upregulated after partial hepatectomy, possibly being involved in the drastic regeneration defect observed in ob/ob mice. To finish, we also showed that growth hormone injections on a small period of time in ob/ob mice were capable of rescuing hepatocyte proliferation post hepatectomy. This phenotypic rescue was associated with a reexpression of EGFR at the transcription and protein level. This work led us to propose that the defect of the growth hormone/EGFR pathway represents a general mechanism associated with hepatic steatosis and is responsible for the liver regeneration defect linked to this disease
Tran, Sophie My-Yen. "Diversité des macrophages dans un modèle murin de stéatohépatite non alcoolique." Thesis, Sorbonne université, 2019. http://www.theses.fr/2019SORUS468.
Kupffer cells (EmKCs), the liver resident macrophages, develop embryonically and self-maintain by local proliferation in the adult independently from blood Ly-6C+ monocytes (MO). However, Ly-6C+ MO can differentiate into inflammatory macrophages derived monocytes (MoDMacs) in an inflamed liver. Here, we study macrophages (Macs) and specifically KCs homeostasis during NASH (a chronic inflammatory liver disease), where the use of KC-specific markers allowed discrimination of EmKCs from MoDMacs. While we validated MoDMacs were derived from Ly-6C+ MO, we revealed that the KC pool was almost half-composed by KCs of monocytic origin (MoKCs) during NASH. That was confirmed by observing the MCDD-fed CCR2 KO mice, which lacked Ly-6C+ MO and had almost no MoDMacs in their livers with a decrease in KCs of 50%. More MoKCs appeared during NASH and were partly immature and hyperproliferative. They engrafted the KCs pool in the long term and self-maintained after disease regression, losing their hyperproliferative state and acquiring mature KCs markers. During NASH, MoKCs generated was a response to EmKCs death and they differentially influenced hepatic triglycerides build-up. Our data suggest functional differences between EmKCs and MoKCs. As a conclusion, KCs homeostasis was significantly reduced during NASH, with long-lasting impact on the KCs pool and direct effect on liver lipid burden
Collin, De L'Hortet Alexandra. "La dérégulation de l'axe GH/EGFR inhibe la régénération du foie dans le cadre de la stéatose hépatique." Phd thesis, Université René Descartes - Paris V, 2014. http://tel.archives-ouvertes.fr/tel-00986411.
Pawlak, Michal. "Effets hépatoprotecteurs de PPARα : rôle physiopathologique et bases moléculaires des activités PPARα dans l'inflammation aiguë et la stéatohépatite non alcoolique". Thesis, Lille 2, 2013. http://www.theses.fr/2013LIL2S047/document.
Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent liver condition characterized by excessive lipid deposition in the hepatocytes steatohepatitis (NASH) is hallamarked by chronic inflammation. NASH markedly increases the risk of progression towards liver fibrosis, cirrhosis ans hepatocellular carcinoma. The nuclear peroxisome proliferator-activated receptor alpha (PPAR⍺) regulates hepatic fatty acid utilization and represses pro-inflammatory signaling pathways. [...]Liver-specific expression of wild type or DNA binding-deficient PPAR⍺ in acute and chronic models of inflammation demonstrated that PPAR's anti-inflammatory, but not metabolic activities, result from DNA binding-independent mechanisms in vivo. We futher show that PPAR⍺ inhits the transition from steatosis toward NASH and fibrosis through a direct, anti-inflammatory mechanism independent of its effetc on hepatic lipid metabolism
Hammoutene, Adel. "Rôle de l’autophagie dans les cellules endothéliales du foie dans le développement de la stéatohépatite non alcoolique A defect in autophagy in liver sinusoidal endothelial cells occurs in NASH and promotes inflammation and fibrosis." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCB179.
Background and Aims: Non alcoholic steatohepatitis (NASH) is defined as the excessive lipids accumulation in the liver, hepatocellular injury and inflammation with or without fibrosis. NASH has the potential for cirrhosis and hepatocellular carcinoma. Recent studies suggest that microvascular alterations and sinusoidal endothelial dysfunction precede inflammation and fibrosis in NASH. Autophagy is a cellular process by which the dysfunctional cytoplasmic material joins lysosomes for degradation. The role of autophagy in hepatocytes, in hepatic stellate cells and in liver monocyte-macrophages has been studied but nothing is known about the role of autophagy in liver sinusoidal endothelial cells (LSECs) in NASH. The aim of my thesis work was to investigate the potential implication of autophagy in LSECs in NASH and liver fibrosis. Method: (a) Human samples: I used liver biopsies from patient without liver histological abnormalities, with simple steatosis or with NASH to analyze autophagy in LSECs by electron microscopy. (b) Cultured LSECs: I tested the effect of TNFa and IL6 (at concentrations present in the portal venous blood of patients with metabolic syndrome) on autophagy in LSECs exposed to shear stress. I characterized the effect of autophagy deficiency on the phenotype of LSECs by transducing transformed LSECs with a shRNA targeting ATG5. (c) Transgenic mice: I analyzed the effect of a defect in endothelial autophagy on early stages of NASH, by using mice deficient in autophagy specifically in endothelial cells (Atg5lox/lox-VE-CadherinCre), fed a high fat diet (HFD) for 16 weeks, and on advanced stages of liver fibrosis by treating Atg5lox/lox-VE-CadherinCre mice with carbon tetrachloride (CCl4). Results: (a) Human samples: Patients with NASH had twice less LSECs containing autophagic vacuoles than patients without liver histological abnormalities or patients with simple steatosis. (b) Cultured LSECs: The combination of TNFa and IL6 decreased autophagy level in LSECs. This reduction of autophagy involved the inhibition of AMPKa. LSECs deficient in autophagy overexpressed Mcp1 and Rantes genes and VCAM1 protein expression. Deficiency in autophagy in LSECs induced the expression of the endothelial to mesenchymal transition markers a-SMA, Collagen1a1, Collagen1a2 and Tgf-b1. (c) Transgenic mice: As compared to littermate controls, mice deficient in endothelial ATG5 fed a HFD had a more frequent nodular liver surface, a higher liver inflammation (increased liver gene expression of Mcp-1 and Rantes and VCAM1 protein) and more liver fibrosis (increased liver gene expression of Collagen1a2 and Tgf-b1, higher expression a-SMA protein and more collagen deposition). Mice deficient in ATG5 in endothelial cells treated with CCl4 had more liver fibrosis (increased liver gene expression of a-SMA, Collagen1a1, Collagen 1a2 and Tgf-b1 and more collagen deposition). Conclusion: Autophagy is defective in LSECs of patients with NASH. TNFa and IL6 at concentrations present in the portal blood of patients with NASH could be responsible for this defect through the impairment of AMPKa activity. Autophagy defect in LSECs contributes to the development of liver inflammation and fibrosis at early and advanced stages of the disease. Stimulating endothelial autophagy could be an attractive strategy for NASH treatment
Nawrot, Margaux. "Rôle du récepteur nucléaire Farnesoid X Receptor intestinal dans la fonction immune de l’intestin dans le contexte physiopathologique de la stéatohépatite non alcoolique." Thesis, Université de Lille (2018-2021), 2021. https://pepite-depot.univ-lille.fr/ToutIDP/EDBSL/2021/2021LILUS053.pdf.
Energy homeostasis is the result of a dialogue between metabolic organs, especially gut and liver. The intestine is an interface between the organism and the external environment. Its role as a barrier is possible thanks to a complex immune system and intercellular junctions. In metabolic diseases such as type 2 diabetes and non-alcoholic steatohepatitis (NASH), there is an increase in systemic low-grade inflammation, particularly in intestine, and an increase in intestinal permeability. The nuclear bile acid receptor, Farnesoid X Receptor (FXR), is expressed in metabolic organs. FXR Knock-Out (KO) mice fed a standard diet show increased intestinal permeability compared to their littermate controls, although they are protected against high-fat diet-induced obesity and insulin resistance. The role of FXR in the intestine is reported in a more contradictory way in the literature because according to the studies its inactivation in the epithelium decreases the synthesis of ceramides which would then contribute to protect the liver from steatosis, and its activation induces the browning of adipose tissue, reducing obesity and insulin resistance. In this context, we wanted to understand whether gut immune functions are under the control of intestinal FXR in a nutritional context inducing NASH.At the beginning of my thesis, I participated in the establishment in the laboratory of the breeding of mice deficient in FXR only in the intestine (intFXR KO) by a cre-lox system. The model was validated and the metabolic status of the mice on a standard diet was checked. Although intFXR KO mice appeared to have similar hepatic histological characteristics to control mice, the expression of genes related to innate immunity is perturbed suggesting that intestinal FXR deficiency may alter the hepatic and global inflammatory state. By immunophenotyping, we showed that cytotoxic lymphocytes (CD8+ TL) are increased in the intestine of intFXR KO mice. This change may be due to an increase in circulating CD8+ TL targeting the intestine. This disruption of intestinal immunity may be due to a decrease in the expression of tight junction proteins that would facilitate the passage of microbial products. The study of the gut microbiota of intFXR KO mice shows an increase in a bacterial population reported to be involved in colitis.Our next objective was to study the consequences of intestinal FXR deficiency in a nutritional context inducing NASH in 24 weeks. We found that were well protected against hepatic steatosis, gut transcriptomic analysis suggesting a modulation of intestinal lipid metabolism. However, intFXR KO mice are not protected against the development of NASH and FXR deficiency in the gut would even amplify the expression of inflammation-related genes in the liver compared to control mice. In intFXR KO mice, we observed an increase in CD8+ TLs, an increase in intestinal permeability markers and intestinal bacterial populations described in inflammatory bowel disease.Thus, while protecting against weight gain and hepatic steatosis, intestinal FXR deficiency appears to amplify hepatic inflammation under standard and also NASH nutritional conditions. Modulation of intestinal immunity by FXR agonists therefore appears to be an interesting approach to modulate the gut-liver dialogue in the treatment of NASH
Abarrategui-Pontes, Cécilia. "Mise au point de stratégies d'édition de gène à l'aide d'endonucléases artificielles pour le traitement des hépatopathies héréditaires : application à la maladie de Crigler Najjar de type I." Nantes, 2014. http://archive.bu.univ-nantes.fr/pollux/show.action?id=a293f552-5bf5-4c97-aef0-fc19f1307cd1.
Crigler Najjar type 1 (CNI) disease is a liver metabolic inherited disease due to UDP-glucuronosyl transferase (UGT1A1) enzyme deficiency. The patients have a mutation into the UGT1A1 gene responsible for an unconjugated hyperbilirubinemia that lead to an icterus. They are treated with phototherapy and liver transplantation. CNI is a paradigm for liver inherited diseases. Gene therapy represents a new hope for the treatment of such diseases. Lifelong cure of the Gunn rat model of CNI has been obtained through gene therapy with viral vectors. However, there are still drawbacks, such as risks of insertional mutagenesis. Thus, it is important to develop strategies of targeted gene therapy. Zinc Finger Nucleases (ZFNs) and Transcription Activator-like Effectors Nucleases (TALENs) allow targeted genome editing, through gene repair for example. They induce a specific DNA double strand break that promotes the insertion of an exogenous custom DNA donor through homologous recombination. The first part of this thesis consisted in the development of lentiviral and AAV vectors to deliver a whole ZFNs pair. The second part consisted in using these tools for in vivo gene repair in the Gunn rat. We showed that the endogenous mutation of UGT1A1 gene in the Gunn rat can be repaired in vivo at a level sufficient to obtain a subtherapeutic effect. Such recent strategies may offer safer therapeutic options to treat inherited monogenic diseases
Coilly, Audrey. "Marqueurs diagnostiques et pronostiques de la stéatohépatite métabolique Metabolism dysregulation induces a specific lipid signature of nonalcoholic steatohepatitis in patients MMP9 Identified as predictive factors of poor prognosis in patients with nonalcoholic fatty liver using data mining approaches and gene expression analysis Recent Insights into Treatment of Non-Alcoholic Steatohepatitis International Liver Transplantation Consensus Statement on End-stage Liver Disease Due to Nonalcoholic Steatohepatitis and Liver Transplantation. Quantitative assessment of triglycerides by Fourier Transform InfraRed (FTIR) spectroscopy of donor liver helps predicting outcome after liver transplantation." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS211.
Obesity is a major public health problem in France since 50% of the population has overweight. Several hepatic complications of obesity exist including NASH, pathology characterized by the combination of histological lesions of hepatic steatosis and hepatitis, liver test abnormalities and the absence of known liver disease, particularly toxic (alcohol) or virus. In one third of patients, NASH leads to fibrosis and then cirrhosis. It also promotes the development of hepatocellular carcinoma.The pathophysiology of NASH is characterized by a deregulation of lipid metabolism that leads to the accumulation of lipids in the hepatocytes. This accumulation of lipids is toxic and one of the causes of insulin resistance and the development of diabetes mellitus. All stages of lipid metabolism are affected by an accumulation of triglycerides, an increase in hepatic lipogenesis and a decrease in ß-oxidation. The composition and the role of lipids as a promoter of NASH is being increasingly studied.The first part of the thesis concerns the detection of diagnostic markers of NASH. In this study, we established for the first time a lipid signature of nonalcoholic steatohepatitis by quantification of 32 lipids. The overall lipid signature allowed distinguishing controls from NAFL and NASH. We have also demonstrated a deregulation of the metabolic pathway involved in the synthesis of fatty acids in NASH. This deregulation has been observed in both humans and animal models in our study.The second part aimed to identify new hepatic prognostic markers of NASH. Microarray analysis of gene expression showed 1549 genes discriminating patients with NAFL or NASH, healthy obese or controls. Among them, 58 genes discriminated NASH from simple steatosis. These genes were involved in extracellular matrix remodeling and inflammation. The most discriminating gene was FABP4 (fatty acid binding protein 4). Among genes strongly associated with high expression of FABP4, matrix metalloproteinase-9 (MMP9) was overexpressed in 55% of NASH patients. We identified a total of 330 differentially regulated genes, of which 229 genes were overexpressed in NASH patients with high levels of MMP9 expression. Using the gene expression levels of the liver FABP4 and MMP9 genes as indicators of disease progression in an independent cohort of NAFLD patients, we identified patients with NAFL and NASH who may have a poor prognosis.Finally, in the third part, we looked at the diagnostic and prognostic value of steatosis of liver grafts, measured by FTIR (Infrared Fourier Transform Microspectroscopy). Indeed, steatosis, when it exceeds 60% and is macrovacuolar, is known to significantly impact the function and survival of liver grafts. In our study, among 58 graft samples, the average percentage of macrovacuolar steatosis and microvesicular steatosis assessed by the pathologist was 2% to 30%, respectively. The average concentration of liver triglycerides measured by gas chromatography-spectrometry was 214 [10-1045] nmol/mg liver tissue. The FTIR triglyceride content estimate was significantly correlated (r2=0.812) with the results of the average hepatic triglyceride concentration measured by gas chromatography-spectrometry. Thirty-four (58%) patients had complications defined by a Dindo-Clavien stage ≥2, including 2 non-primary graft function and 5 deaths. The most discriminating threshold between triglyceride level and TH failure was 59.29 and 54.02 nmol/mg hepatic tissue obtained by spectrometry and FTIR, respectively. Quantification of hepatic triglyceride content by GC/MS was significantly associated with patient survival at the end of follow-up (p <0.0001) and failure of transplantation (p <0.0001). Estimating hepatic triglyceride content using FTIR was significantly associated with one-year post-transplant survival (p <0.0001)
Belot, Audrey. "Régulation du métabolisme du fer et nouvelles stratégies thérapeutiques." Thesis, Toulouse 3, 2020. http://www.theses.fr/2020TOU30009.
Iron homeostasis is a paradox. It is both essential for living organisms but deleterious in excess. Iron balance is maintained by hepcidin, a hormone produced by the liver. Matriptase-2 is an inhibitor of hepcidin expression. The absence of matriptase-2 causes IRIDA, a disease characterized by a severe anemia and an iron deficiency. In this study, I showed in mice that a hepcidin-suppressing molecule corrects the iron deficiency and the anemia of IRIDA. Thus, this molecule could be used in therapy. In this work, I was also interested in the role of iron in fatty liver disease which can progress in some cases to a more severe stage for which no treatments are available. I have shown that hepcidin production is increased in this disease, resulting in liver iron retention that could be an aggravating factor. The characterization of this dysregulation has led to the identification of a promising new therapeutic target to prevent the disease progression
Michaut, Anaïs. "Mise au point d'un modèle de stéatose hépatique liée à l'obésité : application à l'étude de la toxicité du paracétamol." Thesis, Rennes 1, 2015. http://www.theses.fr/2015REN1B015/document.
Obesity and nonalcoholic fatty liver disease (NAFLD) are able to increase the risk and the severity of hepatotoxicity induced by some xenobiotics including drugs, but the involved mechanisms are still poorly understood. For toxic compounds such as ethanol and acetaminophen (APAP), a role of hepatic cytochrome P450 2E1 (CYP2E1) is suspected since the activity of this enzyme is consistently enhanced during obesity and NAFLD. The first aim of our experimental study was to set up a cellular model of NAFLD characterized not only by triglyceride accumulation but also by higher CYP2E1 activity. To this end, differentiated human HepaRG cells were incubated during one week with stearic acid, or oleic acid, in the presence of 3 different concentrations of insulin. Cellular triglycerides and the expression of lipid-responsive genes were similar with both fatty acids. However, CYP2E1 activity was significantly increased only by stearate and this was associated with lower CYP3A4 activity, another metabolic feature reported in NAFLD. CYP2E1 activity in HepaRG cells was reduced by insulin in a concentration-dependent manner and this effect was reproduced in cultured primary human hepatocytes. Hence, the highest CYP2E1 activity was observed in HepaRG cells with stearate and without insulin. Next, the second aim of our study was to assess APAP cytotoxicity in HepaRG cells presenting or not lipid accretion and CYP2E1 induction. Experiments with a large range of APAP concentrations (1 to 20 mM) showed that the cellular loss of ATP and glutathione (GSH) was almost always stronger in the presence of stearic acid. In cells pretreated with the CYP2E1 inhibitor chlormethiazole (CMZ), recovery of cellular ATP was significantly higher in the presence of stearic acid with both low (2.5 mM) and high (20 mM) concentrations of APAP. However, in the absence of insulin, CMZ-induced ATP recovery was significantly greater only for 20 mM of APAP. Surprisingly, there was no recovery of cellular GSH and no reduction of APAP-protein adducts following CMZ pretreatment. Finally, levels of APAP-glucuronide were significantly enhanced in the presence of insulin. Hence, when studied in specific conditions of culture, the HepaRG cell line can be a valuable model of human NAFLD, especially regarding CYP2E1 and CYP3A4 activity. Our data also suggest that higher CYP2E1 activity in NAFLD could be secondary to the hepatic accumulation of some fatty acids and to the presence of low insulin signaling. This cellular model can be thus used to unveil the main metabolic and hormonal factors favoring APAP hepatotoxicity in obese individuals. This thesis also includes a review on APAP hepatotoxicity in the context of obesity and NAFLD (Michaut et al., Liver Int 2014)
Perchet, Thibaut. "Roles of hepatic group 1 ILC during the early stages of non-alcoholic fatty liver diseases." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC314.
Non-alcoholic fatty liver diseases (NAFLD) is a spectrum of liver pathologies that encompass diseases such as steatosis or non-alcoholic steatohepatitis (NASH). With a constant increase of patients diagnosed, NAFLD is becoming a major concern of public health worldwide. A “multiple hits” hypothesis has been described to regroup the metabolic disorders that are associated with the transition from steatosis to NASH. This transition is a critical step during NAFLD pathogenesis as untreated NASH can further develop into fibrosis, cirrhosis and ultimately to hepatocellular carcinoma (HCC). Thus, the analysis of early events occurring during during NAFLD is critical to understand its evolution to more severe pathologies. In the liver, diverse cell populations are involved in hepatic metabolism, function and immune surveillance. Among them, the group 1 ILC is enriched in the liver and can quickly induce an immune response by producing cytokines or inducing cell death. Hepatic group 1 ILC is composed of Natural Killer (NK) cells and Innate Lymphoid Cells 1 (ILC1), two cell populations that share a similar phenotype. Nevertheless they constitute two distinct cell lineages that have unique features. Here we propose to study the roles of NK cells and ILC1 during the early stages of NAFLD.In this work, we demonstrated that NK cells and ILC1 diverge in phenotype and function during the early stages of NAFLD pathogenesis. While ILC1 showed a down-regulation of inhibitory markers and down-regulation of granzyme B, we detected an increase of interferon gamma (IFNg) secreting NK cells. These modifications were found shortly after the induction of steatosis and preceded other hepatic immune cell recruitment or activation. Our work highlighted the role of the immune intestinal populations during liver inflammation and identified the intestinal lamina propria as a potential source of NK cells during this process. Finally, we demonstrated that IFNg is inducing liver damage, but is not involved in hepatic group 1 ILC recruitment or modification in our model of steatosis.This study brings new insights on the early events of NAFLD and the role of hepatic group 1 ILC during liver inflammation. It also underlines the importance of distinguishing the roles of NK cells and ILC1 in liver pathologies
Braud, Laura. "Effets lipotropes des molécules antioxydantes du thé (Camellia sinensis)." Thesis, Toulon, 2015. http://www.theses.fr/2015TOUL0014/document.
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in industrializedcountries because being strongly associated with the development of metabolic syndrome and relateddyslipidemia. To date, the mechanisms of pathology remain poorly defined and available therapeutic meanshave moderate efficacy. Epidemiological studies have reported a beneficial effect of tea consumption in thefight against liver disorders and cardiovascular risk factors such as dyslipidemia. However, the mechanismsby which a blend of green tea, oolong tea and Pu-erh tea, Hao Ling tea, reduces fatty liver and dyslipidemiaremain unknown. Therefore, the objective of this thesis was to evaluate the effects and mechanisms of actionof Hao Ling tea on NAFLD and dyslipidemia, through two approaches, one on cellular model and the other onanimal model. Our results show that Hao Ling tea reduces the hepatic lipogenesis in vitro and in vivo and thusattenuates steatosis induced by a high fat-high sucrose diet in a rat model. We observed that this tea improvesthe blood lipid profile by increasing plasma HDL levels. We were also able to highlight that tea ownsantioxidant and hepato-protective properties to counteract an inducer of oxidative stress in vitro and todecrease lipid peroxidation in vivo. Finally, we have shown that the oxidative stress per se resulted in anaccumulation of intracellular lipid in isolated hepatocytes and that the tea, due to its antioxidant properties,prevented this phenomenon. The Hao Ling tea is a good nutritional approach in preventing NAFLD and tomaintain LDL/HDL ratio
Bernard, Lucie. "Rôle de FAT10 dans la sénescence des hépatocytes et le développement de la NASH." Electronic Thesis or Diss., Université de Lille (2022-....), 2023. https://pepite-depot.univ-lille.fr/ToutIDP/EDBSL/2023/2023ULILS039.pdf.
The accumulation of senescent hepatocytes has been identified as a key factor in the progression of non-alcoholic fatty liver diseases (NAFLDs), which correspond to a spectrum of chronic liver pathologies, ranging from simple steatosis to the development of non-alcoholic steatohepatitis (NASH), cirrhosis or even hepatocellular carcinoma (HCC). However, the mechanisms and actors involved in the regulation of senescence during NASH are still poorly described. The objective of this thesis was therefore to study the mechanisms controlling hepatocyte senescence during the development of NASH. Using transcriptomic and protein analyses, we have shown in the livers of patients and mice that the protein FAT10 (human leukocyte antigen-F Adjacent Transcript 10), also called UBD (Ubiquitin D), is induced during NASH. However, FAT10 is an ubiquitin-like protein that interacts with different partners playing a role in metabolism and senescence, we therefore hypothesized that FAT10 could be involved in the development of NASH, as well as in the induction and spread of hepatocyte senescence. First, we showed in the livers of NASH patients a positive correlation between the expression of FAT10 and the severity of the disease. Conversely, FAT10 expression decreases when the disease regresses. We showed specifically in hepatocytes of NASH mice that the expression of Fat10 negatively correlates with lipid metabolism pathways, and that interestingly, the decrease of Fat10 expression in NASH mice hepatocytes decreases hepatic steatosis, by reducing the size and number of lipid droplets. Secondly, we showed a positive correlation between the expression of FAT10 and of senescence genes in the livers of NASH patients. This correlation is found specifically in hepatocytes in mice. Furthermore, in this mouse model of NASH, Fat10 expression positively correlates with liver SA-β-Gal (Senescence Associated-β-Galactosidase) activity. In vitro, the induction of senescence in human hepatocytes by an irradiation or a treatment with H2O2 induces FAT10 protein as a SASP (Senescence Associated Secretory Phenotype) actor. Interestingly, FAT10 inhibition in this model promotes the induction and propagation of senescence, through an increase of SA-β-Gal activity, an induction of SASP genes, an accelerated cell proliferation arrest, an induction of the DNA damage response system and a greater accumulation of lipid droplets. Conversely, stable overexpression of FAT10 in senescent hepatocytes accelerates the loss of senescent status (decreased SA-β-Gal activity), and promotes the senescence escape and the acquisition of a pro-cancerous phenotype. In the end, all of these data suggest that the induction of FAT10 within hepatocytes during the development of NASH promotes the progression of the disease, on one hand by altering lipid metabolism within steatotic hepatocytes, and on the other hand by gradually promoting the escape of senescent hepatocytes, which could lead to the development of HCC
Bricambert, Julien. "Régulation de l'homéostasie énergétique par le facteur de transcription ChREBP et ses protéines associées : implication dans la physiopathologie de la NAFLD." Paris 7, 2014. http://www.theses.fr/2014PA077177.
The spectrum of NAFLD (Non Alcoholic Fatty Liver Disease) is characterized by liver damage ranging from simple steatosis to cirrhosis. The understanding of the mechanisms responsible for this ectopic lipid storage is essential in the search for therapeutic approaches. In this context, we show that the serine / threonine kinase SIK2 (Salt inducible kinase 2) inhibits the histone acetyltransferase (HAT) p300 by a phosphorylation on its serine 89, which in turn, abolishes the activity of the transcription factor ChREBP (Carbohydrate Responsive Element Binding Protein), decreasing its acetylation. ChREBP mediates the transcriptional effects of glucose, controling the expression of glycolitics and Iipogenics genes. We show that this control loop limits the synthesis of fatty acids and the development of NAFLD in the liver. We also show that the histone demethylase PHF2 (Plant homeodomain Finger 2) activation promotes the uptake, the synthesis, the esterification and the storage of fatty acids into the lipid droplets. PHF2 acts as a co - activator for ChREBP which, specifically demethylates the dimethylated lysine 9 of the histone H3 in the promoter of its targets genes to induce the recruitment of the transcriptional machinery, to induce transcription in response to glucose. Thus PHF2 and ChREBP increase the synthesis of monounsaturated fatty acids insulin-sensitizing and anti- oxidant defenses of the liver by stimulating the expression and actiyity of the transcription factor Nrf2 (nuclear factor E2 -related factor 2). This epigenetic regulation of ChREBP allows the development of a benign hepatic steatosis dissociated from resistance to the action of insulin and fibrosis
Viera, Élodie. "Contribution des cellules innées lymphoïdes de groupe 1 dans le développement de la stéatohépathie non alcoolique du foie." Thesis, Université Côte d'Azur, 2020. http://www.theses.fr/2020COAZ6009.
The chronic liver diseases associated with obesity (NAFLDs) emerge as a public health problem with a growing incidence in Western countries. NAFLDs develop from fatty liver (accumulation of lipids in hepatocytes) which can progress into steatohepatitis (NASH) characterized by significant liver inflammation and injury. NASH can then progress to more severe complications such as fibrosis, cirrhosis and hepatocellular carcinoma. Chronic liver inflammation associated with NASH is the main driver of NAFLDs progression which results from multiple and complex intra and extra-hepatic mechanisms occurring in the liver, gut and adipose tissue. Therefore, a better understanding of the immunological mechanisms involved in liver complications during NASH is a major issue for the discovery of new therapeutic targets. Group 1 innate lymphoid cells (ILCs) including NK cells and ILC-1 are mainly located within epithelial tissues such as the intestine and liver, excepted for NK cells which are also abundant in blood. These cells are part of the body's first line of defence against external aggressions (pathogens, tumours) and rapidly react to environmental changes to establish appropriate immune responses. Recent studies have shown that these group 1 ILC members contribute to metabolic responses and the onset and the chronicity of inflammation during obesity. In addition, the CD44 surface glycoprotein is mainly expressed by immune cells and regulate their physiology (adhesion, interaction, migration, activation). Interestingly, it has been reported that CD44 regulates adipose tissue and liver inflammation and also plays a key role in the recruitment/activation of liver macrophages during obesity and NASH.In that context, the objectives of my thesis were : i) evaluate the contribution of hepatic and intestinal NKp46+ group 1 ILC during NASH; ii) evaluate the role of CD44 in the behaviour and functions of these NKp46+ ILCs. To implement this project, I used a mouse model of steatohepatitis (methionine and choline-deficient diet, MCDD) that mimics liver inflammation observed in human during obesity. In addition, I contributed to the generation of a mouse model with a specific deficiency of CD44 in NKp46+ ILCs (NKp46iCre/+ CD44flox/flox mice). The results obtained during my Ph.D. demonstrated that the number of liver and intestine NK cells and ILC-1 correlated with hepatocyte injury during NASH. Furthermore, using NKp46iCre/+ CD44flox/flox mice challenged with MCDD, I showed that CD44 regulates the proportion of hepatic group 1 ILC. In addition, the absence of CD44 in NKp46+ ILC leads to increased infiltration of inflammatory macrophages into the liver, aggravation of liver damage and increased in the priming of fibrosis. The severity of these hepatic lesions is associated with the loss of expression of the ZO-1 tight junction protein in the terminal portion of the small intestine, the ileum. Altogether, these results suggest that the CD44 regulates the cross-talk between group 1 ILC and macrophages in the liver as well as intestinal homeostasis during NASH. This study provided a better understanding of the pathogenesis of NASH and highlighted the role of CD44 in group 1 ILC in maintaining tissue integrity in chronic liver diseases
Smati-Grangeon, Sarra. "Influence du sexe dans la susceptibilité aux hépatopathies métaboliques." Thesis, Toulouse 3, 2019. http://www.theses.fr/2019TOU30213.
Non Alcoholic Fatty Liver Disease (NAFLD), ranging from steatosis to steatohepatitis (NASH), is the most common liver disease and a major public health issue worldwide. There are strong clinical and preclinical evidence for sexual dimorphism. The establishment of reliable animal models is essential to understand the mechanisms underlying such gender specific susceptibility to the disease. We aimed at identifying a mouse model of NAFLD that replicates at best the sexual dimorphism observed in humans. We tested different hypercaloric diets: High-Fat Diet (HFD), Choline Deficient HFD, Western Diet enriched with cholesterol and co-administered or not with drinking water containing glucose and fructose in male and female C57BL/6J mice (n=12/group). Histological, biochemical, transcriptomic and metabolomic analyses were performed. The Western Diet induces a strong dimorphic phenotype for the onset of NASH. Males develop major steatosis associated with severe inflammation and fibrosis whereas females show much less steatosis. Both sexes develop obesity and have impaired glucose tolerance. In contrast, insulin resistance is more severe in males than in females. Finally, liver transcriptome analysis highlights contrasted gene expression profiles between males and females in response to the different diets. Gene network analysis suggest that nuclear receptors are influential in this sexual dimorphic response to dietary challenges. Among nuclear receptors, ERalpha is the major effector of estrogen signaling in the liver. We tested the western diet in male and female mice in absence of ERalpha in hepatocytes. This deletion did not cause significant changes in hepatic phenotype in response to western diet in males and females. Another nuclear receptor has been studied, PPARalpha plays a central role in lipid metabolism and is protective against NAFLD. In the absence of PPARalpha in hepatocytes, fatty acid catabolism is defective during fasting in male mice. Therefore, to investigate whether hepatocyte PPARalpha activity shows sexual dimorphism, we tested the effect of fasting in female mice. In vivo experiments in mice with a hepatocyte specific knock-out of PPARalpha reveal that fasting induces similar PPARalpha-dependent ketogenesis in mice from both sexes.[...]
Hannou, Sarah Anissa. "Rôle du régulateur du cycle cellulaire p16INK4a dans le développement du diabète de type 2 et dans les maladies métaboliques du foie gras ou NAFLD (Non-Alcoholic Fatty Liver Disease) : rôle de p16INK4a dans le contrôle de la néoglucogenèse hépatique et dans le développement de la stéatose hépatique non alcoolique." Thesis, Lille 2, 2014. http://www.theses.fr/2014LIL2S012/document.
P16INK4a is a tumor suppressor protein well described as a cell cycle regulator. p16INK4a blocks cyclin D/ cyclin dependent kinase (CDK) 4 activity by binding to the catalytic subunit of CDK4, preventing retinoblastoma protein phosphorylation and subsequently the release of the E2F1 transcription factor. As a consequence; the transcription of genes required for progression to the S phase is restrained. Recently, genome-wide association studies (GWAS) associated the CDKN2A locus, encoding, amongst other genes, p16INK4A, with an increased risk of type 2 diabetes (T2D) development. However, the pathophysiological link between p16INK4a and hepatic glucose homeostasis remains unknown. In this context, we investigated the role of p16INK4a in hepatic glucose metabolism in vivo using p16+/+ and p16-/- mice and in vitro using primary hepatocytes and the AML12 hepatocyte cell line.p16-/- mice exhibited a higher response to fasting as shown by an increased hepatic gluconeogenic gene expression including phosphoenolpyruvate carboxykinase (PEPCK), fructose-1,6-biphosphatase (F1,6P) and glucose-6-phosphatase (G6Pase). p16-/- mice displayed an enhanced hepatic gluconeogenic activity in vivo upon administration of pyruvate, a gluconeogenic substrate. Consistent with this, in vitro data show that p16-/- primary hepatocytes display an enhanced gluconeogenic response to glucagon. In addition, knock down of p16INK4a by siRNA in AML12 cells increased gluconeogenic gene expression. These effects were associated with an increased activity of the PKA-CREB signaling pathway which leads to increased PPARg coactivator 1 (PGC1)α expression, a key transcriptional co-activator that regulates genes involved in energy metabolism. These findings describe a new function for p16INK4a as an actor in the hepatic adaptation to metabolic stress and suggest that p16INK4a could play a role during T2D development
Massimino, William. "Impact d’une manipulation thermique embryonnaire chez le canard mulard." Thesis, Pau, 2019. http://www.theses.fr/2019PAUU3050.
Various studies have shown that events that occurred very early in the life of an animal could have "programming" effects on the physiology of the adult. Recently, it has been shown that embryonic thermal manipulation (TM) has an impact on hepatic metabolism in Pekin ducks, 15 days post hatch.The first objective of this thesis was to measure the impact of an embryonic TM on the performances of mule ducks, used for the production of “foie gras”. For that, we tested three experimental modalities of temperature increase on mule ducks embryos. Our results showed that all the embryonic TM significantly increased liver weight (up to + 16.9%, P <0.0001) after overfeeding, compared to the control group (without TM), associated with an increase in lipid content in the three TM groups (+2.5 to 3%). These results therefore demonstrate the great reproducibility of this technique, and pave the way for a new simple and inexpensive procedure for the industry. However, two of the TM groups have the same cumulative increase of temperature (+ 332 °C) also had a lower hatchability and a higher lipid-melting rate at cooking. This suggests that optimization of embryonic thermal manipulation could be considered to improve the quality of the “foie gras”, especially by choosing a moderate and discontinuous TM.In a second step, we therefore undertook to identify the best possible TM window without exceeding + 332 ° C to reduce the negative effects. For this, we have studied the expression of genes of interest in mule duck liver throughout development. We have demonstrated a peak expression for many genes involved in carbohydrate and lipid metabolism around embryonic day E20, suggesting that a reduction in the programming window could be considered for the production of “foie gras” in mule ducks.In a third study, we studied the effect of embryonic TM on the expression, measured after gavage in 95-day-old ducks, of numerous genes involved in lipid and carbohydrate metabolism, stress and thyroid hormones. After overfeeding, only the expressions of some genes seem specifically modulated by the embryonic TM. These results being analyzed could allow us to identify targets that are particularly sensitive to TM applied during incubation, and that play an important role in the phenotype observed after overfeeding, characterized by better fattening of the liver
Mesdom, Pierre. "Étude du rôle de PRDM16 dans l'activation des cellules hépatiques stellaires." Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066595.
NAFLD (nonalcoholic fatty liver diseases) are closely linked to type 2 diabetes and obesity and are becoming the first cause in liver chronic diseases around the world. One of the key step in NAFLD progression is the fibrogenesis characterized by hepatic stellate cells (HSC) activation. In this context, we identified PRDM16 as a key factor in this activation. Our first prospective study revealed a correlation between fibrosis score and Prdm16 expression in human biopsies and in murine model of fibrosis. Prdm16 expression is also positively correlated in HSC with the activation state. Our results on Prdm16 invalidation in HSC highlight a role for PRDM16 in the increase expression of Col-11 and Col-31 during HSC activation in part by the binding of PRDM16 to SMAD3. Prdm16 invalidation in HSC also leads to a decrease Sma expression and an increase Srebp-1c expression, showing that PRDM16 control HSC activation through other mechanisms which will be the subject of our next studies
Cepero, Donates Yuneivy. "Pathogenic role of IL-15 in non-alcoholic fatty liver disease." Mémoire, Université de Sherbrooke, 2014. http://hdl.handle.net/11143/5871.
Harb, Zeinab. "Effets de l’inflammation viscérale dans deux modèles de stéatohépatite non alcoolique (NASH) induite par la programmation foetale ou la carence en donneurs de méthyles." Thesis, Université de Lorraine, 2019. http://www.theses.fr/2019LORR0027/document.
Deficiency of methyl donors (folic acid and vitamin B12) (MDD) during pregnancy and lactation produces non-alcoholic steatohepatitis (NASH) in animals fed high fat (HE) diet, despite histological and metabolic normalization by a normal diet between weaning (J21) and puberty (J50). The microbiota can trigger inflammation by lipopolysaccharides (LPS) by inadaptation of Toll-like receptor activation 4 (TLR4). Our basic assumption is that MDD, HE diet, microbiota LPS and intestinal inflammation (Dextran Sodium Sulfate (DSS) model) as triggers and innate immunity as a modulator are part of the same scenario leading to NASH. Deficient rats (MDD), whether or not exposed to the high-fat diet in adulthood (HE) and whether or not exposed to two inducers of local and systemic inflammation, DSS (intestinal inflammation) or LPS (systemic effects intestinal inflammation) were studied. We did not observe alterations in innate immunity (TLR4) in the MDD/DSS, MDD/HE and MDD/HE/LPS groups. Inflammation observed in the intestines in MDD/DSS rats is also observed in the liver, with steatosis and activation of the inflammasome and chemokine MCP-1 and IL-1beta. Surprisingly, this systemic effect does not involve the TLR4 pathway and its ligand LPS even when the rats were exposed to LPS directly at the peritoneal level. Our study conclude that NASH favored by the systemic effects of Intestinal inflammation is mediated by MCP-1/IL-1β, but not by activation of TLR4 by translocation of LPS. Since innate immunity is not involved even by the direct injection of LPS, the respective and synergistic effects of MDD diet, HE diet and LPS remain to be decribed thereafter
Viglino, Damien. "Douleur et stéatopathie hépatiques, des manifestations systémiques sous estimées de la BPCO." Thesis, Université Grenoble Alpes (ComUE), 2018. http://www.theses.fr/2018GREAS023.
Chronic Obstructive Pulmonary Disease (COPD) is one of the most common chronic diseases and is one of the leading causes of death in the world with major societal impact and considerable health costs. COPD is now considered a multi-systemic disease whose prognosis is largely related to its comorbidities and the occurrence of exacerbations. The exacerbations that punctuate the evolution of COPD precipitate the decline of respiratory function and promote the decompensation of comorbidities and the occurrence of cardiovascular events such as myocardial infarction or cerebrovascular accidents. The modern management of COPD is based on the implementation of integrated care including the management of comorbidities and better detection and management of exacerbations.In this thesis we address liver injury (non-alcoholic fatty liver disease - NAFLD) in COPD as an underestimated comorbidity (publication 1), although it probably has important prognostic implications (publication 2). COPD is also associated with non-respiratory symptoms such as pain, the variations and locations of which are poorly known during and after exacerbation (publication 3). Treatment of this pain with opiates may have a specifically deleterious effect in this population (publication 5). The challenges of health system reform with cost-effectiveness optimization encourage the development and validation of new methods of outpatient management of exacerbations (publication 6).In a first part of the thesis we explore the epidemiological links between COPD and NAFLD. We will also explore the consequences of such an association on the cardiovascular outcome of patients in the medium term. In a second part, we seek to define the characteristics of pain before and after exacerbation during COPD, the link between pain, anxiety and depression in these patients and the safety of opioids in this fragile population. In the last part, we will discuss the stratification of the risk linked to an exacerbation of COPD, and the possibility of outpatient care for exacerbations of moderate severity
Régnier, Marion. "Homéostasie des céramides et hépatopathies métaboliques." Thesis, Toulouse 3, 2018. http://www.theses.fr/2018TOU30222/document.
Prevalence of obesity and type II diabetes is constantly increasing in industrialized countries. NAFLD (" Non-Alcoholic Fatty Liver Disease ") is the hepatic manifestation of these pathologies. NAFLD represents a significant public health problem and is defined as a nexus of metabolic and hepatic diseases. NAFLD begins with fatty accumulation in the liver named "hepatic steatosis". Lipids can accumulate in different forms like triglycerides, cholesterol esters, diglycerides and ceramides. Lipotoxicity induced by the accumulation of these lipid species leads to cellular dysfunction and insulin resistance. In this context, we studied the role of ceramides in apparition and evolution of NAFLD in vivo. For this purpose, we used pharmacological, genetic and nutritional approaches. By pharmacological approach, we showed that fumonisin b1, a mycotoxin targeting ceramide synthesis, leads to hepatic toxicity, which is dependent from LXR ("Liver X Receptor"), a major transcriptional regulator of lipid metabolism. Then, we combined genetic and nutritional approaches in order to induce or protect from hepatic steatosis. For this, we used mice with hepatic or total deletion for PPARa (" Peroxisome Proliferator-Activated Receptor alpha "), a transcriptional factor essential in fatty acid catabolism. First, this model allow us to confirm the role of hepatocyte PPARa in response to fasting and second, to demonstrate the systemic involvement of PPARa in regulating ceramide metabolism during obesity induced by an HFD ("High Fat Diet"). Last, we used p110a liver-specific knockout mice, the catalytic subunit of PI3Kinase alpha. With this model, we confirmed the critical role of p110a-dependent insulin signaling in insulin resistance dissociated from hepatic steatosis induced by a HFD. Interestingly, we demonstrated with this model that free fatty acid released from adipocyte lipolysis (rather than inhibition by p110a-dependent insulin signaling) determines PPARa activity in the liver. Finally, this work highlights the key role of ceramides in lipotoxicity associated with hepatic steatosis
Chavez, Talavera Oscar Manuel. "Rôle des acides biliaires dans la physiopathologie de l'obésité, la résistance à l'insuline, le diabète de type 2, la stéatose hépatique non alcoolique et dans le contexte de la chirurgie bariatrique Bile Acid Control of Metabolism and Inflammation in Obesity, Type 2 Diabetes, Dyslipidemia, and Nonalcoholic Fatty Liver Disease Bile Acid Alterations in Nonalcoholic Fatty Liver Disease, Obesity, Insulin Resistance and Type 2 Diabetes: What Do the Human Studies Tell?” Bile acids associate with glucose metabolism, but do not predict conversion to diabetes Bile acid alterations are associated with insulin resistance, but not with NASH in obese subjects Roux-en-Y gastric bypass increases systemic but not portal bile acid concentrations by decreasing hepatic bile acid uptake in minipigs The functional relevance of bile acids in the improvement of HDL-mediated endothelial protection after bariatric surgery Metabolic effects of bile acid sequestration: impact on cardiovascular risk factors." Thesis, Lille, 2019. http://www.theses.fr/2019LILUS057.
In addition to their role in the solubilization of dietary lipids, bile acids are signaling molecules regulating their own metabolism, glucose and lipid homeostasis, energy expenditure, cardiovascular function and inflammation via the activation of the Farnesoid X Receptor (FXR) and the Takeda G protein coupled Receptor 5 (TGR5). Indeed, changes in bile acid concentrations are associated with metabolic diseases and therefore they are candidates to participate in the pathophysiology of these diseases or predict their progression.In the first part of this thesis, we studied bile acid changes in the context of obesity, insulin resistance, type 2 diabetes and non-alcoholic steatohepatitis. We demonstrated that bile acids are correlated with glucose homeostasis in humans, but that they are not predictors for the progression from prediabetes to type 2 diabetes in a longitudinal cohort study.In the second part of this thesis, we studied the bile acids in the context of bariatric surgery. Our results showed that bariatric surgery reduces the hepatic recapture of certain bile acids, causing them to increase in the systemic circulation. Additionally, we showed that it is not the bile limb but the common limb the one responsible for metabolic changes after bariatric surgery in the minipig. Finally, we showed in humans that bile acids linked to high-density lipoproteins (HDL) increase after bariatric surgery, and that this increase is correlated with the restoration of their vasoprotective functions
Bison, Anaïs. "La programmation foetale de la carence en donneurs de méthyles entraîne une stéato-hépatite chez les rats soumis à un régime hyper-énergétique au cours de la vie adulte." Thesis, Université de Lorraine, 2015. http://www.theses.fr/2015LORR0285/document.
The influence of fetal programming hypothesis on non-alcoholic steato-hepatitis (NASH) has deserved insufficient interest. Methyl donor deficiency during pregnancy and lactation is frequent in population and is an experimental model of fetal programming. In this model, it produces a liver steatosis in 21 days old pups, which results from decreased fatty acid oxidation. We evaluated the effects of fetal programming on NASH in Wistar rats born from mothers fed either a control or a methyl donor deficient (iMDD) diet during pregnancy and lactation. Pups received a control diet after weaning (D21 to D50) and a part from adult rats were fed with an high-fat diet (HF) (D50 to D185). Animals were sacrificed at D50 and D185. In D50 iMDD rats, we observed an increased abdominal fat and ASAT/ALAT ratio, but no liver histological abnormality. However, D185 iMDD/HF rats have developed NASH, with hallmarks of insulin resistance and increased expression of several genes and proteins involved in inflammasome, stellate cell stimulation, fibrosis and tissu remodelling, including AngII, TGFβ1 and NFκB. In conclusion, MDD during pregnancy and lactation produces NASH in animals subjected subsequently to an high-fat diet during adulthood, despite the recovery of a control diet. These results suggest that MDD during pregnancy is a risk factor of NASH development in subjects subsequently exposed to high-fat diet
Bucher, Simon. "Effets d’une co-exposition chronique au benzo[a]pyrène et à l’éthanol sur l’évolution de la NAFLD dans un modèle in vitro." Thesis, Rennes 1, 2018. http://www.theses.fr/2018REN1B015/document.
Obesity and associated metabolic diseases such as non-alcoholic fatty liver diseases (NAFLD) are steadily increasing in the global population. Fatty liver (also called steatosis) which is the first stage of NAFLD described by a retention of lipids in the liver is considered to be benign. However, this pathology is likely to evolve into non-alcoholic steatohepatitis (NASH), much more severe since it is supplemented with necrosis and inflammation. This evolution is multifactorial in origin: alcohol or drugs may be involved, but more and more studies have mentioned the likely role of environmental contaminants. Thus, in this study we were interested in the impact of an alcohol/benzo[a]pyrene (B[a]P, a xenobiotic of the family of polycyclic aromatic hydrocarbons) co-exposure on the progression of NAFLD towards NASH. To this end, we used the human hepatic cell line called HepaRG. In this cell line, we established an in vitro model of NAFLD by incubating the cells with a mixture of fatty acids for 14 days, whereby we would carry out some chronic investigations about the effects of B[a]P and ethanol. At the end of these treatments, we found that alcohol potentiated B[a]P cytotoxicity on steatotic HepaRG cells. This cytotoxicity was also combined with pro-inflammatory cytokine production, suggesting the presence of a NASH condition. We also demonstrated a change in the metabolic profile of B[a]P, in addition to a ROS production, a global dysfunction of the mitochondrial respiratory chain and an induction of apoptosis. Finally, these observations were absent or decreased when the exposure was individual and when the cells were not steatotic. Thus, these results suggest the importance to consider multifactorial exposure to xenobiotics in the progression of NAFLD as well as the fact that the presence of NAFLD alone could exacerbate xenobiotic toxicity
Gauthier, Marie-Soleil. "Stéatose hépatique non-alcoolique et exercice." Thèse, 2005. http://hdl.handle.net/1866/15449.
Maltais, Mélanie. "Association entre la stéatose hépatique non alcoolique et les hyperchylomicronémies familiale et multifactorielle." Thesis, 2020. http://hdl.handle.net/1866/25192.
Nonalcoholic fatty liver disease (NAFLD) is a disorder caused by hepatic triglyceride accumulation. It ranges from hepatic steatosis to steatohepatitis with fibrosis. Obesity and other elements of the metabolic syndrome, such as hypertriglyceridemia and type 2 diabetes, are risk factors for NAFLD, which affects between 20% and 29% of Canadians. These statistics are alarming, especially knowing that there is still no treatment for this condition and considering the increasing prevalence of obesity. Lipoprotein lipase (LPL) hydrolyzes triglycerides contained in very low-density lipoproteins (VLDL) and chylomicrons. LPL is often down-regulated in the metabolic syndrome and some patients may present triglycerides level higher than 10 mmol/L, as multifactorial chylomicronemia syndrome (MCS). Chylomicronemia also characterizes total LPL deficiency, known as familial chylomicronemia syndrome (FCS). FCS and MCS are two dyslipidemias associated with severe hypertriglyceridemia, which is associated with increased risk of recurrent acute pancreatitis. Whereas FCS is monogenic, MCS is polygenic and directly related to the metabolic syndrome with a significant influence of the environment. Results of the present study compare the expression of NAFLD in FCS and MCS patients. NAFLD was assessed using transient elastography performed in 18 FCS and 18 MCS patients matched for age and sex. Controled attenuation parameter (CAP) score ≥ 280 dB/m, suggesting NAFLD expression, were observed in 50% of FCS and 83.3% of MCS. The difference between degrees of hepatic steatosis in both groups is significant with a p-value of 0.036. In addition, only 22.2% of FCS with NAFLD are obese compared to 71.4% for MCS (p = 0.001). It is also interesting to note that FCS patients have NAFLD even in the presence of a very low body mass index (BMI<18 kg / m2). Besides, CAP score in FCS was negatively correlated with the number of acute pancreatitis (p=0.004). Our study shows that NAFLD was frequently observed in FCS and MCS but occurred independently of BMI and could be associated with a lower occurrence of acute pancreatitis.
Chapados, Natalie A. "Mécanismes contributifs au développement de la stéatose hépatique non alcoolique (SHNA) : effets de l'entraînement." Thèse, 2009. http://hdl.handle.net/1866/6477.
Paquette, Amélie. "Implication du retrait de l'action estrogénique dans le développement de la stéatose hépatique non-alcoolique." Thèse, 2008. http://hdl.handle.net/1866/6478.
Charbonneau, Alexandre. "Le rôle de l'exercice physique dans le développement de la résistance hépatique au glucagon résultant de la stéatose hépatique non-alcoolique." Thèse, 2006. http://hdl.handle.net/1866/15452.