Dissertationen zum Thema „Fonctions hépatiques“
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Mion, François. „Exploration des fonctions métaboliques hépatiques : intérêts et limites des tests respiratoires utilisant le carbone 13“. Lyon 1, 1996. http://www.theses.fr/1996LYO1T054.
Der volle Inhalt der QuellePastor, Catherine M. „Modifications de la circulation et des fonctions hépatiques au cours du choc endotoxinique : rôle du monoxyde d'azote (NO)“. Paris 5, 1995. http://www.theses.fr/1995PA05CD05.
Der volle Inhalt der QuelleNG-Bonaventure, Kim Heng. „Clonage d'une séquence d'ADN de foie humain qui rétablit l'expression des fonctions hépatiques dans une cellule dédifférenciée d'hépatome de rat“. Paris 7, 1990. http://www.theses.fr/1990PA077071.
Der volle Inhalt der QuelleBosquier, Hélène. „Maintien de fonctions hépatospécifiques du métabolisme des xénobiotiques dans une lignée hépatocytaire (mhPKT) issue d'une souris transgénique exprimant L-PK/TAg“. Paris 5, 1997. http://www.theses.fr/1997PA05P003.
Der volle Inhalt der QuelleSafwan, Zaiter Hasan. „Le marqueur de sénescence p16Ink4a dans le développement, l'âge adulte et le vieillissement“. Electronic Thesis or Diss., Université Côte d'Azur, 2023. http://www.theses.fr/2023COAZ6029.
Der volle Inhalt der QuelleAging is a biological feature that is characterized by gradual degeneration of function of cells, tissues, organs, or an intact organism due to accumulation of environmental factors and stresses with time. Several factors have been attributed to aging such as oxidative stress, telomere shortening, DNA damage and most importantly, the deposit of senescent cells (SnCs). These are irreversibly mitotically inactive, yet metabolically active cells. The reason underlying their senescence lies within the extrinsic and the intrinsic arms. The extrinsic arm is mainly characterized by the expression and the secretory profile known as the senescence associated secretory phenotype (SASP). The intrinsic arm results from the impact of several genes meant to regulate the cell cycle, such as the tumor suppressor genes p16Ink4a (p16), p19ARF (p19) and p21. P16 is a tumor suppressor and cell cycle regulator that has been linked to aging and senescence. Extensive research has revealed that p16 expression is significantly increased in SnCs, as well as during natural aging or age-related pathologies. Based on this fact, p16 is considered as a specific biomarker for identifying SnCs and aging. Whilst a potential role of p19 and p21 has been demonstrated in embryonic development, yet p16 has been less well documented. To investigate p16's potential role in development, we conducted a developmental expression study of p16, beside the tumor suppressors p19 and p21, and examined their RNA expression in the brain, heart, liver, and kidney of mice at embryonic, postnatal, adult, and old ages. Moreover, immunohistochemistry (IHC) was used to examine p16 expression at the protein level. We found that p16 expression was highly dynamic in all organs during embryonic and postnatal stages, and it was significantly more upregulated in old mice compared to p19 and p21. Furthermore, we found that p16 mRNA and protein were more prevalent in liver endothelial cells (ECs) than parenchymal cells in old mice. These findings point to a possible role for p16 in embryonic development, as well as a potential selective role for p16 in liver ECs.Therefore, we aimed at better understanding the role of p16 in biological processes of liver ECs Hence, we used small hairpin (shRNA) constructs and a p16 cDNA-GFP vector transduced via a lentivirus, to knock-down and over-express p16 in-vitro, in order to assess the loss and gain of function in two types of liver ECs, CD31+ vascular ECs and CD146+ sinusoidal endothelial cells (LSECs). Cells were isolated from the liver through magnetic activated cells sorting (MACS) assay using a magnetic bead-attached monoclonal antibodies against CD31 and CD146 surface markers. Non-coding sequence and an empty-GFP vector transduced cells were used as a control for shRNA and p16-GFP transduced cells, respectively
Margall, Ducos Germain. „La ploïdie hépatique : mécanismes et fonctions“. Paris 6, 2008. http://www.theses.fr/2008PA066068.
Der volle Inhalt der QuelleAdler, Michael. „Contribution à l'étude de la fonction hépatique: application pour l'indication d'une transplantation hépatique“. Doctoral thesis, Universite Libre de Bruxelles, 1990. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/213099.
Der volle Inhalt der QuelleHajdari, Shefqet. „Fonctions des protéines HP1 dans l'homéostasie du foie“. Thesis, Montpellier, 2016. http://www.theses.fr/2016MONTT079.
Der volle Inhalt der QuelleChromatin is known for its essential role in establishment and maintenance of cellular identity. Accordingly, disturbances in chromatin’s dynamics are common events in cancers. Chromatin structure and dynamics is highly dependent upon HP1, small non-histone chromosomal proteins that are known to be involved in heterochromatin silencing but also in gene expression regulation, DNA replication and DNA damage repair. To better characterize HP1 functions in mammals, we have studied the consequences of the inactivation of the corresponding genes in mice. Unexpectedly, we demonstrated that inactivation of either HP1a or HP1g lead to a high predisposition of mice to develop tumors specifically within liver. Hence, we established mice models allowing simultaneous inactivation of HP1a/HP1b and HP1a/HP1g specifically within hepatocytes. These models (HP1abliverKO and HP1agliverKO) displayed a significant increased incidence of tumor development within liver, demonstrating that HP1 are liver specific tumor suppressors. Histological analysis of HP1abliverKO livers showed defects that resembled those observed in a human liver pathology known as nonalcoholic steatohepatitis (NASH) characterized by an increase of steatosis, followed by an increased inflammation and the development of fibrosis that finally leads to tumors in old animals. In the case of HP1agliverKO mice, even though inflammation and tumor development were observed, this was not linked with steatosis, strongly suggesting that the underlying mechanisms are specific of each HP1 isoform. In order to reveal molecular mechanisms, we did expression analysis in the liver of 5 weeks old mice, which revealed a strong enrichment of genes encoding for members of the KRAB-ZFP of transcriptional repressors family within genes regulated by HP1ag or HP1ab. This result is of particular interest since it is known that these repressors are regulated by the corepressor TRIM28 which has been shown to require its interaction with HP1 to fulfill its functions suggesting a loop of auto-regulation between HP1, TRIM28 and KRAB-ZFP. Using mice expressing a TRIM28 protein unable to interact with HP1 specifically within hepatocytes, we demonstrated here that the disruption of the interaction between TRIM28 and HP1 lead to spontaneous development of tumors within liver and to over-expression of the same KRAB-ZFP as those deregulated in HP1abliverKO and HP1agliverKO mice. Chromatin immunoprecipitation (ChIP) pinpointed that TRIM28 and HP1 are inter-dependently recruited to the 5’ and/or 3’ ends of KRAB-ZFP genes to regulate their expression. We also observed deregulation of some cancer related genes, such as Tert (Telomerase reverse transcriptase), Nox4 (NADPH oxidase 4), AR (Androgen receptor), GPC3 (Glypican3), Arid1a (AT-Rich Interaction Domain 1A), and interestingly these alterations are depended upon the inactivated HP1 isotype, reflecting distinct molecular oncogenesis. In order to elucidate the possible impact of HP1 on global organization of the nucleus, I performed immunofluorescence analysis in the liver cryosections of 5 weeks old mice. Our data suggest that constitutive heterochromatic features (H3K9me3) are replaced by facultative heterochromatic features (H3K27me3) in absence of HP1ag and that heterochromatic pericentric foci tend to slightly be delocalized. Finally, to better understand the chromosomal rearrangements profile in HP1-dependent liver tumor, we performed Comparative genomic hybridization (CGH) in old tumoral liver. As anticipated, multiple events of gain and loss in copy number variations (CNV) in subchromosomal regions were observed, especially for chromosomes 4, where some KRAB-ZFP members are affected. Altogether, our data demonstrated that HP1 are liver-specific tumor suppressor. They also suggest that HP1 main function within liver is to regulate TRIM28 activity and thereby regulate the expression and repression activity of KRAB-ZFP and ultimately liver homeostasis
Comte, Blandine. „Néoglucogénèse à partir du glycérol dans les cellules hépatiques isolées de rat : utilisation des isotopes stables“. Lyon 1, 1990. http://www.theses.fr/1990LYO1T059.
Der volle Inhalt der QuelleFirrincieli, Delphine. „Le récepteur nucléaire de la vitamine D en physiopathologie hépatique : fonctions protectrices dans l'épithélium biliaire“. Paris 6, 2012. http://www.theses.fr/2012PA066186.
Der volle Inhalt der QuellePilette, Christophe. „Evaluation et prévention pharmacologique de la fibrose hépatique : biologie cellulaire et fonctions des processus digestifs“. Angers, 1999. http://www.theses.fr/1999ANGE0512.
Der volle Inhalt der QuelleLe, Hecho Sara. „Les myofibroblastes portaux : fonction angiogénique et implication dans la progression de la fibrose hépatique“. Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066252/document.
Der volle Inhalt der QuelleLiver angiogenesis and fibrogenesis are closely linked and most of studies have shown thatangiogenesis could worsen fibrosis in chronic liver diseases. Our previous works havedemonstrated that portal myofibroblasts (PMF) greatly contributed to liver fibrogenesis. Theaim of this present work was to determine if PMF could also contribute to liver angiogenesis.We identified collagene XV (col15a1) as a new specific marker for PMF. In vivo, weobserved PMF proliferation (measured by expression of col15a1) at advanced stages offibrosis both in liver from animals models ( CCl4 and BDL) and in livers from patients withchronic liver disease (primary biliary cirrhosis and non alcoolic fatty liver disease). PMFproliferation was correlated with endothelial proliferation. In human cirrhotic liver, PMF werelocated around vessels in fibrotic septa, in proximity to ductular reaction. PMF effects onendothelial cells were assessed in angiogenic tests in vitro and in vivo. PMF conditionedmedium enhanced migration and tubulogenesis of endothelial cells and stimulatedvascularization of matrigel plugs in mice. In coculture, PMF developed junctions withendothelial cells (demosomes and gap junctions) and enhanced endothelial tubulogenesis. Weshowed that PMF secreted VEGFA containing microparticles, able to activate VEGFR-2 inendothelial cells and to mediate their angiogenic function. Cholangiocytes could increasePMF angiogenic properties by stimulating VEGFA expression and microparticles secretion.In conclusion, PMF, studied with a new marker, col15a1, are key cells in hepatic vascularremodeling
Rat, Patrice. „Mise au point d'un test à la caféine comme marqueur de la fonction hépatique“. Paris 5, 1990. http://www.theses.fr/1990PA05P060.
Der volle Inhalt der QuelleGilot, David. „Contrôle de l'apoptose des hépatocytes en fonction de leur état fonctionnel : effets des agents toxiques et protecteurs“. Rennes 1, 2002. http://www.theses.fr/2002REN10069.
Der volle Inhalt der QuelleAudet, Robert M. „Encéphalopathie hépatique chronique, étude des neurotransmetteurs et du métabolisme énergétique cérébral en fonction de l'âge“. Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/NQ61369.pdf.
Der volle Inhalt der QuelleVergier, Jean-François. „Pharmacocinétique du Milnacipran chez le patient insuffisant hépatocellulaire comparativement au patient à fonction hépatique normale“. Bordeaux 2, 1990. http://www.theses.fr/1990BOR23048.
Der volle Inhalt der QuellePlin, Catherine. „Implication du pore géant mitochondrial dans l'évolution des fonctions mitochondriales et cellulaires au cours d'une ischémie-reperfusion hépatique“. Paris 12, 2004. https://athena.u-pec.fr/primo-explore/search?query=any,exact,990002140970204611&vid=upec.
Der volle Inhalt der QuelleLiver transplantation is the last resort treatment for end-stage liver diseases. But the cold ischemia followed by the warm reoxygenation required by the surgery can cause damages to mitochondria. This organelle could be involved in hepatocyte cell death since opening of the permeability transition pore (PTP) can lead to necrosis and apoptosis. The purpose of this work was to study the involvement of PTP in ischemia-reperfusion damages and to determine if PTP represents a relevant pharmacologic target to protect liver during these episodes. Results show that PTP opening occured during reperfusion and that it was correlated with mitochondrial and cellular damages. Direct or indirect PTP inhibition by cyclosporine A or resveratrol, respectively, protected partially mitochondria, limited apoptosis in a concentration-dependent manner, but had no effect on necrosis
Fresson, Anne. „Le propanolol chez le cirrhotique : effets sur la fonction myocardique“. Montpellier 1, 1992. http://www.theses.fr/1992MON11088.
Der volle Inhalt der QuellePayen, Cyrielle. „Implication des troubles métaboliques maternels sur la programmation fœtale des fonctions métabolique hépatique et vasculaire de la descendance“. Thesis, Angers, 2019. http://www.theses.fr/2019ANGE0047.
Der volle Inhalt der QuelleIn utero exposure to maternal metabolic pathologies leads to fetal programming, which increases the occurrence of metabolic, vascular and hepatic diseases in offspring. In this thesis, we focused on fetal programming induced by two types of maternal metabolic dysfunctions : obesity and diabetes. We highlighted that maternal obesity induced direct fetal programming of the vascular function in offspring regardless of metabolic disorders. In addition, we showed that disruption of perinatal nutrition leads to the early occurrence of metabolic disorders in offspring of obese mothers, without modifying the fetal programming of vascular function. Bariatric surgery doesn’t seem tobe able to reverse fetal programming of metabolic and vascular functions as described in obese mothers offspring. We also showed that fetal programming of vascular dysfunction of diabetic mother’s offspring can be transmitted from the F1 to the F2 generation. Finally, we highlighted the importance of sexual dimorphism in the fetal programming of vascular function. These results demonstrate that vascular (arterial hypertension) and metabolic (obesity, diabetes) diseases are not exclusively behavioral diseases but can also have a fetal life origin. They can be transmitted over several generations, thus contributing to explain the worldwide spread of obesity and associated metabolic disorders
Francoz, Claire. „Evaluation de la fonction rénale au cours de la cirrhose“. Paris 7, 2014. http://www.theses.fr/2014PA077078.
Der volle Inhalt der QuelleLiver transplantation (LT) is the best option in selected patients with advanced cirrhosis. These patients usually have renal dysfunction that is underestimated in most cases. There are many causes of renal diseases in patients with cirrhosis, including both functional (theoretically reversible after LT) and organic (irreversible) lesions but diagnostic as well as prognostic markers are still lacking. Kidney biopsy remains difficult to perform in this population. After LT, chronic renal disease is frequent and pre-LT renal dysfunction is one of the most important factors. Theoretically, both end-stage liver and kidney diseases justify combined liver and kidney transplantation. However, markers identifying the reversibility of renal failure after LT alone are still lacking and the selection of candidates for combined transplantation remains difficult in clinical practice. The evaluation of glomerular filtration rate using MDRD-6 formula represents the most robust tool, however it overestimates the true renal function in patients with severe renal failure, possibly leading to kidney transplantation by excess. The identification of markers reflecting the reversibility of renal dysfunction after LT represents one attractive option to accurately select candidates for combined transplantation. Preliminary data suggest that the identification of microRNA profiles (both in urine and in plasma) could be interesting in the future. Imaging, especially contrast-enhanced ultrasound and MRI, is also promising
Deveaux, Vanessa. „Mise en évidence de deux nouvelles fonctions du système endocannabinoïde dans la physiopathologie de la stéatose hépatique : propriétés stéatogènes du récepteur CB2 et profibrogéniques du récepteur CB1“. Phd thesis, Université Paris-Est, 2008. http://tel.archives-ouvertes.fr/tel-00462145.
Der volle Inhalt der QuelleLoeuillard, Emilien. „Régulation des fonctions des myofibroblastes portaux par le stress du réticulum endoplasmique“. Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066071/document.
Der volle Inhalt der QuelleHepatic fibrosis is the consequence of all chronic liver diseases and is characterized by an abnormal extra cellular matrix deposition by myofibroblasts. Portal myofibroblasts (PMF), a subpopulation of hepatic myofibroblasts, play a major role in fibrosis progression and angiogenesis. Accumulating evidences indicate an important role of endoplasmic reticulum (ER) stress in hepatic fibrosis. The aims of this study were to determine whether an ER stress occured in PMF during fibrosis and affected the functions of these cells, and to study the effect of the molecular chaperone TUDCA used in biliary diseases, on ER stress. The phenotype of in vivo activated-PMF obtained from rat fibrotic liver after cholestasis was compared with the phenotype of control PMF that we previously characterized. Our results showed that in vivo activated-PMF underwent ER stress with PERK pathway activation. This ER stress had no effect on myofibroblastic differentiation but reduced PMF proliferation and migration and increased PMF angiogenesis capacity. TUDCA had no effect on these parameters. In conclusion, PMF display ER stress during their activation. ER stress stimulates their pro-angiogenic proprieties and thereby may promote fibrosis progression. However, ER stress also inhibits their proliferation and migration functions, and thereby could provide a negative control loop to restrict their expansion
Bedu, Elodie. „Adaptation du métabolisme hépatique chez le caneton en croissance au froid“. Lyon 1, 2002. http://www.theses.fr/2002LYO10100.
Der volle Inhalt der QuelleDubuquoy, Céline. „Expression et fonction de l’adiponutrine/PNPLA3 dans le foie : Relation entre la voie Wnt/β-caténine, la sensibilité à l’insuline et la stéatose hépatique“. Thesis, Paris 5, 2012. http://www.theses.fr/2012PA05T008/document.
Der volle Inhalt der QuelleThe prevalence of metabolic syndrome (MetS) has increased in industrial countries. The hallmark of MetS in the liver is an excessive accumulation of triglyceride, which is called hepatic steatosis. Different SNP (Single Nucleotide Polymorphism) are associated with hepatic steatosis or MetS. One of them is found on adiponutrin/PNPLA3 (Patatin-like Phospholipase Domain-Containing) gene (SNP I148M) and is now considered as a new marker of hepatic steatosis and severity of NAFLD (Non-alcoholic Fatty Liver diseases). In order to understand the physiological role of adiponutrin in the liver, we studied its transcriptional regulation by SREBP1c (Sterol Responive Element Binding Protein) and ChREBP (Carbohydrate Responsive Element Binding Protein), mediators of insulin and glucose respectively. Moreover, by overexpressing adiponutrin in mice liver, we investigated its role in hepatic carbohydrate and lipid metabolism. We showed that adiponutrin is regulated as lipogenic genes and could have a role lipid metabolism. As for adiponutrin I148M, different SNP are found on substrats of Wnt/β-catenin pathway, a major pathway controlling acinus zonation. We examined the regulation of this pathway by nutritionnal status and in a pathophysiological context of insulin resistance and steatosis. We showed that Wnt/β-catenin pathway is regulated by pancreatic hormones (insulin and glucagon) in the liver in order to adapt hepatocyte phenotype to energetic needs. Moreover, this pathway is dysregulated in insulin resistant mice liver. These data may suggest a link between Wnt/β-catenin pathway deregulation and hepatic metabolic disorders
Ruberto, Anthony. „Rôle du facteur de transcription circadien KLF10 dans la physiologie hépatique“. Electronic Thesis or Diss., Université Côte d'Azur (ComUE), 2019. http://www.theses.fr/2019AZUR4031.
Der volle Inhalt der QuelleThe circadian timing system (CTS) rhythmically controls most aspects of physiology and behaviour over the 24-hour day and perturbations of the CTS lead to metabolic disorders. All the circadian rhythms are under the control of a molecular clock present in all organs. We previously showed that the transcription factor Krüppel-like factor 10 (KLF10) is a clock-controlled gene in liver. Comparison of Klf10-/- and WT mice revealed that KLF10 is a link between the core circadian clock and metabolism in liver as it regulates genes associated with glucose and lipid metabolism. To further decipher the role of KLF10 in hepatic circadian physiology and overcoming the limitations of systemic knockout models, we have generated a mouse model with a conditional hepatocyte specific deletion of Klf10 (hK10). These hK10 mutant mice display altered glycemia pattern and glycogen content, with no change in feeding consumption and behaviour. Analysis of the hepatic circadian transcriptome in these mice revealed that KLF10 deletion in hepatocytes leads to a change of rhythmicity of a significant number of transcripts without affecting expression of core clock genes. Furthermore, enrichment analysis indicates loss of temporal coordination of transcripts involved in energy homeostasis in hK10. When faced with different nutritional challenges, we show that Klf10 expression is downregulated by glucocorticoids and upregulated by carbohydrates. Using primary hepatocytes, we also show that KLF10 repress glucose production and glucose uptake. KLF10 plays a critical role in the response of hepatocytes to high carbohydrates by downregulating genes involved in amino acid catabolism, gluconeogenesis, glycolysis, fatty acid β-oxidation, ketogenesis and lipogenesis. Collectively these results indicate that KLF10 integrates circadian, endocrine and metabolic signaling to allow hepatocytes to adapt their metabolism to nutrient availability over the 24 hr day
Vigan, Finlin Ines Nadège. „Caractéristiques phénotypiques et fonctionnelles des lymphocytes T intra-hépatiques et périphériques au cours de l'hépatite virale chronique C“. Université Joseph Fourier (Grenoble), 2001. http://www.theses.fr/2001GRE10117.
Der volle Inhalt der QuelleJavary, Joaquim. „Rôle de la Reptine in vivo dans la physiopathologie hépatique“. Thesis, Bordeaux, 2017. http://www.theses.fr/2017BORD0719/document.
Der volle Inhalt der QuellePrevious studies of the laboratory have shown that Reptin, an AAA+ ATPase, is overexpressed in hepatocellular carcinoma where it is necessary for proliferation and cell survival. It is known that Reptin plays a critical role in the stabilization of the mTOR kinase, but its pathophysiological role in vivo remains unknown. The objectives of my thesis were to study the role of Reptin in liver metabolism and regeneration using a new hepato-specific Reptin knock-out murine model (Reptin LKO). We have shown that hepatic Reptin maintains mTOR protein level in vivo through its ATPase activity. Unexpectedly, loss or pharmacological inhibition of Reptin induces an inhibition of mTORC1 activity and an increase of mTORC2 activity, associated with inhibition of lipogenesis and hepatic glucose production. The deletion of Reptin completely rescued pathological phenotypes associated with the metabolic syndrome induced by a high fat diet. Thus, inhibition of Reptin ATPase could represent a new therapeutic perspective for the metabolic syndrome. In Reptin LKO model, we have observed a progressive loss of Reptin invalidation associated with a liver regeneration phenomenon. Our preliminary data suggest that Reptin is necessary for hepatocyte survival and is required for hepatocyte proliferation during liver regeneration after partial hepatectomy. To conclude, altogether our results suggest that Reptin plays a crucial role in glucose and lipid metabolism in the liver, and in hepatocyte proliferation and survival
Larosche, Isabelle. „Altérations du génome mitochondrial et des fonctions mitochondriales induites par l'alcool et le tamoxifène“. Paris 5, 2008. http://www.theses.fr/2008PA05P604.
Der volle Inhalt der QuelleMitochondrial impairment and mitochondrial DNA (mtDNA) lesions contribute to xenobiotic-induced liver lesions. The aim of this study was to evaluate the toxic effects of tamoxifen and alcohol on hepatic mitochondria and to assess the modulating role of manganese superoxide dismutase overexpression (MnSOD) on ethanol-induced mitochondrial damage. We showed that tamoxifen accumulates inside mitochondria, inhibits topoisomérases and alters mtDNA replication leading to a progressive depletion of mtDNA. This decrease in mtDNA levels was associated with the inhibition of mitochondrial respiration and β-oxidation of fatty acids and the development of hepatic steatosis. In the second part, we showed that transgenic mice overexpressing MnSOD are more prone to alcohol-induced mitochondrial damage than wild type mice, probably because of enhanced formation of H202, hydroxyl radical and lipid peroxidation products. Our results show the implications of mitochondrial lesions in tamoxifen-induced steatosis as well as the negative effect of MnSOD overexpression on mitochondrial functions during chronic alcohol consumption
Dubuquoy, Céline. „Expression et fonction de l'adiponutrine/PNPLA3 dans le foie : Relation entre la voie Wnt/β-caténine, la sensibilité à l'insuline et la stéatose hépatique“. Phd thesis, Université René Descartes - Paris V, 2012. http://tel.archives-ouvertes.fr/tel-00713660.
Der volle Inhalt der QuelleRoudaut, Méryl. „Les cellules souches pluripotentes induites humaines : un modèle innovant pour la découverte d’une nouvelle fonction de PCSK9 et la mise en place d’organoïdes de foie“. Thesis, Nantes, 2020. http://www.theses.fr/2020NANT1023.
Der volle Inhalt der QuelleHuman induced pluripotent stem cell (hiPSC) offer an attractive alternative to study novel functions linked to diseases and to setup innovative models. In this context, we studied a key player of the hepatic cholesterol metabolism regulation, PCSK9. Upon hiPSC differentiation into hepatocyte-like cells, we found an unexpected role of PCSK9 in undifferentiated cells. Using tools such as overexpression, CRISPR/Cas9-mediated gene invalidation, and hiPSC derived from a patient carrying PCSK9 loss of functions mutations, we found a regulatory effect of PCSK9 on the TGFß pathway. This effect is mediated by DACT2, a negative regulator of the TGFßR subunit R1. Through DACT2 modulation by PCSK9, the SMAD2 phosphorylation is impacted, thus hiPSC proliferation. In parallel, to enhance hepatic cells functions generated from hiPSC, we setup a new simplified procedure to obtain liver organoïdes. hiPSC are cultured in a modified hydroscaffold, BIOMIMESYS®, produced by HCS Pharma in a 96-well format suitable for molecular screening. Our procedure, recapitulating key steps of liver development, allowed us to generate liver organoids including not only hepatocytes but also, biliary-, stellate- and endothelial-cells. Functional characterizations showed enhanced cytochrome activities compared to HLC and excellent pharmacological responses with lipid accumulation upon amiodarone or ethanol treatments and LDL-bodipy uptake upon statin treatments. As our model can be personalized and automatized, if offers a new perspective for high content molecular screening
Daniele, Nathalie. „Rôle de la phosphatidylinositol-3 kinase dans l'inhibition de la glucose-6 phosphatase hépatique par l'insuline“. Lyon 1, 1998. http://www.theses.fr/1998LYO1T066.
Der volle Inhalt der QuelleGourdon, Laurence. „USF et HNF4, deux acteurs de la régulation transcriptionnelle par le glucose et l'AMPc du gène de la pyruvate kinase hépatique“. Paris 11, 1999. http://www.theses.fr/1999PA11T020.
Der volle Inhalt der QuelleRoumie, Rima. „Implication des phosphodiestérases spécifiques des nucléotides cycliques dans le relachement vasculaire et la fonction rénale chez le rat cirrhotique“. Strasbourg 1, 2005. https://publication-theses.unistra.fr/public/theses_doctorat/2005/ROUMIE_Rima_2005.pdf.
Der volle Inhalt der QuelleTheurey, Pierre. „Implication of mitochondria endoplasmic-reticulum interactions in the control of hepatic metabolism“. Thesis, Lyon 1, 2015. http://www.theses.fr/2015LYO10104.
Der volle Inhalt der QuelleThe liver is an essential organ in the control of energetic homeostasis of the human body. Particularly, hepatic metabolism is crucial for glucose and lipid homeostasis. Catabolism and anabolism of both substrates are in constant equilibrium and synergically regulated in regard of nutrient availability and energetic demand. Disruption of this equilibrium, especially in the case of obesity, can lead to hepatic accumulation of lipids, which is a major cause of hepatic insulin resistance (HIR) leading to chronic hyperglycaemia and type 2 diabetes (T2D). The eukaryotic cell is a highly compartmented structure, and in this respect compartmentation of anabolic and catabolic processes is an integral part of managing metabolic pathways together. In this context, the mitochondrion is a key organelle, housing oxidation of lipids, the tricarboxylic acid (TCA) cycle and cellular respiration. In this way, mitochondrial function is a crucial element in maintaining energetic and reductionoxidation state of the cell within physiological ranges, as well in regulating the proper activity of glucose and lipid metabolism for the all body homeostasis. Mitochondrial function is directly regulated by its interaction with the endoplasmic reticulum (ER) via proximity points between the organelles called Mitochondria-Associated-ER-Membranes (MAM). In this context I have participated during my Ph.D. in a work that has shown the importance of mitochondria-ER interactions in insulin signalling and highlighted MAM disruption as a main actor in HIR. Furthermore, I have studied the regulation of MAM in the physiological context of nutritional transition in the healthy and insulin resistant (IR) liver. Particularly, we have shown that MAM disruption induces impaired insulin signalling, while their reinforcement protects against its appearance and restore insulin sensitivity in lipid-induced IR condition. Moreover, we have pointed out a consistent decrease of MAM quantity in the IR liver of ob/ob, high-fat high-sucrose diet (HFHSD) and Cyclophilin D - knock-out (CypD-KO) mice
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.
Der volle Inhalt der QuelleEnergy 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
Hachfi, Lamia. „Effets de stress physico-chimiques sur l’expression de gènes impliqués dans l’homéostasie et la fonction de l’axe hypothalamo-hypophyso-gonado-hépatique chez le loup (Dicentrarchus labrax L.)“. Thesis, Toulon, 2013. http://www.theses.fr/2013TOUL0018/document.
Der volle Inhalt der QuelleMarine ecosystems are a major target of global changes that continuously affect our planet. In the present study we investigated two of these changes that may threaten the marine environment: global warming, through the study of the effect of heat stress on ho-1 expression and marine pollution through the study of the impact of heavy metals acting as endocrine disruptors (cadmium and lead) on the hypothalamic-pituitary-gonadal-liver (HHGL) axis in the sea bass (Dicentrarchus labrax L.). Our results show an important response of ho-1 to both thermal and chemical stress in the liver. We also demonstrated a high hepatic accumulation of Cd, and to a lesser extent of Pb. This accumulation was correlated with an overexpression of mt gene coding for metallothionein. Changes in the expression of candidate genes (arom b, fshß, arom a…) along the HHGL axis were observed after metal intoxication but no physiological effects were observed.The question then arises to what extent the synergy of physicochemical stressors impacts the dynamics and the welfare of marine species
Moreau, Amélie. „Etude dans l'hépatocyte humain des gènes cibles des récepteurs nucléaires CAR et PXR, régulateurs de la fonction de détoxication entéro-hépatique et nouveaux perturbateurs métaboliques et endocriniens“. Montpellier 2, 2009. http://www.theses.fr/2009MON20040.
Der volle Inhalt der QuelleCAR and PXR are two nuclear receptor devoted to potentially toxic xenobiotics and endobiotics. Their activation allow the transcription of major genes involved in the detoxication process (CYP450, transferase, transporters). The aim of this study was to identify new PXR and/or CAR target involved in others metabolics pathways which could lead to metabolic or endocrinal disruption. We first show that, like PXR, CAR activation provokes an increase in VitD3 catabolism via the induction of CYP24. Then, from a large transcriptomic screening validated by molecular biology and biochemical approaches, we dig out a new lipogenic pathway involving the direct induction of S14 by PXR. These results show that long term PXR and CAR activation could lead to bone demineralisation (CYP24) or intrahepatic steatosis (S14)
Fougeray, Tiffany. „Fonction de la signalisation de l'insuline dans le foie : impact sur la régulation de l'horloge circadienne et le dimorphisme sexuel de l'homéostasie glucidique“. Thesis, Toulouse 3, 2020. http://www.theses.fr/2020TOU30262.
Der volle Inhalt der QuelleThe prevalence of obesity and type II diabetes is constantly increasing in the majority of industrialized countries and represents a major public health issue. The progression of this pathology can result in a desynchronization of the liver clock. This is controlled by food intake, which induces a hepatocyte response induced by various metabolic and endocrine signals, including Insulin. Indeed, the oscillation of its secretion correlates to feeding. The first objective of my PhD was to determine the contribution of hepatocyte Insulin Receptor to the liver clock. Moreover, clinical studies have shown that type 2 diabetes is a sexually dimorphic disease, which is more prevalent in men than in women. Thus, the second objective was to determine whether hepatocyte Insulin receptor signaling is sexually dimorphic and could contribute to these sex specificities. For this, we used a mouse model with inducible Insulin receptor deletion in hepatocytes (IRhep-/-). Both targeted and untargeted approaches were used. Firstly, we were able to highlight the essential role of the Insulin receptor in the maintenance and reprogramming of the hepatic clock. Secondly, we evidenced a sexual dimorphism in the regulation of carbohydrate homeostasis as IR deletion induces hyperglycaemia and glucose intolerance in males but not in females. All of these results provide a better understanding of the physiological functions associated with hepatocyte Insulin receptor and its sex-specific functions
Suárez, Catherine. „Function and regulation of a serine protease implicated in malaria parasite remodelling and egress“. Thesis, Montpellier 2, 2012. http://www.theses.fr/2012MON20209.
Der volle Inhalt der QuelleMalaria remains one of the deadliest infectious diseases in the world. Propagated by the bite of an infected female Anopheles mosquito, the malaria parasite (Plasmodium) enters the bloodstream and infects hepatocytes. In the liver, the parasite differentiates and reproduces by schizogony within a membrane-bound parasitophorous vacuole (PV) resulting in the production of several thousands of merozoites per infected hepatic cell. These parasites are subsequently released into the blood stream where they infect circulating red blood cells and undergo repetitive cycles of infection, replication, and egress (active release of parasites) which are responsible for the clinical symptoms of the disease.Work on P. falciparum, has shown that P. falciparum SUB1 (PfSUB1), a serine protease of the subtilisin-like family, is discharged into the PV just prior to egress from the erythrocyte and mediates the proteolytic maturation of members of the SERA family (a family of papain-like proteins) as well as a number of merozoite surface proteins (MSPs). Pharmacological inhibition of PfSUB1 activity inhibits both egress and invasion of released merozoites in blood stages in vitro.The liver stage of the parasite is an ideal target for development of prophylactic anti-malarial drugs, as it is clinically silent. It is thus of importance to gain more detailed knowledge about parasite development in this stage. The main aim of this project was to study the role of SUB1 in the liver stage of the parasite life cycle. The work was performed on the orthologue of PfSUB1 in the murine malaria species P. berghei. Initially, expression of PbSUB1 in liver stages was confirmed using specific antibodies and by generating a transgenic P. berghei clone expressing epitope-tagged PbSUB1. Next, recombinant enzymatically-active PbSUB1 was expressed in insect cells and partially characterised with respect to its function and substrate specificity. This confirmed that the protease is able to process substrates based on PbMSP1 and PbSERA3, two putative substrates expressed in late hepatic stages of the parasite.Finally, to further study PbSUB1 function, two conditional gene knock-out approaches were applied to study the phenotypic consequences of loss of PbSUB1 expression. Working from a ~10 kb genomic DNA library clone comprising pbsub1 and flanking genes, a method to insert Flp recombinase recognition (FRT) sites into intergenic regions was developed. This was achieved by combining inducible Flp activation in E. coli with recombinase mediated engineering techniques similar to those that underlie the PlasmoGEM project (Pfander et al., 2012). This strategy overcomes challenges of existing techniques and is also suitable for flanking large genes with FRT sites. With these newly generated tools, an inducible knock-out of pbsub1 was successfully generated in vivo, in which stage-specific excision of the gene was accompanied by concomitant induction of GFP expression, facilitating identification of the knock-out parasites. A preliminary analysis of these PbSUB1-deficient parasites suggests an essential role for the protease in the development of liver stage schizonts
Roques, Beatrice. „Bases mécanistiques des effets d'un insecticide agrovétérinaire, le fiproni, et/ou de ses métabolites sur la fonction thyroïdienne chez le rat“. Thesis, Toulouse, INSA, 2012. http://www.theses.fr/2012ISAT0029/document.
Der volle Inhalt der QuelleThe widely used insecticide fipronil is a thyroid disruptor in rat acting on thyroid hormone hepatic metabolism. In sheep, a more relevant species for the human thyroid regulation, fipronil-induced thyroid-disruption is much more limited. The goal of this thesis was to characterize the mode of action of fipronil on thyroid function at the hepatic level focusing on 1) the potential role of fipronil sulfone, the main fipronil metabolite formed in vivo, and on 2) interspecific differences in terms of fipronil metabolism and/or sensitivity to thyroid disruption that can prejudge of the relevance of the different animal models for the risk assessment of fipronil for human health. Fipronil sulfone was as efficient as fipronil to induce the expression and/or activity of enzymes involved in thyroid hormone or fipronil hepatic metabolism both in vivo in rat and in vitro on hepatocytes. The use of knock-out mice for xenosensors nuclear receptors strongly suggested an implication of the nuclear receptor Constitutive Androstane Receptor and/or Pregnane X Receptor on fipronil-induced thyroid disruption
Djohan, Youzan Ferdinand. „Influence d’un régime riche en huile de palme sur le statut antioxydant, la fonction mitochondriale et les désordres métaboliques associés à l'obésité“. Thesis, Montpellier, 2017. http://www.theses.fr/2017MONTT035/document.
Der volle Inhalt der QuellePalm oil is the most consumed vegetable oil in the world. Because of its high content of saturated fatty acids (SFA), particularly palmitic acid, this oil is considered by some authors as potentially harmful to health. The aim of this study was to compare the effects of palm oil (red or olein), olive oil (considered good for health) and lard (rich in SFA), on health. To do this, 40 male Wistar rats were divided into 5 groups of 8 rats each: 1 control group et 4 groups fed by high fat diet (HFD) containing respectively red palm oil, palm olein, olive oil or lard. After 12 weeks of diet, the rats were sacrificed and the tissues removed. Tissue tests have shown that palm oil (red or olein) induces an antioxidant status and a lipid profile superimposed on those of olive oil. All HFD contributed to weight gain, impaired mitochondrial function, and disturbance of carbohydrate metabolism by the induction of insulin resistance. The study shows that olive oil is more deleterious to the liver than palm oil (red or olein) and lard. Apart from red palm oil, palm olein, olive oil and lard negatively influence adipose tissue. Studies on the aorta have shown that the vascular effects of palm oil are less deleterious to the aorta than lard and olive oil.Overall, the results of this study show that harmfull effects of palm oil (red or olein) were not worse than that of olive oil on organ that were analyzed
Kadar, Ali. „Evaluation de l'effet mélange sur la clairance hépatique humaine de pesticides appartenant à deux groupes de matières actives communément retrouvées dans l'alimentation française : développement analytique et études cinétiques“. Thesis, Aix-Marseille, 2018. http://www.theses.fr/2018AIXM0322.
Der volle Inhalt der QuelleGeneral population is exposed to several pesticides, mainly via the diet. Whereas these active ingredients obtained their marketing authorization individually, the available data regarding their impact as a mixture on the human body are scarce. In order to help better understanding this “mixture effect”, we aimed at studying the human hepatic in vitro metabolism of two pesticides mixtures commonly found in the diet
Mourad, Abbas. „Modélisation de la morbi-mortalité du carcinome hépatocellulaire en France par stade de gravité : évaluation de différentes stratégies en fonction du dépistage et des ressources thérapeutiques“. Phd thesis, Université du Droit et de la Santé - Lille II, 2014. http://tel.archives-ouvertes.fr/tel-00989711.
Der volle Inhalt der QuelleVial, Guillaume. „Métabolisme hépatocytaire et insulinorésistance : effets d'un régime enrichi en graisse et d'un nouvel antidiabétique "E008"“. Phd thesis, Grenoble 1, 2009. http://www.theses.fr/2009GRE10269.
Der volle Inhalt der QuelleWith a steadily increasing prevalence, type II diabetes is becoming a major public health issue. This pathology is characterized by an increase of the hepatic glucose production, reflecting a raise of gluconeogenesis, which evolves into chronic hyperglycemia. Liver is thus a privileged target to fight against imbalances of glucose metabolism. A new drug derived from the Metformin and devoid of side effects, the E008, was synthesized by Merck-Santé to normalize blood glucose levels in diabetic patients. The dual objective of our work consisted in (i) studying liver metabolic fluxes in a nutritional rat model which exhibits a metabolic syndrome, and (ii) analysing the effects of this new compound while elucidating its mechanisms of action. Animals fed a high-fat diet have an increased gluconeogenesis, associated with disturbances of the mitochondrial function: increase of ROS production, inhibition of oxygen consumption and changes in redox potential. A common denominator in these events could be a mutual alteration of the composition of membrane lipids and quinones. On rats fed with a high-fat diet, E008 treatment decreases the hepatic glucose output by modifying metabolic control. Furthermore, it induces a subtle inhibition of cellular respiration while acting, at the same time, on the respiratory chain activity and phosphorylating system. (Inhibition of complex I and ANT reduced expression). Its action is also related to an activation of AMP-activated protein kinase (AMPK), by modification of adenine nucleotides ratios
Corbel, Tanguy. „Mécanismes toxicocinétiques impliqués dans l'exposition foetale au Bisphénol A“. Thesis, Toulouse, INSA, 2013. http://www.theses.fr/2013ISAT0034/document.
Der volle Inhalt der QuelleBisphenol A (BPA) an endocrine disruptor interfering with developmental processes in rodents, raises the question of risk for human health related to fetal exposure to BPA. The goal of this work was to determine the toxicokinetic mechanisms involved in fetal exposure to BPA. The disposition of BPA and its metabolites in the maternal-placental-fetal unit in an in vivo ovine model enabled us to identify the placental transfer and the fetal-placental metabolism as the major determining factors of fetal exposure to BPA. Bidirectional placental transfer of BPA occurs by passive diffusion leading to a ratio of free BPA between the fetal and maternal plasma concentrations of about 1. By contrast, the permeability of BPA-G is very limited, particularly in materno-to-fetal direction. The hepatic conjugation activities were very low in ovine fetus at an early stage of development and increased throughout pregnancy. Hydrolysis of BPA conjugates observed ex vivo into fetal ovine gonads could lead to local exposure to native BPA. Altogether, these results suggest that the early stage of pregnancy is a critical window of exposure for the developing fetus