Dissertations / Theses on the topic 'Acides et sels biliaires – analyse'
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Descat, Amandine. "Développements de méthodes d'analyse des plastifiants de type phtalates et des acides biliaires dans des matrices biologiques : applications dans différents contextes physiopathologiques." Electronic Thesis or Diss., Université de Lille (2022-....), 2023. http://www.theses.fr/2023ULILS054.
This thesis has two main focuses:1/ Plasticizers, including phthalates, have been identified as category 1b carcinogenic, mutagenic and reprotoxic (CMR) and as endocrine disruptors. Di-2-ethylhexyl phthalate (DEHP) is one of the most common plasticizers and is generally associated with polyvinyl chloride (PVC) in medical devices. As DEHP is not covalently bound to PVC, it can easily migrate into lipophilic matrices and then reach the bloodstream. It is metabolized by the liver into mono-2-ethylhexyl phthalate (MEHP), which is just as toxic. In recent years, alternative plasticizers to DEHP have been developed, notably di-2-ethylhexyl terephthalate (DEHT), which is metabolized in vivo to mono-2-ethylhexyl terephthalate (MEHT).The first part of this thesis involved developing methods for measuring plasticizers and their metabolites in various biological matrices, such as plasma. Two LC-MS/MS methods were developed for the determination of DEHP and MEHP as well as DEHT metabolites. As the ionization in mass spectrometry of DEHT is very low, a LC-UV method was developed to quantify this terephthalate. These methods have made it possible to estimate the release of DEHP and DEHT from blood bags and to measure their primary metabolites in blood products.2/ Bile acids (BA) are a large family of steroids made up of numerous species. They are synthesized in the liver and intestine and represent the main route of cholesterol catabolism. 7a-hydroxy-4-cholesten-3-one (C4) is the precursor of BA. BA play an essential role in lipid absorption but also in cell signaling, as they are ligands for the nuclear receptor 'Farnesoid X receptor' (FXR) and/or the G protein-coupled membrane receptor, TGR5. These receptors, and hence their ligands, are involved in glucose homeostasis, lipid homeostasis and energy expenditure. Any modulation of the BA profile can therefore lead to changes in metabolic homeostasis. The second part of this thesis involved developing two LC-MS/MS assay methods for 31 BA species and C4 in different biological matrices, including plasma. A specific method for the determination of recently described BA derived from LCA in caecal contents is currently being optimized. These methods have made it possible to analyze variations in the BA profile in various cardiometabolic disease contexts (obesity, insulin resistance, type 2 diabetes, NAFLD).In conclusion, the analytical methods developed for quantifying plasticizers and BA have been validated and applied in preclinical and clinical studies. Interestingly, data from the literature and preliminary transient transfection assays have shown that phthalates and their metabolites modulate the activity of the peroxisome proliferator-activated receptor alpha (PPARa), a key regulator of metabolic homeostasis and expression of CYP7A1 (a major enzyme in hepatic BA synthesis). The analytical tools developed in this thesis open up original perspectives for studying the effects of phthalates on metabolic homeostasis via the regulation of BA metabolism. All of this work has made it possible to link analytical developments and applications in the field of biology and health
Pean, Noémie. "Récepteur TGR5 des acides biliaires : impact sur la régénération du foie et l'homéostasie biliaire." Paris 7, 2014. http://www.theses.fr/2014PA077055.
BA composition (plasma, liver, bile, urine, stools) was more hydrophobic in TGR5-KO than in W1 mice. After PH, severe hepatocyte necrosis, prolonged cholestasis, exacerbated inflammatory response and delayed regeneration were observed in TGR5-KO mice. Hepatocyte adaptive response to post-PH BA overload was similar in WT and TGR5-KO mice. However, kidney and biliary adaptive responses to post-PH BA overload were strongly impaired in TGR5-KO as compared with WT mice. Cholestyramine treatment, as well as Kupffer cell depletion, significantly improved the post-PH TGR5 KO mice phenotype. After bile duct ligation or upon a cholic acid-enriched diet, TGR5 KO mice exhibited more severe liver injury than WT as well as impaired BA elimination in urine. In TGR5-KO mice, hepatic bile acid synthesis and cholecystohepatic shunt were not altered, but gallbladder relaxation and biliary epithelium hyperpermeability were observed as compared to WT mice. TGR5 is crucial for liver protection against BA overload after PH, primarily through the control of bile hydrophobicity and cytokine secretion. In the absence of TGR5, intrahepatic stasis of abnormally hydrophobic bile and excessive inflammation, in association with impaired bile flow adaptation and deficient urinary BA efflux, lead to BA overload-induced liver injury and delayed regeneration. TGR5 may control both bile acid pool hydrophobicity via the control of gallbladder motor function, and epithelial permeability in the biliary tract
Xupei, Huang. "Contribution à l'étude de l'activation de la protéine kinase C par deux familles de promoteurs de tumeurs : les sels biliaires et les acides gras insaturés." Paris 12, 1992. http://www.theses.fr/1992PA120015.
Claudel, Thierry. "Rôle du récepteur nucléaire FXR dans le métabolisme lipidique." Lille 2, 2003. http://www.theses.fr/2003LIL2P005.
Pasqualini, Eric. "La lipase sels biliaires-dépendante du pancréas : rôle de la phosphorylation et caractérisation d'une isoforme oncofoetale." Aix-Marseille 3, 1998. http://www.theses.fr/1998AIX30059.
Yolou, Séri. "Analyse vibrationnelle et structurale de diacides aliphatiques oxo et gem-dimethyle substitués et de leurs sels alcalins en solution aqueuse." Montpellier 1, 1992. http://www.theses.fr/1992MON13520.
Olivier, Jean-François. "Influence du pH dans la capacité d'adsorption des sels biliaires et des lysolécithines "in vitro" par les antiacides contenant de l'argile et/ou de l'aluminium." Paris 5, 1995. http://www.theses.fr/1995PA05P110.
Ramière, Christophe. "Interactions entre le métabolisme hépatique des sels biliaires et des lipoprotéines et les infections par les virus des hépatites B et C." Thesis, Lyon 1, 2012. http://www.theses.fr/2012LYO10016.
Hepatitis B and C viruses (HBV and HCV) infections are tightly linked with hepatic lipid metabolism. HBV replication depends on specific nuclear receptors, such as HNF4α and PPARα, both implicated in this metabolism. HCV assembly depends on the synthesis of Very-Low-Density Lipoproteins (VLDL), and the virus circulates in the blood as lipo-viral-particles associated in particular with apoB, an essential component of VLDL. In this study, we first studied the influence of FXRα, the nuclear receptor for bile acids, on HBV replication. We showed that, in vitro, bile acids, via FXRα, were able to activate the HBV Core promoter which controls the level of viral replication. Then, in the study of the interactions between HCV and lipoproteins, we demonstrated that apoB, which is associated with a proportion of viral particles, played an important role in HCV infectivity in vitro, and that Cideb, a protein involved in VLDL assembly, was implicated in the association between HCV and apoB and influenced the infectivity of secreted viral particles. Finally, we showed that, besides HCV infectious particles, sub-particles bearing only viral envelope glycoproteins circulated in the blood of infected patients. Interactions of HBV with the metabolism of bile acids, and of HCV with the metabolism of lipoproteins, are two examples of adaptation of a parasite to its host. The potential benefits from these interactions are still to be determined, as well as the possibility to develop anti-viral strategies targeting lipid metabolism
Ramsis, Hassan. "Analyse vibrationnelle et structurale de biomolécules en solution aqueuse : acides adipique, diglycolique, thiodiglycolique et leur sels alcalins." Montpellier 1, 1996. http://www.theses.fr/1996MON13508.
Favé, Gaëlle. "Stratégies d'amélioration de la biodisponibilité des acides gras : approches physico-chimiques et enzymatiques." Aix-Marseille 2, 2006. https://tel.archives-ouvertes.fr/tel-00689483.
Foucaud, Laurent. "Régulation nutritionnelle, hormonale et biliaire de l'expression des FABP du tractus digestif." Dijon, 1997. http://www.theses.fr/1997DIJOS065.
Spinelli, Valeria. "Les acides biliaires et la régulation de l’homéostasie métabolique : rôle du récepteur Farnesoid X Receptor (FXR) dans la cellule bêta-pancréatique : variation du pool des acides biliaires et chirurgie bariatrique Roux-en-Y Gastric Bypass." Thesis, Lille 2, 2015. http://www.theses.fr/2015LIL2S054.
Bile acids (BAs) are molecules produced in the liver, stored in the gallbladder, secreted into the intestine and returning to the liver via the enterohepatic circulation. A fraction of BAs escapes the reuptake by the liver and enters the systemic circulation, by which they reach the peripheral organs including the pancreas. Besides their function in facilitating the intestinal absorption of lipids, BAs are signaling molecules that act through receptors for BAs, which are expressed in the key tissues for metabolic regulation, and whose modulation by BAs contribute to regulate energy homeostasis. Thus, variations in the composition of the BAs pool determine the modulation of metabolism via their receptors. The BA-receptor Farnesoid-X receptor (FXR) is involved in the regulation of glucose, lipid and BA metabolism by its action in the liver, intestine, adipose tissue and pancreas. Whole body FXR deficient mice are glucose intolerant and insulin resistant in liver and peripheral tissues, whereas in a context of obesity, FXR deficiency rather improves these parameters. Furthermore, FXR is expressed in the pancreatic beta cell (bcell), where it regulates the synthesis and the secretion of insulin, but the molecular mechanisms have not been fully elucidated yet. To understand 1) the contribution of FXR bcell in the metabolic phenotype of the total FXRKO-mouse, and 2) the molecular mechanisms of the regulation of insulin production by FXR in the bcell, I developed a mouse model invalidated for FXR specifically in the bcell by the Cre-loxP strategy. The development of the model showed nonspecific recombination phenomena, and I developed a genotyping strategy to overcome this problem. To highlight the phenotype of the FXRKObcell mouse I tested various metabolic contexts (standard and high fat diet, fasting and refeeding conditions, circadian variations). Compared to control, FXRKO-bcell mice developed glucose intolerance and has lower insulinémia, defects increased by a high fat diet. The global transcriptomic analysis in the islets identified a set of microRNA strongly deregulated by invalidating FXR in the bcell, which could explain the dysfunctions in insulin secretion. Besides the modulation of the activity of the receptors, metabolic effects can be obtained by varying the composition of the pool of their ligands BAs. Thus, metabolic perturbations (such as insulin resistance and type 2 diabetes, obesity) are associated with qualitative and/or quantitative variations in the BA pool. In addition, variations of the BAs pool are associated to the metabolic improvement that precedes the weight loss after the surgical practice of Roux-en-Y Gastric Bypass (RYGB), which suggests that the BAs can be among the actors of the ‘weight loss-indipendent’ beneficial metabolic effects of RYGB. To investigate this hypothesis, some preclinical models of RYGB have been developed. During my thesis I compared the pool of BAs pre and post RYGB among three species (rat, pig and human; Coll. Prof. F. Pattou and Dr. E.Osto) with the aim of assessing which preclinical model is most suitable for these studies in terms of characteristics of the BAs pool. In a second study, I focused on the causes and mechanisms underlying the increased concentrations of circulating BAs induced by RYGB. In the model of minipig (coll. Pr. F. Pattou), the analysis of the plasma BA pool composition and the hepatic gene expression before and after RYGB, allowed to show that changes in the hepatic function are - at least in part - responsible for the increase of the BA pool following RYGB
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
Piessen, Guillaume. "Rôles des mucines MUC1 et MUC4 dans l'adénocarcinome de l'oesophage : études in vitro, ex vivo et dans un modèle animal de carcinogenèse induite." Lille 2, 2007. http://www.theses.fr/2007LIL2S048.
Queniat, Gurvan. "Rôle des acides biliaires et de leur récepteur TGR5 dans la régulation de la somatostatine pancréatique et intestinale : conséquences fonctionnelles sur les îlots pancréatiques humains." Thesis, Lille 2, 2015. http://www.theses.fr/2015LIL2S024/document.
Bile acids (BAs) have evolved over the years from being considered as simple lipid solubilizers to metabolically active molecules. In addition to their function in dietary lipid absorption, they have also been shown to activate farnesoid X receptor (FXR) and TGR5 receptors to initiate signaling pathways and regulate metabolic gene transcription. TGR5 (encoded by the GPBAR1 gene), also known as G-protein-membrane-type receptor for bile acids (M-BAR) or G-protein-coupled bile acid receptor 1 (GPBAR1), was the first identified G-protein coupled receptor specific for bile acids. In normal individuals, the highest level of GPBAR1 mRNA expression was reported in the gallbladder, placenta and spleen, followed by moderate expression in other tissues including lungs, liver, stomach, small intestine and adipose tissue, with a relatively low level of expression in kidney, skeletal muscles and pancreas. In response to binding of BAs to the ligand-binding pocket of the TGR5 protein, the TGR5 receptor is internalized and the GαS subunit is released. This mechanism leads to activation of adenylate cyclase and an increase in cAMP production resulting in induction of the protein kinase A (PKA) pathway. Subsequently, PKA phosphorylates the cAMP-response element-binding protein (CREB) and enhances the transcription of its target genes in response to extracellular signals.To date, extensive work has been done to investigate the role of TGR5 in metabolism. In rodents, BA-activated TGR5 receptor stimulates energy expenditure in brown adipose tissue and skeletal muscle and prevents obesity and insulin resistance induced by a high fat diet. TGR5 is also implicated in intestinal L-cells secreted GLP-1, which plays an essential role in glucose homeostasis through the stimulation of glucose-dependent-insulin-secretion and inhibition of glucagon secretion, inhibition of gastric emptying and increasing satiety through neuroendocrine pathways. In terms of the immunological function of TGR5, it is now known that TGR5 is expressed in several immune cells such as monocytes, alveolar macrophages and Kupffer cells. The beneficial effects of TGR5 on macrophage-driven inflammation include reduced proinflammatory cytokine expression, thus protecting against atherosclerosis and liver steatosis. On the contrary, TGR5 activation has also been implicated in itch and analgesia, gastrointestinal-tract cell carcinogenesis, pancreatitis, and cholelithiasis, suggesting a potential role for TGR5 as a regulator of signal transduction pathways responsible for cell proliferation and apoptosis. BAs may also influence islet function via both direct and indirect mechanisms as recent studies have shown that Farnesoid X receptor (FXR) is expressed by pancreatic beta cells, and regulates insulin signaling in cultured cell lines. Kumar et al., [14] also reported that the TGR5 agonists INT-777 + oleanolic acid (OA) stimulated glucose-mediated insulin release via TGR5 activation, also in cultured cells. Still, little is known about the regulation of TGR5 expression or its involvement in pancreatic hormone secretion in response to physiological or pathological conditions such as T2D, as these studies have been performed mainly in cultured cell lines. In these contexts, the biological function of TGR5 remains enigmatic. The aim of the present study was first to establish the specific expression of TGR5 in human pancreatic islet cell subtypes. Then, a cross-sectional cohort of human islets isolated from individuals with various degrees of insulin resistance was exploited to determine if TGR5 expression and function was modified in T2D. Finally to determine if targeting TGR5 is clinically relevant, human islets were treated in-vitro with a specific agonist of TGR5 or with siRNA directed against TGR5 and hormone secretion assessed to establish whether TGR5 activation or inhibition modulate pancreatic hormone secretion
Gaëlle, Favé. "Stratégies d'amélioration de la biodisponibilité des acides gras : approches physico-chimiques et enzymatiques." Phd thesis, Université de la Méditerranée - Aix-Marseille II, 2006. http://tel.archives-ouvertes.fr/tel-00689483.
LAMRI, YAMINA. "Etude in vivo des mecanismes cellulaires et tissulaires impliques dans la secretion des proteines plasmatiques et des acides biliaires dans le foie de rat. Analyse par immunoperoxydase et hybridation in situ." Paris 6, 1990. http://www.theses.fr/1990PA066193.
Ploton, Maheul. "Impact de la phosphorylation de FXR par la PKA sur son activité transcriptionnelle et sur la régulation de la néoglucogenèse hépatique." Thesis, Lille 2, 2018. http://www.theses.fr/2018LIL2S032/document.
Glucose homeostasis is maintained during normal fasting through a complex regulatory network controlled mainly by glucagon, a pancreatic hormone. Opposing the effects of insulin, it orchestrates the glucose use, storage and synthesis by the liver, the main organ that produces glucose during fasting. The latter is carried out first by the degradation of glycogen or glycogenolysis and then by de novo glucose synthesis or gluconeogenesis. Hepatic gluconeogenesis is controlled by modulation of various key enzymes activity and/or expression according to allosteric or transcriptional mechanisms.Multiple transcription factors are involved in the transcriptional regulation of hepatic gluconeogenesis. The nuclear bile acid receptor FXR is expressed in the liver and in several organs involved in glucose homeostasis. FXR regulates many essential liver functions, including controlling bile acid and lipid metabolism. The exact role of FXR on gluconeogenesis is still debated. The objective of this work was therefore to study the role of FXR in the control of hepatic gluconeogenesis under experimental conditions reflecting certain aspects of fasting. We demonstrated that FXR, in the presence of glucagon, positively regulated gluconeogenesis according to two mechanisms.The first mechanism involves phosphorylation of FXR by PKA, a glucagon-activated kinase. This FXR post-translational modification allows synergistic induction of key gluconeogenic enzymes expression by FXR and the CREB transcription factor. This mechanism identification constitutes the major part of the work presented in this thesis. These were integrated with work previously conducted in the laboratory that allowed us to identify an additional mechanism for regulating gluconeogenesis. The FXR direct interaction with the transcription factor FOXA2, itself activated by glucagon, inhibits the ability of FXR to induce the expression of SHP, a gluconeogenesis inhibitory nuclear receptor.This work has therefore identified for the first time that hepatic gluconeogenesis is positively regulated by FXR in the glucagon signalling pathway. For this, FXR integrates the "glucagon" signal by two distinct mechanisms: via post-translational modification, its phosphorylation by PKA on S325 and S357 serines and via protein-protein interaction with FOXA2
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
Mazuy, Claire. "Etude de l’interaction entre le récepteur nucléaire FXR et le facteur de transcription FOXA2 dans le foie." Thesis, Lille 2, 2015. http://www.theses.fr/2015LIL2S055/document.
The liver is a key regulator of whole-body energy metabolism. The nuclear receptor super-family plays a leading role in the metabolic sensing of the liver. Among the nuclear receptors, the bile acid nuclear receptor FXR contribute to the modulation of liver activity in particular through the regulation of bile acid, lipids and glucose homeostasis. Consequently, FXR became a potential therapeutic target for many diseases implicated metabolic disorder such as cholestasis, type 2 diabete or Non-Alcoholic Steatohepatitis (NASH). Despite promising results especially on NASH, patient treatment with FXR agonist the INT747 seems to increase LDL-Cholesterol plasma concentrations together with a decreased concentration of HDL-Cholesterol suggesting a higher risk to develop atherosclerosis. These effects on plasma lipid profile are the major break against the development of agonists in clinics. Giving the poor understanding and knowledge of the molecular mechanisms which govern FXR regulation of activity on various signaling pathways, it is of major interest to find new partners and regulators of FXR and especially on lipid and cholesterol homeostasis. One of the transcription factor known to be active in the control of these signaling pathways in the liver is the forkhead box transcription factor FOXA2. This transcription factor whose activity is dependent of physiological conditions is activated by glucagon and inhibited by insulin. In addition, this factor is known to regulate bile acid, cholesterol and lipid metabolism, functions very close from FXR activities in the liver.The objective of this PhD was to study the interaction between FXR and FOXA2 signaling pathways in different hepatic cells lines from human or mouse origin and in the liver. We established that FOXA2 and FXR are colocalised in HepG2 cells and liver chromatin near genes implicated in the lipid and cholesterol metabolism. These FXR/FOXA2 cobinding zones present few consensus FOXA2 response elements suggesting the implication of non consensus binding motifs or a “tethering” mechanism. We show that FOXA2 binding to FXR/FOXA2 cobinding zones is increased when FXR is activated and/or more present in the chromatin evoking a potential interaction between these two factors. We demonstrate that FXR and FOXA2 interact physically and that FOXA2 is a repressor of FXR transcriptional activity using different approaches and cellular models. Finally, we show that FOXA2 is implicated in glucagon-induced repression of FXR transcriptional activity on Shp gene.To conclude, our results show for the first time that the fasting key regulator of lipid and cholesterol homeostasis FOXA2 is a repressor of FXR transcriptional activity through a plausible mechanism involving “tethering” process. This work gives a novel mechanism by which FXR activity can be modified by nutritional status in a gene-specific manner