Role of TGR5 in Bile Acid Metabolism

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dc.contributor.advisorMangelsdorf, David J.en
dc.creatorLi, Tingtingen
dc.date.accessioned2011-08-26T17:32:23Z
dc.date.available2011-08-26T17:32:23Z
dc.date.issued2011-08-10
dc.description.abstractTGR5 is a G protein-coupled bile acid receptor present in various tissues in the body. Its agonism increases energy expenditure and lowers blood glucose. Thus, it is an attractive drug target for treating human metabolic disease. However, TGR5 is highly expressed in the gallbladder, where its function is less well-characterized. In addition, Tgr5-/- mice are resistant to cholesterol gallstone disease (CGD), although the mechanism is poorly understood. Here, we demonstrate that TGR5 stimulates the filling of the gallbladder with bile. Gallbladder volume was increased in wild-type (WT) but not Tgr5-/- mice by administration of either the naturally-occurring TGR5 agonist, lithocholic acid (LCA), or the synthetic TGR5 agonist, INT-777. This effect did not require the presence of fibroblast growth factor-15, an enteric hormone previously shown to stimulate gallbladder filling. Ex vivo analyses using gallbladder tissue showed that TGR5 activation increased cAMP concentrations and caused smooth muscle relaxation in a TGR5-dependent manner. These data reveal a novel, gallbladder-intrinsic mechanism for regulating gallbladder contractility. Further, a markedly decreased cholic acid/muricholic acid ratio was observed in Tgr5-/- mice, indicating increased hydrophobicity in the bile acid pool. Dysregulation of the expression of genes involved in bile acid transport were also observed. Our findings further suggest that TGR5 agonists should be assessed for effects on bile acid metabolism as these agonists are developed for treating metabolic disease. Potential mechanisms for TGR5 regulation of these different physiological and pathological processes are discussed.en
dc.identifier.oclc758978990
dc.identifier.urihttps://hdl.handle.net/2152.5/869
dc.language.isoenen
dc.subjectReceptors, G-Protein-Coupleden
dc.subjectGallbladderen
dc.titleRole of TGR5 in Bile Acid Metabolismen
dc.typeThesisen
dc.type.materialTexten
thesis.date.available2013-08-10
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineCell Regulationen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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