TGR5-Mediated Bile Acid Sensing Controls Glucose Homeostasis

Institut de Génétique et Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 67404 Illkirch, France.
Cell metabolism (Impact Factor: 17.57). 10/2009; 10(3):167-77. DOI: 10.1016/j.cmet.2009.08.001
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TGR5 is a G protein-coupled receptor expressed in brown adipose tissue and muscle, where its activation by bile acids triggers an increase in energy expenditure and attenuates diet-induced obesity. Using a combination of pharmacological and genetic gain- and loss-of-function studies in vivo, we show here that TGR5 signaling induces intestinal glucagon-like peptide-1 (GLP-1) release, leading to improved liver and pancreatic function and enhanced glucose tolerance in obese mice. In addition, we show that the induction of GLP-1 release in enteroendocrine cells by 6alpha-ethyl-23(S)-methyl-cholic acid (EMCA, INT-777), a specific TGR5 agonist, is linked to an increase of the intracellular ATP/ADP ratio and a subsequent rise in intracellular calcium mobilization. Altogether, these data show that the TGR5 signaling pathway is critical in regulating intestinal GLP-1 secretion in vivo, and suggest that pharmacological targeting of TGR5 may constitute a promising incretin-based strategy for the treatment of diabesity and associated metabolic disorders.

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Available from: Antonio Macchiarulo, Oct 03, 2015
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    • "From a mechanistically viewpoint, bile acids may play a role in the development of HCC, for example, by the production reactive oxygen species, thereby producing oxidative stress and DNA damage (Baptissart et al, 2013). Some of the bile acids have also been described as versatile signalling molecules (Thomas et al, 2008, 2009; Gadaleta et al, 2011), for instance, lithocholic acid and DCA are both involved in the promotion of energy expenditure and participation in glucidic metabolism by acting on the G-protein-coupled receptor TRG5 (Baptissart et al, 2013). "
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    ABSTRACT: Materials and Methods Discussion and conclusion References Figures and TablesHepatocellular carcinoma (HCC) ranks third in overall global cancer-related mortality. Symptomatic presentation often means advanced disease where potentially curative treatment options become very limited. Numerous international guidelines propose the routine monitoring of those with the highest risk factors for the condition in order to diagnose potential tumourigenesis early. To aid this, the fields of metabonomic- and proteomic-based biomarker discovery have applied advanced tools to identify early changes in protein and metabolite expression in HCC patients vs controls. With robust validation, it is anticipated that from these candidates will rise a high-performance non-invasive test able to diagnose early HCC and related conditions. This review gathers the numerous markers proposed by studies using mass spectrometry and proton nuclear magnetic resonance spectroscopy and evaluates areas of consistency as well as discordance.
    British Journal of Cancer 03/2015; 112(7):1141-1156. DOI:10.1038/bjc.2015.38 · 4.84 Impact Factor
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    • "In biological systems, effects of bile salts are based on their surface activity (formation of micelles, mixed micelles with phospholipids, solubilization of cholesterol, solubilization and emulgation of lipid components of food) [11] [12] [13] or on their regulatory potential towards some enzymatic reactions and transport processes through binding to proteins (farnesoid X (FXR); G-protein-coupled receptors (GPCRs); TGR5 (GPBAR1, M-BAR and BG37); large conductance Ca 2+ -activated K + channel (BK Ca ), etc.) [1,14–16]. This gave rise to the increasing application of bile acid derivatives as therapeutics in metabolic disorders [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29]. "
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    ABSTRACT: Bile salts are steroidal biosurfactants. Micellar systems of bile salts are not only important for solubilisation of cholesterol, but they interact with certain drugs changing thus their bioavailability. The number-average aggregation numbers (n¯) are determined using Moroi-Matsuoka-Sugioka thermodynamic method. Critical micellar concentrations were determined by spectrofluorometric method using pyren and by surface tension measurements. Micelles of ethylidene derivatives posess folowing values for n¯: 7-Eth-D (n¯=11 (50mM) - n¯=14.8 (100mM); 12-Ox-7-Eth-L (n¯≈8.8, without concentration dependence) and 7,12-diOx-3-Eth-Ch (n¯≈2.9,without concentration dependence). In the planes n¯ - ln k and ln CMC - ln k derivative 7-Eth-D is outlier in respect to hydrophobic linear congeneric groups. Gibbs energy of formation for 7-Eth-D anion micelles in adition to the Gibbs energy of hydrophobic interactions consist excess Gibbs energy (G(E)) from hydrogen bond formation between building blocks of micelles. Gibbs energy of formation for 12-diOx-3-Eth-Ch and 12-Ox-7-Eth-L anion micelle is determined by the Gibbs energy of hydrophobic interactions. Relative increase in hydrophobicity and aggregation number for ethylidene derivatives is larger when ethylidene group is introduced from C7 lateral side of steroidal skeleton then it is when ethylidene group is on C3 carbon. Position of outlier towards hydrophobic congeneric groups from n¯ - ln k and ln CMC - ln k planes indicates the existence of excess Gibbs energy (G(E)) which is not of hydrophobic nature (formation of hydrogen bonds). For the bile salts micelles to have G(E) (formation of secondary micelles) it is necessary that steroidal skeleton possess C3-α-(e)-OH and C12-α-(a)-OH groups. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 03/2015; 1850(7). DOI:10.1016/j.bbagen.2015.03.010 · 4.66 Impact Factor
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    • "Please cite this article in press as: Sombetzki M et al. 24-nor-ursodeoxycholic acid ameliorates inflammatory response and liver fibrosis in a murine model of hepatic schistosomiasis. J Hepatol (2015), (norUDCA) [6], were identified as promising new treatment options for common and important diseases such as arteriosclerosis , metabolic syndrome, and liver fibrosis [7] [8] [9], which has fostered a rebirth of bile acid research [10] [11]. Data obtained in Abcb4/Mdr2 À/À (canalicular phospholipid export pump/multidrug resistance protein 2) mice, representing a well characterized model system for sclerosing cholangitis and biliary type of liver fibrosis, suggest potential direct anti-inflammatory and antifibrotic effects of norUDCA [6] [12] [13]. "
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    ABSTRACT: Intrahepatic granuloma formation and fibrosis characterize the pathological features of Schistosoma mansoni (S.m.) infection. Based on previously observed substantial anti-fibrotic effects of 24-nor-ursodeoxycholic acid (norUDCA) in Abcb4/Mdr2(-/-)mice with cholestatic liver injury and biliary fibrosis, we hypothesized that norUDCA improves inflammation-driven liver fibrosis in S.m. infection. Adult NMRI mice were infected with 50 S.m. cercariae and after 12 weeks received either norUDCA- or ursodeoxycholic acid (UDCA)-enriched diet (0.5% wt/wt) for 4 weeks. Bile acid effects on liver histology, serum biochemistry, key regulatory cytokines, hepatic hydroxyproline content as well as granuloma formation were compared to naive mice and infected controls. In addition, effects of norUDCA on, primary T-cell activation/proliferation and maturation of the antigen-presenting-cells (dendritic cells, macrophages) were determined in vitro. UDCA as well as norUDCA attenuated the inflammatory response in livers of S.m. infected mice but exclusively norUDCA changed cellular composition and reduced size and of hepatic granulomas as well as TH2-mediated hepatic fibrosis in vivo. Moreover norUDCA affected surface expression level of major histocompatibility complex (MHC) class II of macrophages and dendritic cells as well as activation/proliferation of T-lymphocytes in vitro, whereas UDCA had no effect. This study demonstrates pronounced anti-inflammatory and anti-fibrotic effects of norUDCA compared to UDCA in S.m. induced liver injury and indicates that norUDCA directly represses antigen presentation of antigen presenting cells and subsequent T-cell activation in vitro. Therefore norUDCA represents a promising drug for the treatment of this important cause of liver fibrosis. Copyright © 2014. Published by Elsevier B.V.
    Journal of Hepatology 11/2014; DOI:10.1016/j.jhep.2014.11.020 · 11.34 Impact Factor
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