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
Source: PubMed


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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    • "TGR5 activation in brown adipose tissue increases type 2 iodothyronine deiodinase, which converts T 4 to the active T 3 , which increases energy expenditure (Watanabe et al., 2006). TGR5 activation in the enteroendocrine cells of the intestine increases glucagon-like peptide-1 (GLP-1) secretion (Katsuma et al., 2005; Thomas et al., 2009). Patients treated with a BA-binding resin to reduce cholesterol levels also have improved glycemic control, and these BA-binding resins also improved hyperglycemia in rodent models of obesity (Kobayashi et al., 2007; Chen et al., 2010). "
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    ABSTRACT: It is known that (1) elevated serum bile acids (BAs) are associated with decreased body weight, (2) elevated GLP-1 levels can decrease body weight, and (3) germ-free (GF) mice are resistant to diet-induced obesity. The purpose of this study was to test the hypothesis that lack of intestinal microbiota results in more BAs in the body, resulting in increased BA mediated TGR5 signaling and increased serum GLP-1, as a mechanism of resistance of GF mice to diet-induced obesity. GF mice had 2-4 fold increased total BAs in serum, liver, bile, and ileum. Fecal excretion of BAs was 63% less in GF mice. GF mice had decreased secondary BAs and increased taurine-conjugated BAs, as anticipated. There was an increase in non-12α-OH BAs, namely β-muricholic acid (βMCA), ursodeoxycholic acid (UDCA) and their taurine conjugates in GF mice. Further, in vitro experiments confirmed that UDCA is a primary BA in mice. There were minimal changes in mRNA of FXR target genes in ileum (Fgf15, SHP, Ibabp), in liver (SHP, Lrh-1, Cyp7a1), and BA transporters (Asbt, Ostα, Ostβ) in ileum of GF mice. Surprisingly, there were marked increases in BA transporters in large intestine. Increased GLP-1 levels and gallbladder size were observed in GF mice, suggesting activation of TGR5 signaling. In summary, the GF condition results in increased expression of BA transporters in colon, resulting in an (1) increase in total BA concentrations in tissues, (2) change in BA composition to favor an increase in non-12α-OH BAs, and (3) activation of TGR5 signaling with increased gallbladder size and GLP-1. The American Society for Pharmacology and Experimental Therapeutics.
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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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    • "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.
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