TGR is a class A GPCR transducing signal through Gs

TGR5 is a class A GPCR, transducing signal through Gs-protein mediated cAMP accumulation, and was recently reclassified as the founder member of the bile–acid receptor subclass of GPCRs [22]. The cAMP-mediated signaling of TGR5 activation has been implicated in a range of cellular physiological activities (Figure 2) and will be discussed further in detail in the review. TGR5 is expressed on the plasma membrane and is internalized into the cytoplasm in response to its agonists [19]. Of the different bile acids serving as natural endogenous ligands for the receptor, taurine-conjugated lithocholic Pam2CSK4 mg (TLCA), lithocholic acid (LCA), deoxycholic acid (DCA), chenodeoxycholic acid (CDCA) and cholic acid (CA) dose-dependently induced the accumulation of cAMP in TGR5-transfected CHO cells with the following rank order potency of—TLCA (0.33μM)>LCA (0.53μM)>DCA (1.01μM)>CDCA (4.43μM)>CA (7.72μM) but not in mock-transfected cells, independent of nuclear receptor expression [19]. A recent study conducted with a set of bile acids and its derivatives in CHO cells transfected with TGR5 and in human intestinal NCI-H716 cells, has identified some potent, selective TGR5 agonists with the following rank order of potency: 7ξ-Me-LCA (0.076μM) 7α-F-LCA (0.25μM) and CDC-Sul (0.44μM) with respective fold selectivity over FXR binding of 213, >400 and >200 [23]. Agonist potency appeared to be directly related to hydrophobicity. Ursodeoxycholic acid and cholesterol exhibit poor activity; however, pregnandione had a potency ∼50% of that of TLCA, implying the importance of hydroxyl groups, as well as 5β-cholanic acid structures in the agonistic activity on TGR5. The absence of little or no activity with (E)-([tetrahydrotetramethylnapthalenyl]propyl) benzoic acid (TTNPB), rifampicin, and 22(R)-hydroxysterol, which are potent agonists for FXR, pregnane X receptor and liver X receptor, respectively, and a difference in rank order potency of bile acids for TGR5 compared with bile acid nuclear receptors demonstrated an independent signaling pathway for bile acids through TGR5 for rapid response [19].
TGR5 and energy homeostasis Bile acids have been reported to inhibit diet-induced obesity and prevent the development of insulin resistance through their effects on regulation and expression of key genes involved in hepatic fatty acid and triglyceride biosynthesis, very low density lipoprotein production and through increased energy expenditure in metabolically active tissues in the body 24, 25, 26, 27, 28. The former effects are mediated by sterol-regulatory-element-binding protein 1c through activation of FXR-α [29]; however, energy homeostasis is maintained by the activation of TGR5 receptor [28]. The administration of bile acids to mice increased energy expenditure in brown adipose tissue (BAT) through induction of the cAMP-dependent thyroid hormone-activating enzyme, type 2 iodothyronine deiodinase (D2). Bile acid treatment of rodent BAT and human skeletal muscle cells increases D2 activity, oxygen consumption (a measure of aerobic mitochondrial oxidation) and extracellular acidification rate (a measure of glycolysis, lactate production and anaerobic metabolism) [28]. The effect was independent of nuclear bile acid receptors and was mediated through the activation of TGR5 as demonstrated by the use of highly selective synthetic agonist (benzyl 2-keto-6-methyl-4-(2-thienyl)-1,2,3,4-tetra-hydropyrimidine-5-carboxylate) for TGR5 [28]. The bile acid-TGR5-cAMP-D2 signaling pathway, therefore, represents a crucial mechanism for regulating energy homeostasis in order to improve metabolic control (Figure 3). The targeted disruption of the TGR5 (Gpbar1) gene reduced energy expenditure with increased body weight owing to accumulation of fat in homozygous mice compared with wild-type mice [30] also confirms the therapeutic importance of TGR5 as a metabolic switch to control energy homeostasis and consequent management in diet-induced obesity and insulin resistance.