Modulating bile acid pathways and TGR5 receptors for treating liver and GI diseases

Abstract

Bile acids are central signals in enterohepatic communication and also integrate microbiota-derived signals into this signaling axis. Discovery of the tissue distribution and signaling pathways activated by the natural receptors for bile acids, farnesoid X receptor and G protein-coupled bile acid receptor 1 (GPBAR1) also known as TGR5, and bile acid transporters has led to the development of therapeutic agents that target these molecules. Obeticholic acid, a selective FXR agonist, and NGM282, a non-mitogenic FGF-19 analog, are two of the agents in this pipeline. Obeticholic acid has been approved by regulatory agencies for use in patients with primary biliary cholangitis.

Figure 1. Synthesis, secretion and enterohepatic circulation of bile acids in humans

(1) Primary bile acids (BAs) are synthesized in hepatocytes from cholesterol. (2) BAs are conjugated to glycine and taurine and are stored in the gallbladder at high concentrations. (3) After feeding, conjugated BAs are secreted in the intestine where they emulsify dietary fats and form mixed micelles that facilitate digestion and absorption of the products of triglyceride digestion. (4) Conjugated BAs are actively absorbed by the apical sodium BA co-transporter (ASBT [IBAT]) at the apical membrane of enterocytes of the terminal ileum. (5) In the colon, bacteria deconjugate and dehydroxylate primary BAs to form secondary BAs, which are passively absorbed. (6) Conjugated and unconjugated BAs enter the portal vein and recirculate to the liver for re-use. Reproduced with permission from ref. , Bunnett NW. Neuro-humoral signalling by bile acids and the TGR5 receptor in the gastrointestinal tract. J Physiol 2014; 592:2943–2950.

Figure 2. Bile acid induced FXR and TGR5 signaling in hepatocytes and cholangiocytes

The farnesoid X receptor (FXR) is expressed in hepatocytes and cholangiocytes. Of the natural bile acids, chenodeoxycholic acid (CDCA), most potently activates FXR leading to the induction of small heterodimer protein (SHP) and inhibition of cytochrome P450 (CYP) 7A1 and CYP8B1 and negative feedback regulation of bile acid synthesis from cholesterol. FXR stimulated FGF-19 (Fgf15 in mice) from enterocytes activates fibroblast growth factor 4 (FGFR4) and β klotho leading to inhibition of CYP7A1 and CYP8B1. Bile acids activation of FXR also inhibits lipogenesis and FGF19 inhibits lipogenesis and gluconeogenesis. Though FXR is expressed on cholangiocytes its biologic relevance is less well defined. Lithocholic acid (LCA) activates TGR5 which is expressed on cholangiocytes, and not on hepatocytes. TGR5 activation leads to an increase in intracellular cyclic AMP (cAMP) and bicarbonate secretion. *TGR5 activation leads to cholangiocyte proliferation, except in the case of ciliated cholangiocytes, where proliferation is inhibited. NTCP, sodium taurocholate cotransporting polypeptide. BSEP, bile salt export pump.

Figure 3. Role of BAs in the control of metabolic and immune homeostasis via activation of their receptors FXR and TGR5

COX, cyclooxygenase; IDL, intermediary density lipoprotein; IL, interleukin; Lp, lipoprotein; Lp(a), lipoprotein (a); VLDL, very-low-density lipoprotein. Reproduced with permission from ref. , Chavez-Talavera O, et al. Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia and nonalcoholic fatty liver disease. Gastroenterology 2017;152:1679–1694.