Mechanism of action of the bile acid receptor TGR5 in obesity

Abstract

G protein-coupled receptors (GPCRs) are a large family of membrane protein receptors, and Takeda G protein-coupled receptor 5 (TGR5) is a member of this family. As a membrane receptor, TGR5 is widely distributed in different parts of the human body and plays a vital role in regulating metabolism, including the processes of energy consumption, weight loss and blood glucose homeostasis. Recent studies have shown that TGR5 plays an important role in glucose and lipid metabolism disorders such as fatty liver, obesity and diabetes. With the global obesity situation becoming more and more serious, a comprehensive explanation of the mechanism of TGR5 and filling the gaps in knowledge concerning clinical ligand drugs are urgently needed. In this review, we mainly explain the anti-obesity mechanism of TGR5 to promote the further study of this target, and show the electron microscope structure of TGR5 and review recent studies on TGR5 ligands to illustrate the specific binding between TGR5 receptor binding sites and ligands, which can effectively provide new ideas for ligand research and promote drug research.

Keywords: Appetite; Bile acids; GLP-1; Inflammation; Ligand; Metabolism; Obesity; TGR5.

Graphical abstract

Figure 1

Cryogenic electron microscope structure of TGR5 complexes. (A) 23-H/TGR5 complex. Reproduced with permission from Ref. . Copyright © 2020, Springer Nature. (B) R399/TGR5 complex. Reproduced with permission from Ref. . Copyright © 2022, Proceedings of the National Academy of Sciences. (C) P395/TGR5 complex. (D) INT-777/TGR5 complex. (E) INT-777 simultaneously complexes two ligand-binding cavities at the orthosteric and allosteric sites. Reproduced with permission from Ref. . Copyright © 2020, Springer Nature.

Figure 2

Bile acid synthesis pathways. In the classical pathway, cholesterol is converted to primary bile acids. The alternative pathway is the replacement of CYP7A1 by oxysterol 27α hydroxylase, dehydrogenation of cholesterol to oxysterol, followed by 7α dehydrogenation catalyzed by oxysterol 7α hydroxylase, and then into the classical pathway. Chole acid and chenodeoxycholic acid combine with glycine or taurine to form conjugated bile acids, which are excreted into the intestinal tract through the bile duct. Abbreviation: the rate-limiting enzyme cholesterol 7α hydroxylase (CYP7A1); 7α-hydroxy-4-cholestene-3-one (C4); 3β-hydroxyΔ5-C27-steroid dehydrogenase (HSD3B7); sterol 12-hydroxylase (CYP8B1); AKR1D1 and AKR1C4; sterol 27 hydroxylase (CYP27A1); 3α,7α,12α-trihydroxy-5β-cholestanoic acid (THCA); 3α,7α-dihydroxy-5β-cholestanoic acid (DHCA); bile acid CoA: amino acid N-acyltransferase (BAAT); steroid 24-hydroxylase (CYP46A1); sterol 25-hydroxylase (CH25H); oxysterol 7α-hydroxylase (CYP7B1); hydroxy-delta-5-steroid dehydrogenase, 3β- and steroid delta-isomerase 1/2 (HSD3B1/3B2); sterol 7-hydroxylase (CYP39A1); 7β-hydroxysteroid dehydrogenase (7β-HSDH); sterol-6β-hydroxylase (Cyp2c70).

Figure 3

Enterohepatic circulation of bile acids. Primary bile acids are synthesized by cholesterol in the liver and are transported to and stored in the gallbladder. After stimulation of feeding, bile acid is excreted into the duodenum, emulsifying dietary lipids to aid absorption. Most of these bile acids circulate in the liver through reabsorption.

Figure 4

TGR5 promotes the expression of thermogenesis-related genes through cAMP–PKA–D2 signalling pathway and increases energy consumption. Abbreviation: PR domain-containing 16 (PRDM16); carnitine palmitoyltransferase 1B (CPT1B); acyl-CoA synthetase long chain family member 1 (ACSL1); patatin like phospholipase domain-containing protein 2 (PNPLA2); lipase E (LIPE).

Figure 5

TGR5 promoting browning of white adipocytes.

Figure 6

TGR5 controls appetite and regulates satiety.

Figure 7

TGR5 effectively maintains blood glucose balance and improves insulin resistance.

Figure 8

TGR5 inhibits the activation of inflammatory pathway and the secretion of inflammatory factors in macrophages through related pathways, induces M2 typing of macrophages, and effectively improves inflammatory response.