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Review
. 2020 Mar 1;318(3):G554-G573.
doi: 10.1152/ajpgi.00223.2019. Epub 2020 Jan 27.

Bile acid receptors FXR and TGR5 signaling in fatty liver diseases and therapy

John Y L Chiang  1 , Jessica M Ferrell  1
Affiliations
Review

Bile acid receptors FXR and TGR5 signaling in fatty liver diseases and therapy

John Y L Chiang et al. Am J Physiol Gastrointest Liver Physiol. .

Abstract

Bile acid synthesis is the most significant pathway for catabolism of cholesterol and for maintenance of whole body cholesterol homeostasis. Bile acids are physiological detergents that absorb, distribute, metabolize, and excrete nutrients, drugs, and xenobiotics. Bile acids also are signal molecules and metabolic integrators that activate nuclear farnesoid X receptor (FXR) and membrane Takeda G protein-coupled receptor 5 (TGR5; i.e., G protein-coupled bile acid receptor 1) to regulate glucose, lipid, and energy metabolism. The gut-to-liver axis plays a critical role in the transformation of primary bile acids to secondary bile acids, in the regulation of bile acid synthesis to maintain composition within the bile acid pool, and in the regulation of metabolic homeostasis to prevent hyperglycemia, dyslipidemia, obesity, and diabetes. High-fat and high-calorie diets, dysbiosis, alcohol, drugs, and disruption of sleep and circadian rhythms cause metabolic diseases, including alcoholic and nonalcoholic fatty liver diseases, obesity, diabetes, and cardiovascular disease. Bile acid-based drugs that target bile acid receptors are being developed for the treatment of metabolic diseases of the liver.

Keywords: Takeda G protein-coupled receptor 5; alcoholic and nonalcoholic fatty; bile acid metabolism; bile acid therapies; farnesoid X receptor; liver diseases.

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Conflict of interest statement

No conflicts of interest, financial or otherwise, are declared by the authors.

Figures

None
Graphical abstract
Fig. 1.
Fig. 1.
Bile acid synthesis in the liver. The classic bile acid synthesis pathway is initiated by cholesterol 7α-hydroxylase (CYP7A1). Sterol 12α-hydroxylase (CYP8B1) is involved in synthesis of cholic acid (CA), and mitochondrial sterol 27-hydroxylase (CYP27A1) catalyzes steroid side-chain oxidation. CA and chenodeoxycholic acid (CDCA) are the two major primary bile acids synthesized in the human liver. Bile acid-CoA synthase (BACS) catalyzes the addition of a CoA group and then bile acid-CoA-to-amino acid transferase (BAAT) adds taurine (T) or glycine (G) to form T/G-conjugated bile acids for secretion in bile. The alternative bile acid synthesis pathway is initiated by hydroxylation of the steroid side chain, followed by steroid ring modifications. In the liver, cholesterol is hydroxylated by sterol 25-hydroxylase and CYP27A1 to form 25-hydroxycholesterol and 27-hydroxycholesterol [also named 25(R)-26-hydroxycholesterol], respectively, which are then hydroxylated at the 7α-position by oxysterol 7α-hydroxylase (CYP7B1). CYP27A1 and CYP7B1 are widely expressed in macrophages, adrenal glands, and other tissues. In the brain, sterol 24-hydroxylase (CYP46A1) converts cholesterol to 24-hydroxycholesterol, which is 7α-hydroxylated by sterol 7α-hydroxylase (CYP39A1) in the liver. In mice, CDCA is converted to α-muricholic acid (MCA) and β-MCA by Cyp2c70.
Fig. 2.
Fig. 2.
Bile acid transformation in the gut. The primary bile acids are transformed to secondary bile acids by gut bacteria. Bile salt hydroxylase (BSH) deconjugates glycine (G)/taurine (T)-conjugated bile acids, then bacterial 7α-dehydroxylase removes a 7α-HO group from chloric acid (CA) and chenodeoxycholic acid (CDCA) to form deoxycholic acid (DCA) and lithocholic acid (LCA), respectively. CDCA is converted to ursodeoxycholic acid (UDCA) by 7β-hydroxysteroid dehydrogenase (7βHSDH). UDCA can be converted to LCA by 7β-dehydroxylase. In mouse liver, CDCA and UDCA are converted to α-muricholic acid (MCA) and β-MCA by Cyp2c70, and β-MCA is converted to ω-MCA by 6β-epimerase by the gut bacteria. CDCA also can be converted to hyocholic acid by 7α-epimerase in human and pig livers. In mice, LCA can be hydroxylated to hyodeoxycholic acid (HDCA) and murideoxycholic acid (MDCA). DCA and LCA can by rehydroxylated to CA and CDCA, respectively, in mouse liver. Bile acid hydrophobicity index is shown at the bottom.
Fig. 3.
Fig. 3.
Farnesoid X receptor (FXR) regulation of bile acid homeostasis. In hepatocytes, activation of FXR induces small heterodimer partner (SHP) to inhibit cholesterol 7α-hydroxylase (CYP7A1) and sterol 12α-hydroxylase (CYP8B1) gene transcription. FXR induces bile salt expert pump (BSEP) to efflux bile acids into bile. ATP-binding cassette (ABC) G5/ABCG8 heterodimer effluxes cholesterol, whereas multidrug resistant (MDR) 3 effluxes phospholipids into bile. Bile acids, cholesterol, and phospholipids form mixed micelles. In the intestinal lumen, gut bacterial bile salt hydrolase (BSH) deconjugates taurine (T)/glycine (G) chenodeoxycholic acid (CDCA) and T/G cholic acid (CA) and bacterial 7α-dehydroxylase removes a 7α-HO group to form deoxycholic acid (DCA) and lithocholic acid (LCA), respectively. Bile acids are reabsorbed into enterocytes via apical sodium-dependent bile acid transporter (ASBT), which is inhibited by bile acids. In enterocytes, FXR induces ileum bile acid binding protein (IBABP) and organic solute transporter heterodimer (OST) α and OSTβ to efflux bile acids into portal blood circulation. DIET1 is coexpressed with FGF15 in enterocytes and modulates FGF15 levels, bile acid secretion, and bile acid pool size. FXR also induces FGF19, which binds to hepatic FGF receptor (FGFR) 4/β-Klotho complex to activate ERK1/2 and inhibit CYP7A1 gene transcription. FXR and Takeda G protein-coupled receptor 5 (TGR5) are coexpressed in enteroendocrine L cells; FXR induces TGR5 to activate cAMP and intracellular Ca2+ to secrete glucagon-like peptide-1 (GLP-1), which stimulates insulin secretion from pancreatic β cells. AC, adenylyl cyclase; BAAT, bile acid-CoA-to-amino acid transferase; BACS, bile salt CoA-synthase; CYP27A1, sterol 27-hydroxylase; CYP7B1, oxysterol 7α-hydroxylase; MRP, MDR-related protein; NTCP, sodium/taurocholate cotransporting polypeptide.
Fig. 4.
Fig. 4.
Bile acids (BAs) in the gut-liver-brain axis and circadian rhythms. Circadian rhythms are generated and maintained by the suprachiasmatic nucleus (SCN) via rhythmic transcription and translation of core clock genes. Clock and Bmal1 induce Period (Per) and Cryptochrome (Cry), which feed back to inhibit Clock/Bmal1. All peripheral organs have molecular clocks that are synchronized to the SCN to regulate rhythms in lipid, glucose, and cholesterol metabolism, as well as cholesterol 7α-hydroxylase (CYP7A1) expression in the liver. In the gastrointestinal (GI) tract, gut bacteria metabolize bile acids, which control bacterial overgrowth. Dysbiosis, caused by circadian disruption, alcohol, or high-fat diets, impairs intestinal barrier function and causes inflammation. Dysbiosis also contributes to obesity, fatty liver, and type 2 diabetes mellitus. In the gut-to-brain axis, glucagon-like peptide-1 (GLP-1), FGF19, and bile acids mediate signaling cross-talk between the gut and brain, and FGF21 and bile acids mediate signaling cross-talk between the brain and liver.
Fig. 5.
Fig. 5.
Nutrient regulation of bile acid synthesis and hepatic metabolism. Feeding rapidly induces cholesterol 7α-hydroxylase (CYP7A1) but inhibits sterol 12α-hydroxylase (CYP8B1) expression to increase bile acid synthesis and aid in nutrient absorption during the postprandial state. Stimulating bile acid synthesis induces hepatic autophagy via insulin/AKT signaling to inhibit the mammalian target of rapamycin complex 1 (mTORC1). Farnesoid X receptor (FXR) activates insulin receptor substrate 1-AKT (protein kinase B) signaling to inhibit mTORC1/pS6K-signaling to promote nuclear translocation of sterol regulatory element binding protein 1c (nSREBP-1c) and lipogenesis. During the postprandial state, glucose is transported to enterocytes via the sodium-glucose-cotransporter 2. Chenodeoxycholic acid (CDCA) activates FXR in enteroendocrine L cells to induce Takeda G protein-coupled receptor 5 (TGR5) signaling and stimulate glucose-induced glucagon-like peptide-1 (GLP-1) secretion via increased intracellular cAMP and Ca2+. GLP-1 promotes insulin secretion from pancreatic β cells and increases insulin sensitivity. Activation of TGR5 in brown adipose tissue stimulates energy metabolism and the conversion of thyroxine to 3,5,3′-triiodothyronine. In the late post-prandial state to postabsorptive state, intestinal FXR induces FGF19, which activates hepatic FGF receptor (FGFR) 4-ERK1/2 signaling to inhibit bile acid synthesis. FGF19 regulates glucose metabolism, glycogen synthesis, and protein synthesis when insulin levels are decreased. In the intestine, activation of FXR induces ceramide synthesis. Ceramides activate mTORC1 signaling to induce SREBP-1c-mediated lipogenesis and induce ER stress and ROS to cause insulin resistance. During prolonged fasting or starvation, CYP7A1 expression and bile acid synthesis is reduced, but CYP8B1 is induced to increase chloric acid (CA) synthesis and deoxycholic acid (DCA) content in the colon, promoting ceramide synthesis and SREBP-1c-mediated lipogenesis. Increasing free fatty acids activate peroxisome proliferator-activated receptor (PPAR) α and PPARγ coactivator protein-1α (PGC-1α) to stimulate FGF21 production in liver and adipose tissue. As an adaptation to prolonged fasting to maintain metabolic homeostasis, increased FGF21 stimulates glucose and energy metabolism independent of insulin. FGF21 reduces serum triglycerides by stimulating energy metabolism in adipose tissue. FGF21 also inhibits mTORC1 signaling to improve insulin sensitivity and reduce hepatic steatosis. Green arrows indicate changes in the postprandial state and red arrows indicate changes in the fasting state. ABST, apical sodium-dependent bile acid transporter AC, adenylyl cyclase; CREB, cAMP response element binding protein; DIO2, deiodinase type 2; IRS1, insulin-resistant substrate 1; LCA, lithocholic acid; PDK, phosphoinositide-dependent kinase; PI3K, phosphoinositide 3-kinase; TG, triglycerides.
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