Discovery of farnesoid X receptor and its role in bile acid metabolism

Abstract

In 1995, the nuclear hormone orphan receptor farnesoid X receptor (FXR, NR1H4) was identified as a farnesol receptor expressed mainly in liver, kidney, and adrenal gland of rats. In 1999, bile acids were identified as endogenous FXR ligands. Subsequently, FXR target genes involved in the regulation of hepatic bile acid synthesis, secretion, and intestinal re-absorption were identified. FXR signaling was proposed as a mechanism of feedback regulation of the rate-limiting enzyme for bile acid synthesis, cholesterol 7⍺-hydroxylase (CYP7A1). The primary bile acids synthesized in the liver are transformed to secondary bile acids by the gut microbiota. The gut-to-liver axis plays a critical role in the regulation of bile acid synthesis, composition and circulating bile acid pool size, which in turn regulates glucose, lipid, and energy metabolism. Dysregulation of bile acid metabolism and FXR signaling in the gut-to-liver axis contributes to metabolic diseases including obesity, diabetes, and non-alcoholic fatty liver disease. This review will cover the discovery of FXR as a bile acid sensor in the regulation of bile acid metabolism and as a metabolic regulator of lipid, glucose, and energy homeostasis. It will also provide an update of FXR functions in the gut-to-liver axis and the drug therapies targeting bile acids and FXR for the treatment of liver metabolic diseases.

Keywords: Bile acid receptors; Cholestasis; FXR; Fatty liver diseases; Metabolic disease.

Fig. 1.

Farnesoid X receptor (FXR) is a member of nuclear receptor superfamily. The domain structure of nuclear receptors is shown. Nuclear receptor superfamily consists of 48 nuclear receptors, which can be separated into three types based on ligand identity and 7 groups based on nucleotide sequence alignment. Nuclear receptor binds to the hormone response element, arranged as direct repeat (DR), everted repeat (ER) or inverted repeat (IR) as a monomer or homodimer, or heterodimer with RXR in the gene promoter. Without ligand binding, nuclear receptor binds co-repressors and is inactive. Upon ligand binding, co-repressors are released to allow recruitment of co-activators to stimulate RNA polymerase II transcriptional activity.

Fig. 2.

Bile acid synthesis and the role of FXR in the regulation of bile acid synthesis in hepatocytes and in the enterohepatic circulation of bile acids. Cholesterol is converted to cholic acid (CA) and chenodeoxycholic acid (CDCA) in human liver. The classic pathway is initiated by cholesterol 7α-hydroxylase (CYP7A1), while the alternative pathway is initiated by sterol 27-hydroxylase (CYP27A1) and followed by oxysterol 7α-hydroxylase (CYP7B1). Sterol 12α-hydroxylase (CYP8B1) catalyzes cholic acid (CA) synthesis. In mouse liver, CDCA is converted to α- and β-muricholic acids (αMCA and βMCA) by Cyp2c70 as primary bile acids. Details of bile acid synthesis pathway and enzymes are described in the text. Major regulatory enzymes are shown. CA and CDCA are conjugated to taurine (T) or glycine (G) and secreted into bile. Bile acids are reabsorbed in the ileum. In the colon, gut bacteria bile salt hydrolase (BSH) de-conjugates bile acids and 7α-dehydroxylase (7α-DH) converts CA and CDCA to deoxycholic acid (DCA) and lithocholic acid (LCA), respectively. Bile acids activate FXR, which plays a critical role in regulation of bile acid synthesis. Activation of FXR inhibits CYP7A1 and CYP8B1 through two pathways. In the liver, FXR induces SHP to inhibit CYP7A1 and CYP8B1 gene transactivation by HNF4α and LRH-1 (Pathway 1). In the intestine, FXR induces fibroblast growth factor 19 (FGF19), which activates hepatic FGF receptor 4 (FGFR4)/β-Klotho signaling mainly via ERK1/2 to inhibit CYP7A1 gene transcription (Pathway 2). FXR induces bile salt export pump (BSEP) to efflux bile acids into bile. ATP binding cassette G5 and G8 (ABCG5/G8) effluxes cholesterol and multidrug resistant protein 2/3 (MDR2/3) effluxes phospholipids into bile to form mixed micelles with bile acids. MDR related protein 2/3 (MRP2/3) effluxes bilirubin and glutathione-conjugated bile acids. In the enterocyte of ileum, bile acids are reabsorbed via apical sodium-dependent bile acid transporter (ASBT), which is inhibited by bile acids and FXR. FXR induces intestine bile acid binding protein (IBABP), which binds and transports bile acids across the enterocyte to the sinusoidal membrane to be secreted to portal blood via the organic solute transporter α/β (OSTα/OSTβ) dimer, which are induced by FXR. Bile acids circulated to the liver are taken up by hepatic sodium-dependent taurocholate co-transporting peptide (NTCP), which is inhibited by bile acids via short heterodimer partner (SHP). Organic anion transporting peptides (OATPs) and MRP4 uptake bile acids to hepatocytes independent of sodium. At the sinusoidal membrane, FXR induces OSTα/OSTβ or MRP4 (induced in cholestasis) to efflux bile acids into systemic blood circulation. (+) indicates stimulation, (−) indicates inhibition.

Fig. 3.

The role of FXR signaling in metabolic regulation. In hepatocytes, activation of FXR inhibits bile acid synthesis and reduces bile acid pool size; reduces ApoA1 and HDL and reverse cholesterol transport by scavenger receptor b1 (Srb1) and apoptosis; reduces fatty acid uptake via CD36, lipogenesis and VLDL secretion and increases triglyceride clearance; reduces postprandial glucose by reducing glycolysis and stimulate fasting gluconeogenesis and glycogen synthesis. In Kupffer cells and macrophages, activation of FXR reduces liver inflammation and nonalcoholic steatohepatitis (NASH) fibrosis and primary biliary cholangitis (PBC). In adipose tissue, activation of FXR stimulates adipose tissue browning and energy metabolism. In the intestine, activation of FXR reduces NFκB and inflammatory cytokines, protects barrier function, induces FGF19 and ceramides productions, and glucagon-like peptide-1 (GLP-1) secretion. GLP-1 stimulates insulin secretion and increases insulin sensitivity in pancreatic β cells, where activation of FXR also stimulates insulin synthesis and improves insulin sensitivity.

Fig. 4.

The role of TGR5 signaling in different tissues and organs. In adipose tissue, activation of TGR5 induces cAMP to induce type 2 deiodinase (DIO2) to synthesis T3 and stimulates energy metabolism, and adipose tissue beiging and browning. In enteroendocrine L cells in ileum and colon, activation of TGR5 stimulates GLP-1 secretion to improve insulin sensitivity. In cholangiocyte, activation of TGR5 and S1PR2 stimulates proliferation and inflammation and primary sclerosing cholangitis (PSC), PBC and cholangiocarcinoma (CCA). In monocyte and macrophage, activation of TGR5 reduces NF-kB and Nrlp3 inflammasome, inflammatory cytokine production and M1 to M2 switch. In muscle, activation of TGR5 induces nitric oxide and smooth muscle relaxation and reduces inflammation and atherosclerosis. In the brain, TGR5 reduce satiety, inflammation, and oxidative stress. In the gallbladder, activation of TGR5 stimulates gallbladder refiling. In the intestine, activation of TGR5 reduces NF-kB inflammation and prevents colitis, IBD and colon cancer.