Bile acid metabolism and signaling in liver disease and therapy

Abstract

Bile acids play a critical role in the regulation of glucose, lipid, and energy metabolism through activation of the nuclear bile acid receptor farnesoid X receptor (FXR) and membrane G protein-coupled bile acid receptor-1 (Gpbar-1, aka TGR5). Agonist activation of FXR and TGR5 improves insulin and glucose sensitivity and stimulates energy metabolism to prevent diabetes, obesity, and non-alcoholic fatty liver disease (NAFLD). Bile acids have both pro- and anti-inflammatory actions through FXR and TGR5 in the intestine and liver. In the intestine, bile acids activate FXR and TGR5 to stimulate stimulate fibroblast growth factor 15 and glucagon-like peptide-1 secretion. FXR and TGR5 agonists may have therapeutic potential for treating liver-related metabolic diseases, such as diabetes and NAFLD.

Keywords: Bile acid metabolism; Cholestatic liver; diseases Metabolic diseases.

Fig. 1. Bile acid synthesis pathways

Two bile acid synthesis pathways are involved in the conversion of cholesterol to bile acids in the liver. The classic pathway is initiated by cholesterol 7α-hydroxylase (CYP7A1), and the alternative pathway is initiated by steroid 27-hydroxylase (CYP27A1). 3β-hydroxysteroid dehydrogenase (3β-HSD) converts 7α-hydroxycholesterol to 7α-hydroxy-4-cholesten-3-one (C4). Serum C4 level has been used as a marker for the rate of bile acid synthesis. Sterol 12-hydroxylase (CYP8B1) is a branch enzyme that synthesizes cholic acid (CA). Without 12α-hydroxylation, chenodeoxycholic acid (CDCA) is synthesized. Mitochondrial CYP27A1 catalyzes oxidation of the steroid side chain, and the peroxisomal β-oxidation reaction cleaves a 3C unit to form C24 cholestenoic acid, the backbone of most bile acids. CA and CDCA are the two primary bile acids synthesized in human liver. In mice, CDCA is converted to α- and β-muricholic acids (α-MCA and β-MCA, respectively). Bile acids are immediately conjugated to the amino acids taurine or glycine (TCA or TCDCA, respectively) for secretion into bile. In the ileum, TCA and TCDCA are deconjugated by bacterial bile salt hydrolase (BSH) activity, and the 7α-hydroxyl group is removed by bacterial 7α-dehydroxylase activity to form deoxycholic acid (DCA) and lithocholic acid (LCA), respectively. Bile acids (TCA, TDCA, TCDCA, Tα-MCA, and Tβ-MCA) are re-conjugated and circulated back to the liver. LCA is secreted into feces, and a small amount is circulated to the liver, conjugated to sulfite, and secreted into urine.

Fig. 2. Bile acid metabolism

A. Primary bile acids are metabolized to other bile acids in the liver and intestine. In mice, CDCA is converted to α-MCA, β-MCA, and ω-MCA. In humans and mice, CDCA can be converted to ursodeoxycholic acid (UDCA) or hyocholic acid. UDCA can be 7-dehydroxylated to LCA, which can be hydroxylated to hyodeoxycholic acid and muricholic acid. B. Bile acids can be conjugated to the amino acids taurine or glycine at the C₂₄OOH group by bile acid Co-A synthase (BACS) and bile acid amino transferase (BAAT). Sulfotransferase (SULT2A1) transfers a sulfate to the 3β-HO position. UDP-glucuronosyltransferase (UGT) transfers a glucuronide group to the C₃-OH, C₇-OH, and C₂₄-OOH groups. In the intestine, FXR induces fibroblast growth factor (FGF) 15, which is secreted into portal circulation to activate the FGF receptor 4/β-klotho complex, which activates ERK1/2 and JNK of the MAPK pathway to inhibit bile acid synthesis.

Fig. 3. Mechanisms of bile acid feedback inhibition of bile acid synthesis

Two mechanisms have been proposed for bile acid feedback inhibition of CYP7A1, CYP8B1, and bile acid synthesis. In the liver, FXR induces small heterodimer partner (SHP), a negative nuclear receptor, to inhibit CYP7A1 and CYP8B1 gene transcription. Bile acids are excreted into bile via canalicular bile salt export pump (BSEP). In the ileum, apical sodium-dependent bile salt transporter (ASBT) reabsorbs bile acids into enterocytes, and the bile acids are then secreted into portal circulation via sinusoidal organic solute transporter α/β (OSTαβ). Bile acids are transported into hepatocytes via Na²⁺-dependent taurocholate co-transport peptide (NTCP) located on the sinusoidal membrane. This EHC of bile acids from the intestine to the liver inhibits bile acid synthesis and maintains bile acid homeostasis. In the intestine, bile acid-activated FXR induces fibroblast growth factor (FGF) 15 to activate FGF receptor (FGFR4)/β-Klotho signaling, which inhibits CYP7A1 gene transcription via JNK and ERK1/2 MAPK pathways. Antagonism of FXR activity by T-βMCA reduces FGF15, thus increasing CYP7A1 expression and bile acid synthesis. The secondary bile acids produced in the colon, LCA and DCA, activate intestinal TGR5 to activate cAMP signaling, which stimulates glucagon-like peptide-1 (GLP-1) secretion from enteroendocrine L cells.