Bile Acids as Metabolic Regulators and Nutrient Sensors

Abstract

Bile acids facilitate nutrient absorption and are endogenous ligands for nuclear receptors that regulate lipid and energy metabolism. The brain-gut-liver axis plays an essential role in maintaining overall glucose, bile acid, and immune homeostasis. Fasting and feeding transitions alter nutrient content in the gut, which influences bile acid composition and pool size. In turn, bile acid signaling controls lipid and glucose use and protection against inflammation. Altered bile acid metabolism resulting from gene mutations, high-fat diets, alcohol, or circadian disruption can contribute to cholestatic and inflammatory diseases, diabetes, and obesity. Bile acids and their derivatives are valuable therapeutic agents for treating these inflammatory metabolic diseases.

Keywords: FXR; TGR5; bile acid signaling; bile acid therapy; nonalcoholic fatty liver disease.

Figure 1.

Bile acid synthesis pathways. In the liver, cholesterol is catabolized to bile acids by two pathways involving ~17 enzymes. The classic bile acid synthesis pathway is initiated by CYP7A1 in the liver, and the alternative bile acid synthesis pathway is initiated by CYP27A1 in the liver, macrophages, and adrenal glands, and CYP46A1 in the brain. Key enzymes involved in steroid ring modification, peroxisomal β-oxidation, cleavage of the steroid side chain, and bile acid conjugation are shown. In humans, CA and CDCA are the primary bile acids synthesized in the liver. In mice, Cyp2c70 converts CDCA to α- and β-MCA. In the intestine, primary bile acids undergo biotransformation. Conjugated bile acids are deconjugated by gut bacteria BSH, then bacteria 7α-dehydroxylase converts CA and CDCA to DCA and LCA, respectively. In human intestine, a small amount of CDCA can be converted to UDCA by 7β-HSDH. In mice, Cyp2c70 can also convert UDCA to β-MCA. The location of the hydroxyl group in each of the primary and secondary bile acids are indicated. Abbreviations: 7β-HSDH, 7β-hydroxysteroid dehydrogenase; ABCD3, bile acid-acyl transporter 3; ACOX2, acyl-CoA oxidase 2; AKR1D1 and AKR1C4, Δ⁴–3-oxosteroid-5β-reductase (aldo-keto reductases); AMACR, α-methylacyl-CoA racemase; BAAT: bile acid–CoA:amino acid N-acyltransferase; BSH: bile salt hydrolase; C4, 7α-hydroxy-4-cholesten-3-one; CA, cholic acid; CDCA, chenodeoxycholic acid; Cyp2c70, sterol 6β-hydroxylase; CYP7A1, cholesterol 7α-hydroxylase; CYP7B1, oxysterol 7α-hydroxylase; CYP8B1, sterol 12α-hydroxylase; CYP27A1, sterol 27-hydroxylase; CYP39A1, sterol 7α-hydroxylase; CYP46A1, sterol 24-hydroxylase; DCA, deoxycholic acid; HSD3B7, 3β-hydroxy-Δ⁵-C₂₇-steroid dehydrogenase; HSD17B4, D-bifunctional protein; LCA, lithocholic acid; MCA, muricholic acid; SCPx, sterol carrier protein x; SLC27A5, long-chain acyl-coenzyme A synthase [also known as bile acid-coenzyme A synthase (BACS)]; UDCA: ursodeoxycholic acid.

Figure 2.

FXR and TGR5 regulation of bile acid synthesis and enterohepatic circulation of bile acids. In hepatocytes, FXR induces SHP to inhibit CYP7A1 and CYP8B1 gene transcription. FXR induces BSEP and MDR3, leading to the secretion into bile of, respectively, bile acids and phospholipids. FXR inhibits bile acid uptake via NTCP. In cholangiocytes, small amounts of bile acids are reabsorbed by ASBT and excreted via OSTα and -β, and these are then recycled to hepatocytes via cholehepatic shunting. In enterocytes, 95% of bile acids are reabsorbed via ASBT and may activate FXR, which induces FGF19. FGF19 in portal blood is circulated back to hepatocytes to activate FGFR4 and ERK signaling, inhibiting CYP7A1 and CYP8B1 transcription. Bile acids inhibit ASBT, but FXR induces OSTα and -β. In enteroendocrine L cells, FXR induces TGR5 to stimulate GLP-1 secretion. Abbreviations: ABCG5/G8, ATP-binding cassette subfamily G member 5 and 8; ASBT, apical sodium-dependent bile salt transporter; BSEP, bile salt export pump; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; ERK, extracellular signal-regulated protein kinase; FGF19, fibroblast growth factor 19; FGFR4, fibroblast growth factor receptor 4; FXR, farnesoid X receptor; GLP-1, glucagon-like peptide 1; LCA, lithocholic acid; MDR3, multidrug resistance protein 3; MRP2, MDR-related protein 2; NTCP, Na⁺-taurocholate cotransporting polypeptide; OATP, organic anion transport polypeptide; OST, organic solute transporter; SHP, small heterodimer partner; TGR5, Takeda G protein–coupled receptor 5.