{"doi":"10.1002/cld.861","title":"Bile Acid Biology, Pathophysiology, and Therapeutics","abstract":"Watch a video presentation of this article Watch an interview with the author Bile acids are synthesized from cholesterol exclusively in the liver and function as physiological detergents that facilitate biliary cholesterol excretion. Bile acids are stored in the gallbladder as bile salts. After meal intake, bile acids are released into the gastrointestinal tract to aid in absorption of nutrients, dietary fats, steroids, vitamins, and drugs. Recent advances in basic research have identified bile acids as nutrient sensors and metabolic integrators that activate farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) to regulate lipid, glucose, and energy metabolism, and maintain metabolic homeostasis.1 This review will briefly cover bile acid physiology and synthesis, pathophysiology of cholestatic liver diseases and nonalcoholic fatty liver disease (NAFLD), and bile acid–based therapy for liver-related diseases. There are two major bile acid synthesis pathways in the liver.2 The classic pathway is initiated by cholesterol 7α-hydroxylase (CYP7A1) and synthesizes the two primary bile acids in humans, chenodeoxycholic acid (CDCA) and cholic acid (CA), the latter of which requires sterol 12α-hydroxylase (CYP8B1) (Fig. 1). Serum 7α-hydroxy-4-cholesten-3-one (C4), a common precursor for CA and CDCA, is used as an indicator of bile acid synthesis rate. The alternative pathway is initiated by sterol 27-hydroxylase (CYP27A1), which synthesizes oxidized sterols, followed by oxysterol 7α-hydroxylase (CYP7B1). Bile acids are conjugated to taurine or glycine to increase solubility for biliary secretion. In the colon, gut bacterial bile salt hydrolase (BSH) deconjugates bile acids, and 7α-dehydroxylase removes the 7α-HO-group from CA and CDCA to form the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA), respectively. Conjugated CA, CDCA, and DCA are secreted into portal blood circulation and reabsorbed into the liver to inhibit bile acid synthesis. Emerging research in bile acid metabolism in the past three decades has contributed significantly to our current understanding of the roles of FXR and TGR5 in the pathophysiology of liver-related diseases. FXR is highly expressed in the gastrointestinal system and plays a central role in the regulation of enterohepatic circulation of bile acids. Bile acids activate FXR to induce bile salt export pump (BSEP), which secretes bile acids into bile canaliculi, forming mixed micelles with cholesterol and phospholipids (Fig. 2). In the ileum, most conjugated bile acids are reabsorbed by apical sodium-dependent bile salt transporter (ASBT). FXR also induces sinusoidal organic solute transporter α/β (OSTα/OSTβ) to secrete bile acids into the portal circulation. Bile acids are reabsorbed from portal blood into hepatocytes by sodium-dependent taurocholate transporting peptide (NTCP). Bile acid synthesis is tightly regulated by complex mechanisms to maintain low levels of bile acids in the liver. In the liver, FXR inhibits CYP7A1 gene transcription indirectly via inducing the negative nuclear receptor small heterodimer partner (SHP). In the intestine, FXR induces fibroblast growth factor 19 (FGF19), which activates liver FGF receptor 4 (FGFR4) to inhibit CYP7A1 via extracellular signal-regulated kinase 1/2 signaling. TGR5 is expressed in many tissues, except hepatocytes. Activation of TGR5 by secondary bile acids in enteroendocrine cells stimulates secretion of glucagon-like peptide 1 (GLP-1), which promotes insulin secretion in the pancreas to improve insulin sensitivity. TGR5 signaling also promotes adipose tissue browning and energy metabolism to reduce weight.1 The global epidemic of obesity and type 2 diabetes (T2D) has contributed to the increased prevalence of NAFLD, which is about 25% of the adult population in the world. NAFLD is a spectrum of chronic liver diseases ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) fibrosis and cirrhosis. NA","journal":"Clinical Liver Disease","year":2020,"id":56170,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":87,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9678,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":291733,"name":"Jessica M. Ferrell","orcid":"0000-0003-3691-3330","position":1,"is_corresponding":false},{"id":289557,"name":"John Y.L. Chiang","orcid":"0000-0001-9360-7650","position":0,"is_corresponding":true}],"reference_count":12,"raw_metadata":null,"created_at":"2026-07-18T21:05:49.581291Z","pmid":"32257118","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}