Category: receptor_pharmacology
Bile acids are not just emulsifiers — they are hormones acting through two distinct receptor classes. (1) FXR (farnesoid X receptor, NR1H4) is a nuclear receptor activated principally by CDCA > LCA > DCA > CA. FXR-RXR heterodimer drives transcription of: FGF15/19 (intestinal — feedback signal to liver via FGFR4/βKlotho → ↓CYP7A1 → ↓de novo bile acid synthesis); SHP (small heterodimer partner — represses LRH-1/HNF4α); BSEP (canalicular bile acid efflux); OST-α/β (basolateral efflux); IBABP (intestinal binding); apoC-II (lipoprotein metabolism). FXR also represses NF-κB → anti-inflammatory in liver/gut. (2) TGR5 (GPBAR1) is a Gs-coupled GPCR responding to LCA > DCA > CDCA → cAMP → PKA. Tissue effects: brown adipose / muscle (D2 → T3 → thermogenesis); intestinal L-cells (↑GLP-1 secretion — incretin axis crosstalk); macrophages (anti-inflammatory); biliary epithelium (proliferation + chloride secretion); gallbladder relaxation (postprandial). Microbiota–FXR crosstalk: gut bacteria deconjugate + 7α-dehydroxylate bile acids → secondary BAs (DCA, LCA) → tip the FXR/TGR5 balance; tauro-β-muricholic acid is a natural FXR antagonist (Sayin 2013). Therapeutics: obeticholic acid (OCA, INT-747 — semi-synthetic CDCA derivative, potent FXR agonist) for PBC + cholestatic liver disease, NASH trials; cilofexor + tropifexor (FXR agonists in development); UDCA + tauroUDCA (TUDCA) (PXR/FXR partial modulators — cytoprotective in cholestasis); bile-acid sequestrants (colesevelam, cholestyramine, colestipol) lower bile-acid pool → ↑FXR signal release → glucose effects (metformin-like). Cross-links: [[bile_acid_synthesis]] (upstream), [[insulin_glucose_homeostasis]] (TGR5 → GLP-1), [[gi_endocrine_peptides_misc]] (FGF15/19 endocrine).