Bile acid receptor signaling in metabolic dysfunction-associated steatotic liver disease: Mechanistic insights and emerging therapeutic strategies

Table 1 Bile acid receptors, ligands, and their roles in metabolic dysfunction-associated steatotic liver disease pathogenesis

Receptor/pathway	Ligand/activation	Physiological role/effect	Role in MASLD/MASH
FXR[17]	CDCA, FXR agonists	↓SREBP-1c, ↑LDLR to ↓lipid accumulation; ↓NF-κB to ↓inflammation; ↑FGF19 to ↓gluconeogenesis	Central therapeutic target: Reduces steatosis, enhances insulin sensitivity, and attenuates fibrosis
CAR[18,19]	Bile acids, indirect nuclear activation	Activates Nrf2 to ↓inflammation	Supports anti-inflammatory balance via Nrf2 signaling
PXR[19]	Bile acids, xenobiotics	↓INSR signaling to ↓insulin sensitivity	Detrimental: Worsens insulin resistance and metabolic dysfunction
VDR[13]	Secondary bile acids	↓COL1α1 to ↓fibrosis	Antifibrotic potential via inhibition of extracellular matrix remodeling
TGR5 (liver)[20]	Secondary bile acids	↑AMPK to ↑energy metabolism	Improves hepatic energy metabolism and reduces inflammation
TGR5 (intestine)[20,21]	Secondary bile acids	↑GLP-1 secretion to ↑insulin sensitivity	Enhances incretin response, improving metabolic control
S1PR2[22]	CDCA	Activates PI3K-AKT to ↑insulin sensitivity	Supports insulin signaling and glucose regulation
CDCA[23]	Endogenous bile acid	Activates PI3K-AKT to ↑insulin sensitivity	Therapeutically favorable: Improves metabolic flexibility
LCA[24]	Lithocholic acid	Activates TLR4/MAPK to ↑inflammation	Pro-inflammatory: Promotes progression to MASH
NTCP/BSEP[24]	Conjugated bile acids (e.g., taurocholate)	BSEP: Exports bile acids to bile; NTCP: Reabsorbs bile acids from portal circulation	Maintains bile acid pool and facilitates enterohepatic cycling
OSTα/OSTβ/ASBT[24]	Bile acid transporters	ASBT: Intestinal bile acid uptake; OSTα/β: Efflux to portal vein	Regulate enterohepatic recirculation, essential for gut-liver axis signaling

FXR: Farnesoid X receptor; CAR: Constitutive androstane receptor; PXR: Pregnane X receptor; VDR: Vitamin D receptor; TGR5: Takeda G-protein-coupled receptor 5; S1PR2: Sphingosine-1-phosphate receptor 2; CDCA: Chenodeoxycholic acid; LCA: Lithocholic acid; NTCP: Sodium taurocholate cotransporting polypeptide; BSEP: Bile salt export pump; OST: Organic solute transporters; ASBT: Apical sodium-dependent bile acid transporter; SREBP-1c: Sterol regulatory element-binding protein 1c; LDLR: Low-density lipoprotein receptor; NF-κB: Nuclear factor kappa B; FGF19: Fibroblast growth factor 19; Nrf2: Nuclear factor erythroid-2-related factor 2; INSR: Insulin receptor; COL1α1: Collagen type I alpha 1 chain; AMPK: AMP-activated protein kinase; GLP-1: Glucagon-like peptide-1; PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase B; TLR4: Toll-like receptor 4; MAPK: Mitogen-activated protein kinase; MASLD: Metabolic dysfunction-associated steatotic liver disease; MASH: Metabolic dysfunction-associated steatohepatitis.