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.

Table 2 Summary of pharmacologic agents targeting bile acid signaling in metabolic dysfunction-associated steatotic liver disease pathogenesis

Agent	Target receptor(s)	Mechanism of action	Reported efficacy	Adverse effects
OCA[25,27]	FXR	Potent FXR agonist; suppresses CYP7A1, induces FGF19, reduces lipogenesis and inflammation	Improved fibrosis stage in approximately 23% of patients without NASH worsening; ↓ALT and ballooning in NASH patients	Pruritus (up to 51%), ↑LDL-C levels
Tropifexor[39]	FXR	Non-steroidal FXR agonist; improved selectivity and tolerability	↓ALT and GGT, improved liver fat content (MRI-PDFF); significant reduction in hepatic steatosis	Pruritus (dose-dependent), mild GI symptoms
Cilofexor[29,30]	FXR	Non-steroidal FXR agonist with moderate systemic activity	Modest in ↓ALT and liver fat; greater effects in combination therapy (e.g., with firsocostat or selonsertib)	Pruritus, fatigue, mild ↑LDL-C
MET409[40]	FXR	Non-bile acid FXR agonist with liver targeting	↓ALT and steatosis; improved insulin sensitivity; less lipid disruption than OCA	GI-related adverse effects, mild pruritus
INT-767[41,42]	FXR/TGR5	Dual agonist; activates FXR and TGR5 to anti-inflammatory, insulin-sensitizing, and lipid-lowering effects	In rodent models: ↓Steatosis, ↓fibrosis, ↑GLP-1 secretion, improved insulin resistance	Potential gallbladder issues due to TGR5 activation
norUDCA[43]	Non-receptor (cholehepatic shunting)	Side-chain-shortened UDCA; induces bicarbonate-rich choleresis; anti-fibrotic and anti-inflammatory without FXR activation	↓Hepatic inflammation, ↓TGF-β1 signaling, ↓collagen deposition in MASLD models	Well, tolerated; minimal pruritus, no LDL elevation
BAR502[44]	FXR/TGR5	Dual agonist; enhances bile acid-FGF19 axis and GLP-1 signaling	↓Steatosis and fibrosis in animal models; improved insulin sensitivity	Under investigation
PXL065[45,46]	Mitochondrial PD modulator (PPAR-sparing TZD derivative)	Anti-inflammatory and insulin-sensitizing via mitochondrial bioenergetics modulation	↓ALT, improved hepatic fat content in MASLD	Reduced edema compared to pioglitazone
ASC42[46,47]	FXR	Potent oral FXR agonist with high liver selectivity	Preclinical studies show reduction in hepatic steatosis and inflammation	Data limited

OCA: Obeticholic acid; norUDCA: Norursodeoxycholic acid; FXR: Farnesoid X receptor; TGR5: Takeda G-protein-coupled receptor 5; PD: Protonophoric decoupling; PPAR: Peroxisome proliferator-activated receptor; TZD: Thiazolidinedione; CYP7A1: Cholesterol 7α-hydroxylase; FGF19: Fibroblast growth factor 19; UDCA: Ursodeoxycholic acid; GLP-1: Glucagon-like peptide-1; ALT: Alanine aminotransferase; NASH: Nonalcoholic steatohepatitis; GGT: Gamma-glutamyl transferase; MRI: Magnetic resonance imaging; PDFF: Proton density fat fraction; TGF: Transforming growth factor; MASLD: Metabolic dysfunction-associated steatotic liver disease; LDL-C: Low-density lipoprotein cholesterol; GI: Gastrointestinal; LDL: Low-density lipoprotein.

Table 3 Microbial enzymes, bile acid transformations, and receptor-mediated effects in metabolic dysfunction-associated steatotic liver disease pathogenesis[53,54]

Microbial enzyme	Bile acid transformation	Key products	Receptor binding	Pathophysiological effects in MASLD
BSH	Deconjugation of taurine/glycine-conjugated BAs	Free primary BAs (e.g., CA, CDCA)	↑FXR (CDCA) ↓TGR5	Facilitates FXR activation in ileum to ↑FGF19 to ↓BA synthesis; however, dysregulation may lead to FXR desensitization
7α-dehydroxylase	Removal of 7α-hydroxyl group from primary BAs	DCA (from CA), LCA (from CDCA)	↑TGR5 ↓FXR (weak agonists)	↑GLP-1, ↑energy expenditure (via TGR5); ↑pro-inflammatory signaling (via TLR4, MAPK); ↓intestinal FXR signaling
HSDH	Epimerization and oxidation of hydroxyl groups	Iso- and oxo-BA forms	Varies (limited data)	May alter BA pool toxicity and gut-liver signaling; epimers often show reduced receptor affinity
Sulfatases	Desulfation of secondary bile acids	Unconjugated secondary BAs	↑TGR5	Increases bioavailability of TGR5 agonists (e.g., LCA) to promotes anti-inflammatory and metabolic signaling
Dehydrogenases and reductases	Oxidation-reduction reactions of hydroxyl/keto groups	Oxo-bile acids, dehydro forms	↓FXR (typically weak)	May lead to accumulation of hepatotoxic bile acid species to ↑oxidative stress and inflammation

BSH: Bile salt hydrolase; HSDH: Hydroxysteroid dehydrogenase; BA: Bile acid; CA: Cholic acid; CDCA: Chenodeoxycholic acid; DCA: Deoxycholic acid; LCA: Lithocholic acid; FXR: Farnesoid X Receptor; TGR5: Takeda G Protein-Coupled Receptor 5; FGF19: Fibroblast growth factor 19; TLR4: Toll-like receptor 4; MAPK: Mitogen-activated protein kinase; MASLD: Metabolic dysfunction-associated steatotic liver disease.