JHEP Rep. 2022 Jan;4(1):
100387
Background & Aims: Through FXR and TGR5 signaling, bile acids (BAs) modulate lipid and glucose metabolism, inflammation and fibrosis. Hence, BAs returning to the liver after enteric secretion, modification and reabsorption may contribute to the pathogenesis of non-alcoholic steatohepatitis (NASH). Herein, we characterized the enterohepatic profile and signaling of BAs in preclinical models of NASH, and explored the consequences of experimental manipulation of BA composition.Methods: We used high-fat diet (HFD)-fed foz/foz and high-fructose western diet-fed C57BL/6J mice, and compared them to their respective controls. Mice received a diet supplemented with deoxycholic acid (DCA) to modulate BA composition.
Results: Compared to controls, mice with NASH had lower concentrations of BAs in their portal blood and bile, while systemic BA concentrations were not significantly altered. Notably, the concentrations of secondary BAs, and especially of DCA, and the ratio of secondary to primary BAs were strikingly lower in bile and portal blood of mice with NASH. Hence, portal blood was poor in FXR and TGR5 ligands, and conferred poor anti-inflammatory protection in mice with NASH. Enhanced primary BAs synthesis and conversion of secondary to primary BAs in NASH livers contributed to the depletion in secondary BAs. Dietary DCA supplementation in HFD-fed foz/foz mice restored the BA concentrations in portal blood, increased TGR5 and FXR signaling, improved the dysmetabolic status, protected from steatosis and hepatocellular ballooning, and reduced macrophage infiltration.
Conclusions: BA composition in the enterohepatic cycle, but not in systemic circulation, is profoundly altered in preclinical models of NASH, with specific depletion in secondary BAs. Dietary correction of the BA profile protected from NASH, supporting a role for enterohepatic BAs in the pathogenesis of NASH.
Lay summary: This study clearly demonstrates that the alterations of enterohepatic bile acids significantly contribute to the development of non-alcoholic steatohepatitis in relevant preclinical models. Indeed, experimental modulation of bile acid composition restored perturbed FXR and TGR5 signaling and prevented non-alcoholic steatohepatitis and associated metabolic disorders.
Keywords: ASBT, apical sodium-dependent BA transporter; BA, bile acid; CA, cholic acid; CDCA, chenodeoxycholic acid; CYP27A1, sterol 27-hydroxylase; CYP2A12, bile acid 7α-hydroxylase; CYP7A1, cholesterol 7α-hydroxylase; CYP7B1, oxysterol 7α-hydroxylase; CYP8B1, sterol 12α-hydroxylase; DCA, deoxycholic acid; FABP6, fatty acid binding protein 6; FGF15, fibroblast growth factor 15; FGFR4, fibroblast growth factor receptor 4; FXR; FXR, Farnesoid X receptor; GLP-1, glucagon-like peptide-1; HFD, high-fat diet; LCA, lithocholic acid; LPS, lipopolysaccharide; NAFLD; NAFLD, non-alcoholic fatty liver disease; NAS, NAFLD activity score; NASH; NASH, non-alcoholic steatohepatitis; ND, normal diet; OGTT, oral glucose tolerance test; OST, organic solute transporter; SHP, small heterodimer protein; TGR5; TGR5, Takeda G-protein coupled receptor 5; TLCA, tauro-lithocholic acid; TNFα, tumor necrosis factor α; WDF, western and high-fructose diet; WT, wild-type; metabolic syndrome; αMCA, α-muricholic acid; βMCA, β-muricholic acid; ωMCA, ω-muricholic acid