Hepatocellular cystathionine γ lyase/hydrogen sulfide attenuates nonalcoholic fatty liver disease by activating farnesoid X receptor

BACKGROUND AND AIMS: Hydrogen sulfide (H(2)S) plays a protective role in NAFLD. However, whether cystathionine γ lyase (CSE), a dominant H(2)S generating enzyme in hepatocytes, has a role in the pathogenesis of NAFLD is currently unclear. APPROACH AND RESULTS: We showed that CSE protein expression is dramatically downregulated, especially in fibrotic areas, in livers from patients with NAFLD. In high‐fat diet (HFD)‐induced NAFLD mice or an oleic acid‐induced hepatocyte model, the CSE/H(2)S pathway is also downregulated. To illustrate a regulatory role for CSE in NAFLD, we generated a hepatocyte‐specific CSE knockout mouse (CSE (LKO)). Feeding an HFD to CSE (LKO) mice, they showed more hepatic lipid deposition with increased activity of the fatty acid de novo synthesis pathway, increased hepatic insulin resistance, and higher hepatic gluconeogenic ability compared to CSE (Loxp) control mice. By contrast, H(2)S donor treatment attenuated these phenotypes. Furthermore, the protection conferred by H(2)S was blocked by farnesoid X receptor (FXR) knockdown. Consistently, serum deoxycholic acid and lithocholic acid (FXR antagonists) were increased, and tauro‐β‐muricholic acid (FXR activation elevated) was reduced in CSE(LKO). CSE/H(2)S promoted a post‐translation modification (sulfhydration) of FXR at Cys138/141 sites, thereby enhancing its activity to modulate expression of target genes related to lipid and glucose metabolism, inflammation, and fibrosis. Sulfhydration proteomics in patients' livers supported the CSE/H(2)S modulation noted in the CSE (LKO) mice. CONCLUSIONS: FXR sulfhydration is a post‐translational modification affected by hepatic endogenous CSE/H(2)S that may promote FXR activity and attenuate NAFLD. Hepatic CSE deficiency promotes development of nonalcoholic steatohepatitis. The interaction between H(2)S and FXR may be amenable to therapeutic drug treatment in NAFLD.