Hydrogen Sulfide Alleviates Liver Injury Through the S‐Sulfhydrated‐Kelch‐Like ECH‐Associated Protein 1/Nuclear Erythroid 2–Related Factor 2/Low‐Density Lipoprotein Receptor–Related Protein 1 Pathway

Background and Aims Protein S‐sulfhydration mediated by H 2 S has been shown to play important roles in several diseases. However, its precise role in liver disease and the related mechanism remain unclear. Approach and Results We showed that in streptozotocin (STZ)–treated and high‐fat diet (HFD)–treated low‐density lipoprotein receptor–negative (LDLr −/− ) mice, the H 2 S donor GYY4137 ameliorated liver injury, decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, mitigated lipid deposition, and reduced hepatocyte death. Strikingly, S‐sulfhydration of Kelch‐like ECH‐associated protein 1 (Keap1) was decreased in the livers of patients with fatty liver under diabetic conditions. In STZ+HFD‐treated LDLr −/− mice and in high glucose–treated and oxidized low‐density lipoprotein (ox‐LDL)–treated primary mouse hepatocytes, the GYY4137‐mediated increase in Keap1 S‐sulfhydration induced nuclear erythroid 2‐related factor 2 (Nrf2) dissociation from Keap1, which enhanced the nuclear translocation of Nrf2 itself and the consequent expression of antioxidant proteins. Keap1 Cys151 mutation significantly reduced Keap1 S‐sulfhydration and abolished the hepatoprotective effects of H 2 S both in vivo and in vitro . Nrf2 deficiency inhibited the H 2 S‐induced beneficial impacts in Nrf2 −/− mice. Similarly, in CCl 4 ‐stimulated mice, GYY4137 increased Keap1 S‐sulfhydration, improved liver function, alleviated liver fibrosis, decreased hepatic oxidative stress, and activated the Nrf2 signaling pathway; and these effects were abrogated after Keap1 Cys151 mutation. Moreover, H 2 S increased the binding of Nrf2 to the promoter region of LDLr‐related protein 1 ( Lrp1 ) and consequently up‐regulated LRP1 expression, but these effects were disrupted by Keap1 Cys151 mutation. Conclusions H 2 S‐mediated Keap1 S‐sulfhydration alleviates liver damage through activation of Nrf2. Hence, administration of exogenous H 2 S in the form of the H 2 S donor GYY4137 may be of therapeutic benefit in the context of concurrent hyperlipidemia and hyperglycemia–induced or CCl 4 ‐stimulated liver dysfunction.