Chemerin/CMKLR1 ameliorates nonalcoholic steatohepatitis by promoting autophagy and alleviating oxidative stress through the JAK2-STAT3 pathway.

Abstract Nonalcoholic steatohepatitis (NASH) is a global public health challenge. Overwhelmed oxidative stress and impaired autophagy play an important role in the progression of NASH. Chemerin is an adipokine that has attracted much attention in inflammation and metabolic diseases. This study aimed to examine the effects of chemerin in NASH and its association with oxidative stress and autophagy. In this study, chemerin was found to significantly ameliorate high-fat diet (HFD) induced NASH, marked by decreased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α), decreased insulin resistance (IR) and leptin resistance (LR), and improved liver lesions. Besides, chemerin prevented enhanced oxidative stress in NASH mice by regulating the antioxidant defense system (MDA downregulation and upregulation of superoxide dismutase (SOD)). Moreover, chemerin contributed to the alleviation of NASH through autophagy activation (p62 downregulation, and upregulation of beclin-1 and LC3). Furthermore, these effects were related to increased phosphorylation of JAK2-STAT3 stimulated by chemerin, which could be inhibited by the CMKLR1 specific inhibitor α-NETA. In conclusion, excess chemerin highly probably ameliorated NASH by alleviating oxidative stress and promoting autophagy, the mechanism responsible for this process was related, at least in part, to the increased phosphorylation of JAK2-STAT3 stimulated by chemerin/CMKLR1. Rh-chemerin may represent promising therapeutic targets in the treatment of NASH.