Cardiolipin Synthase 1 Ameliorates NASH Through Activating Transcription Factor 3 Transcriptional Inactivation

Background and Aims NASH is an increasingly prevalent disease that is the major cause of liver dysfunction. Previous research has indicated that adipose cardiolipin synthase 1 (CRLS1) levels are associated with insulin sensitivity; however, the precise roles of CRLS1 and underlying mechanisms involving CRLS1 in the pathological process of NASH have not been elucidated. Approach and Results Here, we discovered that CRLS1 was significantly down‐regulated in genetically obese and diet‐induced mice models. In vitro studies demonstrated that overexpression of CRLS1 markedly attenuated hepatic steatosis and inflammation in hepatocytes, whereas short hairpin RNA‐mediated CRLS1 knockdown aggravated these abnormalities. Moreover, high‐fat diet–induced insulin resistance and hepatic steatosis were significantly exacerbated in hepatocyte‐specific Crls1 ‐knockout ( Crls1 ‐HKO) mice. It is worth noting that Crls1 depletion significantly aggravated high‐fat and high‐cholesterol diet‐induced inflammatory response and fibrosis during NASH development. RNA‐sequencing analysis systematically demonstrated a prominently aggravated lipid metabolism disorder in which inflammation and fibrosis resulted from Crls1 deficiency. Mechanically, activating transcription factor 3 (ATF3) was identified as the key differentially expressed gene in Crls1 ‐HKO mice through transcriptomic analysis, and our investigation further showed that CRLS1 suppresses ATF3 expression and inhibits its activity in palmitic acid‐stimulated hepatocytes, whereas ATF3 partially reverses lipid accumulation and inflammation inhibited by CRLS1 overexpression under metabolic stress. Conclusions In conclusion, CRLS1 ameliorates insulin resistance, hepatic steatosis, inflammation, and fibrosis during the pathological process of NASH by inhibiting the expression and activity of ATF3.