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.
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.