PACS2 deficiency ameliorates hepatic steatosis via inhibition of the JNK signaling pathway in diabetic mice.

Hepatic steatosis is a frequent complication of diabetes. To investigate the role of PACS2 in glucose and lipid metabolism in diabetic mice and to determine the underlying mechanisms. PACS2-/- mice were used to establish diabetic models by a high-fat diet combined with intraperitoneal injection of STZ(HFD/STZ). Body weight, blood glucose, serum indexes, glucose tolerance test and insulin tolerance test were assessed. HepG2 cells were treated with high glucose and palmitic acid (HGPA). To investigate the specific mechanism of PACS2 silencing, HepG2 cells were transfected with the small interfering RNA (siRNA) of PACS2 or treated with an inhibitor of the JNK signaling (SP600125). Western blot was conducted to measure the JNK signaling pathway-related proteins. Our research findings indicate an upregulation of PACS2 expression in the liver tissues of diabetic mice. HFD/STZ induced dramatic exacerbation of higher blood glucose levels, insulin resistance, hepatic steatosis, MAMs formation, mitochondrial dysfunction and overactivation of the JNK signaling pathway in liver tissues, which was reversed by downregulation of PACS2. HepG2 cells treated with siRNA-PACS2 or SP600125 resulted in the inhibition of HGPA-mediated enhancement of JNK activation and the lipogenic enzymes expression (acetyl-CoA carboxylase 1 and fatty acid synthase), as well as the promotion of PPARα and fatty acid β-oxidation (FAO)-associated CPT1A expression. Collectively, our findings demonstrate that PACS2 deficiency alleviates hepatic steatosis and insulin resistance in diabetic mice by inhibition of JNK signaling pathway in hepatocytes.