The Role and Mechanism of CREBH Regulating SIRT3 in Metabolic Associated Fatty Liver Disease

Abstract

AimsTo investigate the effect of cAMP response element-binding protein H (CREBH) on metabolic associated fatty liver disease by regulating sirtuin 3 (SIRT3). Main methodsTwo mouse models of fatty liver induced by a methionine-choline deficient (MCD) diet and a high-fat (HF) diet and an in vitro model of palmitic acid (PA) induced lipid-overloaded hepatocytes were constructed to detect the expression of CREBH, SIRT3, total acetylation, and downstream protein interactions and lipid metabolism phenotype, which were further validated in CREBH−/− mice and lentivirus-overexpressing CREBH hepatocytes. Key findingsIn fatty liver and lipid overload models, the expressions of CREBH and SIRT3 were down-regulated and their expression was positively correlated, accompanied by an increase in the level of total protein acetylation. Overexpression of CREBH alleviated excess lipid accumulation, impaired viability, and the ability to metabolize energy through the fatty acid oxidation pathway in hepatocytes in vitro. Furthermore, overexpression of CREBH restored the interaction of the deacetylase SIRT3 with the molecules carnitine palmitoyl-transferase 2 (CPT2) and long-chain acyl CoA dehydrogenase (ACADL) involved in the fatty acid oxidation pathway and their deacetylation status. However, CREBH−/− aggravated the damage of lipid metabolism in the liver tissue of mice. SignificanceCREBH increased the enzymatic activity of downstream factors by positively regulating the expression of SIRT3, which promoted the oxidative decomposition of fatty acids in hepatocytes and played an important role in fatty acid oxidation in MAFLD.