RASAL2 Deficiency Attenuates Hepatic Steatosis by Promoting Hepatic VLDL Secretion via the AKT/TET1/MTTP Axis

Background and Aims:RAS protein activator like 2(RASAL2)is a newly discovered metabolic regulator involved in energy homeostasis and adipogenesis.However,whether RASAL2 is involved in hepatic lipid metabolism remains undetermined.This study explored the function of RASAL2 and elucidated its potential mechanisms in nonalcoholic fatty liver disease(NAFLD).Methods:NAFLD models were established either by feeding mice a high-fat diet or by incubation of hepatocytes with 1 mM free fatty acids(oleic acid:palmitic acid=2:1).Pathological changes were observed by hematoxylin and eosin staining.Lipid accumulation was assessed by Oil Red O staining,BODIPY493/503 staining,and triglyceride quantification.The in vivo secretion rate of very lowdensity lipoprotein was determined by intravenous injection of tyloxapol.Gene regulation was analyzed by chromatin immunoprecipitation assays and hydroxymethylated DNA immunoprecipitation combined with real-time polymerase chain reaction.Results:RASAL2 deficiency ameliorated hepatic steatosis both in vivo and in vitro.Mechanistically,RASAL2 deficiency upregulated hepatic TET1 expression by activating the AKT signaling pathway and thereby promoted MTTP expression by DNA hydroxymethylation,leading to increased production and secretion of very low-density lipoprotein,which is the major carrier of triglycerides exported from the liver to distal tissues.Conclusions:Our study reports the first evidence that RASAL2 deficiency ameliorates hepatic steatosis by regulating lipid metabolism through the AKT/TET1/MTTP axis.These findings will help understand the pathogenesis of NAFLD and highlight the potency of RASAL2 as a new molecular target for NAFLD.