Sirtuin 2 Prevents Liver Steatosis and Metabolic Disorders by Deacetylation of Hepatocyte Nuclear Factor 4α

Background and Aims Sirtuin 2 (SIRT2), an NAD(+)-dependent deacetylase, is involved in various cellular processes regulating metabolic homeostasis and inflammatory responses; however, its role in hepatic steatosis and related metabolic disorders is unknown. Approach and Results Integrating the published genomic data on NAFLD samples from humans and rodents available in the Gene Expression Omnibus, we found that SIRT2 was significantly down-regulated in livers from patients with advanced NAFLD and high-fat diet (HFD)-induced NAFLD mice. This study further revealed that SIRT2 was markedly decreased in obese (ob/ob) mice and in palmitate-treated HepG2 cells. Restoration of hepatic SIRT2 expression in ob/ob or HFD-fed mice largely alleviated insulin resistance, hepatic steatosis, and systematic inflammation, whereas SIRT2 liver-specific ablation exacerbated these metabolic dysfunctions in HFD-fed C57BL/6J mice. Mechanistically, SIRT2 stabilized the hepatocyte nuclear factor 4 alpha (HNF4 alpha) protein by binding to and deacetylating HNF4 alpha on lysine 458. Furthermore, HNF4 alpha was sufficient to mediate SIRT2 function, and SIRT2-HNF4 alpha interaction was required for SIRT2 function both in vivo and in vitro. Conclusions Collectively, the present study provided evidence that SIRT2 functions as a crucial negative regulator in NAFLD and related metabolic disorders and that targeting the SIRT2-HNF4 alpha pathway may be a promising strategy for NAFLD treatment.

Automated summary

The study showed that SIRT2 is significantly down-regulated in patients with NAFLD and HFD-induced NAFLD mice, restoring its expression in the liver can alleviate insulin resistance, hepatic steatosis, and systemic inflammation. Targeting the SIRT2-HNF4 alpha pathway may be a promising strategy for NAFLD treatment.