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Sirtuin 2 Prevents Liver Steatosis and Metabolic Disorders by Deacetylation of Hepatocyte Nuclear Factor 4α
Author(s) -
Ren Huihui,
Hu Fuqing,
Wang Dan,
Kang Xiaonan,
Feng Xiaohui,
Zhang Lu,
Zhou Bowen,
Liu Siyue,
Yuan Gang
Publication year - 2021
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.31773
Subject(s) - sirt2 , sirtuin , steatosis , hepatocyte nuclear factors , medicine , endocrinology , sirtuin 1 , insulin resistance , hepatocyte nuclear factor 4 , fatty liver , biology , nad+ kinase , cancer research , gene expression , downregulation and upregulation , diabetes mellitus , biochemistry , gene , enzyme , transcription factor , nuclear receptor , disease
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 4α (HNF4α) protein by binding to and deacetylating HNF4α on lysine 458. Furthermore, HNF4α was sufficient to mediate SIRT2 function, and SIRT2‐HNF4α 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‐HNF4α pathway may be a promising strategy for NAFLD treatment.