journal article·2020-11Open access

The Nuclear Orphan Receptor NR2F6 Promotes Hepatic Steatosis through Upregulation of Fatty Acid Transporter CD36

Bing Zhou, Lijing Jia, Zhijian Zhang, Liping Xiang, Youwen Yuan, Peilin Zheng, Bin Liu, Xingxing Ren, Hua Bian, Liwei Xie, Yao Li, Jieli Lu, Huijie Zhang, Yan Lu

Advanced Science· Volume 7· Issue 21

Abstract

Abstract Nuclear receptors (NRs) are a superfamily of transcription factors which sense hormonal signals or nutrients to regulate various biological events, including development, reproduction, and metabolism. Here, this study identifies nuclear receptor subfamily 2, group F, member 6 (NR2F6), as an important regulator of hepatic triglyceride (TG) homeostasis and causal factor in the development of non‐alcoholic fatty liver disease (NAFLD). Adeno‐associated virus (AAV)‐mediated overexpression of NR2F6 in the liver promotes TG accumulation in lean mice, while hepatic‐specific suppression of NR2F6 improves obesity‐associated hepatosteatosis, insulin resistance, and methionine and choline‐deficient (MCD) diet‐induced non‐alcoholic steatohepatitis (NASH). Mechanistically, the fatty acid translocase CD36 is identified as a transcriptional target of NR2F6 to mediate its steatotic role. NR2F6 is able to bind directly onto the CD36 promoter region in hepatocytes and increases the enrichment of nuclear receptor coactivator 1 (SRC‐1) and histone acetylation at its promoter. Of pathophysiological significance, NR2F6 is significantly upregulated in the livers of obese mice and NAFLD patients. Moreover, treatment with metformin decreases NR2F6 expression in obese mice, resulting in suppression of CD36 and reduced hepatic TG contents. Therefore, these results provide evidence for an unpredicted role of NR2F6 that contributes to liver steatosis and suggest that NR2F6 antagonists may present a therapeutic strategy for reversing or treating NAFLD/NASH pathogenesis.
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Research context

OpenAlex topics: Liver Disease Diagnosis and Treatment · Diet, Metabolism, and Disease · Diet and metabolism studies

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

The Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education Department of Endocrinology and Metabolism Fudan Institute for Metabolic Diseases Zhongshan Hospital Fudan University Shanghai 230032 P. R. China

Department of Endocrinology Shenzhen People's Hospital The Second Clinical Medical College, Jinan University, The First Affiliated Hospital of Southern University of Science and Technology Shenzhen Guangdong 518020 P. R. China

Department of Endocrinology and Metabolism Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai 201620 P. R. China

Department of Endocrinology and Metabolism Nanfang Hospital Southern Medical University Guangzhou Guangdong 510515 P. R. China

State Key Laboratory of Applied Microbiology Southern China Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application Guangdong Open Laboratory of Applied Microbiology Guangdong Institute of Microbiology Guangdong Academy of Sciences Guangzhou Guangdong 510070 P. R. China

Department of Laboratory Animal Science Shanghai Jiao Tong University School of Medicine Shanghai 200025 P. R. China

Department of Endocrinology and Metabolism Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200025 P. R. China

Funding

National Basic Research Program of China · National Natural Science Foundation of China · Natural Science Foundation of Guangdong Province

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