Arid1a regulates insulin sensitivity and lipid metabolismResearch in context
Yu-Lan Qu,
Chuan-Huai Deng,
Qing Luo,
Xue-Ying Shang,
Jiao-Xiang Wu,
Yi Shi,
Lan Wang,
Ze-Guang Han
Affiliations
Yu-Lan Qu
Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
Chuan-Huai Deng
Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
Qing Luo
Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
Xue-Ying Shang
Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
Jiao-Xiang Wu
Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China; Collaborative Innovation Center of Systems Biomedicine of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Yi Shi
Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
Lan Wang
Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
Ze-Guang Han
Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China; Corresponding author at: Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
Background: Although significant progress has been made in understanding the mechanisms of steatosis and insulin resistance, the physiological functions of the epigenetic regulators in these processes remain largely elusive. Methods: Hepatocyte-specific Arid1a knockout mice were administrated with high-fat diet (HFD) for 12 weeks, then insulin sensitivity was assessed by glucose tolerance test (GTT) and insulin tolerance test (ITT). The metabolism-related indicators were determined by employing a variety of biological methods, including histology, real-time PCR, enzyme-linked immunosorbent assay (ELISA), Western blotting assay, Chromatin immunoprecipitation (ChIP), RNA-seq and assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq). Findings: Hepatocyte-specific Arid1a deletion significantly increases susceptibility to develop hepatic steatosis, insulin resistance and inflammation in mice fed a HFD. In vitro, Arid1a deletion in isolated hepatocytes directly leads to free fatty acid-induced lipid accumulation and insulin resistance. Mechanically, Arid1a deficiency impairs fatty acid oxidation by downregulating PPARα and altering the epigenetic landscape of some metabolism genes. Interpretation: These findings reveal that targeting Arid1a might be a promising therapeutic strategy for liver steatosis and insulin resistance. Fund: This work was supported by National Natural Science Foundation of China (81672772 and 81472621), China National Science and Technology Major Project for Prevention and Treatment of Infectious Diseases (No.2017ZX 10203207) and National Program on Key Research Project of China (grant no. 2016YFC0902701). Keywords: Arid1a, Steatosis, Insulin resistance, Fatty acid oxidation, PPARα
