Journal
EBIOMEDICINE
Volume 42, Issue -, Pages 481-493Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ebiom.2019.03.021
Keywords
Arid1a; Steatosis; Insulin resistance; Fatty acid oxidation; PPAR alpha
Funding
- National Natural Science Foundation of China [81672772, 81472621]
- China National Science and Technology Major Project for Prevention and Treatment of Infectious Diseases [2017ZX 10203207]
- National Programon Key Research Project of China [2016YFC0902701]
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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 PPAR alpha 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. (C) 2019 The Authors. Published by Elsevier B.V.
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