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Arid1a protects against hepatic steatosis and insulin resistance via PPARα-mediated fatty acid oxidation

Yu-Lan Qu, Chuan-Huai Deng, Qing Luo, Xue-Ying Shang, Jiao-Xiang Wu, Yi Shi, Lan-Wang, Ze-Guang Han
doi: https://doi.org/10.1101/507517
Yu-Lan Qu
1Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Centre for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
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Chuan-Huai Deng
1Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Centre for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
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Qing Luo
1Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Centre for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
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Xue-Ying Shang
1Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Centre for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
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Jiao-Xiang Wu
1Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Centre for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
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Yi Shi
1Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Centre for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
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Lan-Wang
1Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Centre for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
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Ze-Guang Han
1Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Centre for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
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  • For correspondence: hanzg@sjtu.edu.cn
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Abstract

Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) have become a worldwide health concern because of lifestyle changes, but it is still lack of specific therapeutic strategies as the underlying molecular mechanisms remain poorly understood. Our previous study indicated that deficiency of Arid1a, a key component of SWI/SNF chromatin remodeling complex, initiated mouse steatohepatitis, implying that Arid1a might be essentially required for the integrity of hepatic lipid metabolism. However, the exact mechanisms of the pathological process due to Arid1a loss are unclear. In the present work, we show that hepatocyte-specific deletion of Arid1a significantly increases susceptibility to develop hepatic steatosis and insulin resistance in mice fed with high-fat diet (HFD), along with the aggravated inflammatory responses marked by increment of serum alanine amino transferase (AST), aspartate amino transferase (AST) and TNFα. Mechanistically, Arid1a deficiency leads to the reduction of chromatin modification characteristic of transcriptional activation on multiple metabolic genes, especially Cpt1a and Acox1, two rate-limiting enzyme genes for fatty acid oxidation. Furthermore, our data indicated that Arid1a loss promotes hepatic steatosis by downregulating PPARα, thereby impairing fatty acid oxidation which leads to lipid accumulation and insulin resistance. These findings reveal that targeting ARID1a might be a promising therapeutic strategy for NAFLD, NASH and insulin resistance.

Abbreviations
NAFLD
non-alcoholic fatty liver disease
NASH
non-alcoholic steatohepatitis
FAO
fatty acid oxidation
FAs
fatty acids
FD
high fat diet
CD
chow diet
GTT
glucose tolerance test
ITT
insulin tolerance test
LKO
liver-specific knockout
HE
hematoxylin and eosin
TG
triglyceride
TCHO
total cholesterol
NEFA
non-esterified fatty acid
ALT
alanine amino transferase
AST
aspartate amino transferase
ALP
alkaline phosphatase
KEGG
Kyoto Encyclopedia of Genes and Genomes
GO
gene ontology
OA
oleic acid
PA
palmitic acid.
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Posted January 09, 2019.
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Arid1a protects against hepatic steatosis and insulin resistance via PPARα-mediated fatty acid oxidation
Yu-Lan Qu, Chuan-Huai Deng, Qing Luo, Xue-Ying Shang, Jiao-Xiang Wu, Yi Shi, Lan-Wang, Ze-Guang Han
bioRxiv 507517; doi: https://doi.org/10.1101/507517
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Arid1a protects against hepatic steatosis and insulin resistance via PPARα-mediated fatty acid oxidation
Yu-Lan Qu, Chuan-Huai Deng, Qing Luo, Xue-Ying Shang, Jiao-Xiang Wu, Yi Shi, Lan-Wang, Ze-Guang Han
bioRxiv 507517; doi: https://doi.org/10.1101/507517

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