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.