A novel mechanism by which ARID2 regulates lipid homeostasis in the liver

On November 17, 2022, the international academic journal Cell Death & Differentiation published online the research results of Xie Dong's research
group entitled "ARID2 mitigates hepatic steatosis via promoting the ubiquitination of JAK2" by the Xie Dong research group of the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences 。 This study reveals the important role of ARID2 in the development and development of NAFLD and provides a promising therapeutic strategy
for NAFLD patients with ARID2 deficiency.

Nonalcoholic fatty liver disease (NAFLD) has gradually become an important threat
to human health in recent years.
Hepatic steatosis is the main hallmark of NAFLD, manifested by triglyceride (TG) aggregation
in liver cells.
Today, obesity and diabetes lead to a worldwide prevalence of NAFLD, and severe NAFLD can lead to nonalcoholic steatohepatitis (NASH), cirrhosis, liver failure and even hepatocellular carcinoma, thereby increasing mortality from
liver-related diseases.
However, due to the complex pathogenesis of NAFLD, there is no effective treatment strategy
today.
Genetic factors have been reported to play an important role
in the NAFLD process.
Therefore, finding the key genes that affect NAFLD and revealing its function is essential
for the treatment of NAFLD.

ARID2 is one of the subunits of the chromatin remodeling complex SWI/SNF and is involved in several important biological processes
.
SWI/SNF complexes are able to reshape nucleosomes and bind to specific DNA regions, regulating gene expression
by influencing epigenetic modifications.
In recent years, there has been increasing evidence that subunits of SWI/SNF complexes play an important role
in the maintenance of metabolic homeostasis.
For example, BAF60a is thought to be an important regulator of liver lipid metabolism
.
In addition, the deletion of Arid1a in mice causes epigenetic dysregulation of lipid production and oxidation-related genes, which in turn leads to NAFLD
.
However, the role of ARID2 in the development of NAFLD is unclear
.

The study found that mice with Arid2 liver-specific knockout spontaneously developed hepatic steatosis at 7 months under normal diet, a process
exacerbated by a high-fat diet.
The researchers further explored the mechanism and revealed that ARID2 affects liver lipid metabolism
through negative regulation of JAK2-STAT5-PPARγ.
Mechanistic studies have found that ARID2 promotes ubiquitination
of JAK2 by upregulating the transcription of the E3 ligase NEDD4L.
ARID2 recruits CARM1 into the promoter region of NEDD4L, increasing the asymmetric double methylation (H3R17me2a) of arginine at position 17 of histone H3 in this region, thereby facilitating its transcription
.
In addition, in mice with Arid2 liver-specific knockout, the inhibitor Fedratinib of JAK2 was effective in alleviating hepatic steeatosis
induced by a high-fat diet.
In liver samples from commercially acquired NAFLD patients, the researchers detected lower levels of the ARID2 protein and verified a negative correlation
between ARID2 and JAK2.
In summary, this study reveals the important role of ARID2 in maintaining liver lipid homeostasis, and provides an effective therapeutic strategy reference
for patients with NAFLD with ARID2 deficiency.

Cao Huijun, a doctoral graduate of the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, is the first author of the paper, and Li Jingjing, associate researcher and researcher Xie Dong, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, are the corresponding authors
of this paper.
The research was supported by the National Natural Science Foundation of China and the Chinese Academy of Sciences, as well as the public technology platform and animal platform of the Shanghai Institute of Nutrition and Health
, Chinese Academy of Sciences.

Fig.
Schematic diagram of the mechanism by which ARID2 maintains lipid homeostasis in the liver

Original link: https://doi.
org/10.
1038/s41418-022-01090-0