Intestinal NSD2 Aggravates Nonalcoholic Steatohepatitis Through Histone Modifications

Area of Science:

• Gastroenterology
• Molecular Biology
• Metabolic Diseases

Background:

• A compromised intestinal barrier is increasingly linked to nonalcoholic steatohepatitis (NASH) progression.
• The specific molecular mechanisms driving this intestinal dysfunction in NASH remain unclear.

Purpose of the Study:

• To investigate the role of nuclear receptor-binding SET domain protein 2 (NSD2) in the intestinal barrier dysfunction associated with nonalcoholic steatohepatitis (NASH).
• To elucidate the molecular mechanisms by which NSD2 influences intestinal barrier integrity and NASH pathogenesis.

Main Methods:

• Examined NSD2 expression in intestinal tissues from obese humans and mice on a high-fat cholesterol diet (HFCD).
• Utilized intestine-specific NSD2 knockout and overexpression models in mice to assess the impact on intestinal barrier function and NASH.
• Investigated the epigenetic regulation by NSD2, specifically its role in histone H3 lysine 36 dimethylation (H3K36me2) and its effect on Ern1 gene expression and the ERN1-JNK signaling pathway.

Main Results:

• Found significant upregulation of NSD2 in the intestines of obese humans and mice fed an HFCD.
• Intestine-specific NSD2 knockout attenuated intestinal barrier impairment and NASH progression.
• NSD2 overexpression exacerbated intestinal barrier defects and NASH.
• Demonstrated that NSD2 directly promotes the transcriptional activation of Ern1 via H3K36me2 demethylation, activating the ERN1-JNK axis.

Conclusions:

• NSD2 plays a critical role in mediating intestinal barrier impairment through the H3K36me2 epigenetic modification.
• The NSD2-mediated activation of the ERN1-JNK pathway contributes to NASH progression.
• Targeting intestinal NSD2 presents a potential novel therapeutic strategy for managing NASH.