PRMT3 regulates hepatic lipogenesis through direct interaction with LXRα

Area of Science:

• Molecular Biology
• Hepatology
• Biochemistry

Background:

• Arginine methylation, mediated by protein arginine methyltransferases (PRMTs), is crucial for biological functions.
• Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive hepatic lipogenesis, often involving liver X receptor alpha (LXRα).

Purpose of the Study:

• To investigate the role of PRMTs in NAFLD pathogenesis.
• To elucidate the relationship between PRMTs, specifically PRMT3, and LXRα in the context of NAFLD.

Main Methods:

• Utilized palmitic acid (PA) treatment in cell lines and PRMT3 knockout (KO) mouse embryonic fibroblast (MEF) cells.
• Employed overexpression and silencing techniques for PRMT3.
• Conducted studies in high-fat diet-induced animal models and analyzed samples from NAFLD patients.

Main Results:

• PA treatment increased PRMT3 expression, correlating with elevated hepatic lipogenic proteins.
• PRMT3 overexpression enhanced lipogenic protein expression, while silencing or KO reduced it.
• PRMT3 directly bound to LXRα, increasing its transcriptional activity and translocating to the nucleus upon PA treatment.
• High-fat diet and NAFLD patients showed increased LXRα and PRMT3 expression and binding, particularly in LXRα KO mice where this was absent.
• PRMT3 acted as a transcriptional cofactor for LXRα, inducing lipogenesis.

Conclusions:

• PRMT3 translocation, induced by fatty acids, facilitates binding with LXRα, promoting hepatic lipogenesis.
• The LXRα-PRMT3 interaction is a key driver in the onset and progression of fatty liver disease.
• PRMT3 represents a potential therapeutic target for NAFLD.