EVA1A Regulates Hepatic Lipid Homeostasis by Modulating CD36 Expression and Its Palmitoylation

Area of Science:

• Hepatology
• Molecular Metabolism
• Oncology

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) is driven by hepatic lipid dysregulation.
• The precise molecular mechanisms governing hepatic lipid metabolism require further elucidation.

Purpose of the Study:

• To investigate the role of EVA1A, a known hepatocellular carcinoma tumor suppressor, in regulating hepatic lipid metabolism.
• To elucidate the molecular mechanisms by which EVA1A influences fatty liver disease.

Main Methods:

• Examined EVA1A expression in MASLD patients and high-fat diet-induced obese mice.
• Utilized hepatocyte-specific Eva1a knockout and overexpression mouse models.
• Investigated the impact on fatty acid metabolism, including uptake and β-oxidation.
• Analyzed the involvement of mTORC1, PPARγ2, CD36, APT1, and ZDHHC4/5 in EVA1A-mediated regulation.

Main Results:

• Hepatic EVA1A was downregulated in MASLD and high-fat diet models.
• Eva1a knockout led to hepatic steatosis, increased fatty acid uptake, and impaired β-oxidation.
• EVA1A overexpression reversed these metabolic abnormalities.
• EVA1A deficiency activated mTORC1-PPARγ2 signaling, upregulating CD36, and modulated APT1/ZDHHC4/5 to enhance CD36 palmitoylation and cell surface localization.

Conclusions:

• EVA1A is an essential regulator of hepatic lipid homeostasis.
• EVA1A controls fatty acid uptake and β-oxidation by modulating CD36 expression and palmitoylation.
• The EVA1A-CD36 axis presents a potential therapeutic target for MASLD.