SREBP-2/PNPLA8 axis improves non-alcoholic fatty liver disease through activation of autophagy

Area of Science:

• Hepatology
• Molecular Biology
• Metabolic Diseases

Background:

• Dysregulated autophagy is linked to hepatic steatosis and non-alcoholic fatty liver disease (NAFLD).
• Mechanisms connecting autophagy and NAFLD remain incompletely understood.
• Statins are investigated for their potential benefits in managing NAFLD.

Purpose of the Study:

• To elucidate the mechanisms by which lovastatin and ezetimibe impact hepatic steatosis.
• To identify novel molecular pathways regulating lipid homeostasis and autophagy in NAFLD.
• To explore the role of SREBP-2 and PNPLA8 in the context of NAFLD and autophagy.

Main Methods:

• Administration of lovastatin and ezetimibe (L/E) to high-fat diet (HFD)-fed mice.
• Analysis of hepatic triglyceride accumulation and autophagy markers.
• Investigation of sterol regulatory element-binding protein 2 (SREBP-2) and patatin-like phospholipase domain-containing enzyme 8 (PNPLA8) gene expression.
• Live-cell imaging to study PNPLA8 and LC3 interactions.

Main Results:

• Co-administration of L/E significantly reversed hepatic triglyceride accumulation in HFD-fed mice.
• L/E treatment increased SREBP-2 driven autophagy.
• SREBP-2 directly activated PNPLA8 expression, which associated with decreased triglycerides and autophagosomes.
• Over-expression of PNPLA8 reduced hepatic steatosis via enhanced autophagy.

Conclusions:

• The SREBP-2/PNPLA8 axis represents a novel regulatory mechanism for lipid homeostasis.
• PNPLA8 interacts with autophagosomes and LC3, promoting autophagy and reducing hepatic steatosis.
• These findings suggest a potential mechanism for the beneficial effects of statins in NAFLD patients.