Hepatocyte SH3RF2 Deficiency Is a Key Aggravator for NAFLD

Area of Science:

• Hepatology
• Molecular Biology
• Biochemistry

Background:

• Non-alcoholic fatty liver disease (NAFLD) is a prevalent global liver condition with limited pharmacological treatments.
• Understanding the molecular mechanisms underlying NAFLD pathogenesis is crucial for developing effective therapies.

Purpose of the Study:

• To investigate the role of the E3 ligase SH3 domain-containing ring finger 2 (SH3RF2) in NAFLD.
• To elucidate the underlying molecular mechanisms by which SH3RF2 influences NAFLD progression.

Main Methods:

• Assessed SH3RF2 expression in NAFLD models (mice, monkeys, humans).
• Utilized genetic models to study the impact of SH3RF2 deficiency on lipid accumulation in hepatocytes and diet-induced NAFLD mice.
• Investigated the interaction between SH3RF2 and ATP citrate lyase (ACLY) and its effect on ACLY ubiquitination and degradation.

Main Results:

• SH3RF2 expression was found to be suppressed in NAFLD across various models.
• Hepatocyte-specific SH3RF2 deficiency exacerbated lipid accumulation in vitro and in vivo.
• SH3RF2 directly targeted ACLY for degradation, leading to increased acetyl-CoA, enhanced de novo lipogenesis, and cholesterol production.

Conclusions:

• SH3RF2 plays a critical protective role in preventing NAFLD progression.
• SH3RF2 depletion in hepatocytes is a key factor in aggravating NAFLD.
• SH3RF2 emerges as a potential therapeutic target for non-alcoholic fatty liver disease.