TRIB3-TRIM8 complex drives NAFLD progression by regulating HNF4α stability

Area of Science:

• Hepatology and molecular biology
• Liver disease pathogenesis
• Protein degradation mechanisms

Background:

• Endoplasmic reticulum (ER) stress in hepatocytes contributes to non-alcoholic fatty liver disease (NAFLD).
• Reduced hepatic nuclear factor 4α (HNF4α) expression is key in NAFLD and other liver diseases.
• The mechanism of HNF4α protein degradation, particularly under ER stress, was previously unknown.

Purpose of the Study:

• To elucidate the degradation pathway of HNF4α.
• To investigate the role of ER stress in HNF4α regulation.
• To identify therapeutic strategies for NAFLD by stabilizing HNF4α.

Main Methods:

• Evaluated HNF4α and tribbles homologue 3 (TRIB3) correlation in human and mouse NAFLD tissues.
• Employed RNA-sequencing, mass spectrometry, co-immunoprecipitation, and ubiquitination assays.
• Utilized molecular docking and co-immunoprecipitation to identify a peptide inhibiting TRIB3-HNF4α interaction.

Main Results:

• TRIB3 directly interacts with HNF4α, mediating its degradation via ER stress.
• TRIB3, with tripartite motif containing 8 (TRIM8), forms an E3 ligase complex for HNF4α ubiquitination.
• A cell-penetrating peptide disrupting the TRIB3-HNF4α interaction restored HNF4α levels and ameliorated NAFLD in mice.
• A TRIB3 variant (p.Q84R) correlated with NAFLD progression and induced more severe hepatic steatosis in mice.

Conclusions:

• The TRIB3-TRIM8 E3 ligase complex drives HNF4α degradation in NAFLD.
• Targeting the TRIB3-TRIM8 E3 complex offers a potential therapeutic strategy for NAFLD.
• Stabilizing HNF4α by disrupting the TRIB3-HNF4α interaction presents a novel approach for treating NAFLD and other liver diseases.