Fas apoptotic inhibitor molecule 2 mitigates metabolic dysfunction-associated fatty liver disease through autophagic...

Area of Science:

• Cell Biology
• Molecular Biology
• Hepatology

Background:

• Lysosomal membrane proteins are crucial for cellular degradation and are potential therapeutic targets for metabolic dysfunction-associated fatty liver disease (MAFLD).
• Fas apoptotic inhibitory molecule 2 (FAIM2) is a lysosomal protein known to inhibit apoptosis.
• Reduced FAIM2 expression is observed in MAFLD patients.

Purpose of the Study:

• To investigate the role of FAIM2 in fatty acid synthesis and its potential as a therapeutic target for MAFLD.
• To elucidate the mechanism by which FAIM2 regulates lipid metabolism.

Main Methods:

• Utilized Faim2-knockout and FAIM2-overexpressing mouse models fed high-fat/high-cholesterol diets.
• Analyzed gene expression related to fatty acid synthesis in hepatocytes.
• Investigated the interaction between FAIM2, CRTC2, and autophagy-related proteins (LC3) using biochemical assays.

Main Results:

• FAIM2 deficiency aggravated diet-induced hepatic steatosis, inflammation, and fibrosis in mice.
• FAIM2 overexpression alleviated these conditions.
• FAIM2 knockout increased, while overexpression decreased, the expression of genes involved in fatty acid synthesis.
• FAIM2 directly interacts with CRTC2 and mediates its autophagic degradation via its N-terminus.

Conclusions:

• FAIM2 functions as an inhibitor of fatty acid synthesis, suppressing MAFLD progression.
• FAIM2 exerts its function by promoting the autophagic degradation of CRTC2.
• The FAIM2-CRTC2 pathway represents a promising therapeutic target for MAFLD.