Fas apoptotic inhibitor molecule 2 mitigates metabolic dysfunction-associated fatty liver disease through autophagic CRTC2 degradation.

Lysosomal membrane proteins play fundamental roles in the lysosomal degradation of proteins and are attractive drug targets for metabolic dysfunction-associated fatty liver disease (MAFLD). Fas apoptotic inhibitory molecule 2 (FAIM2), a lysosomal membrane protein, has been recognized as an inhibitor of apoptosis in a variety of diseases. Here we reveal that FAIM2 is an inhibitor of fatty acid synthesis and suppresses MAFLD. FAIM2 protein expression is decreased in MAFLD. Moreover, FAIM2 is degraded by the E3 ubiquitin ligase NEDD4L through the catalysis of K48-linked ubiquitination. High-fat and high-cholesterol diet-induced hepatic steatosis, inflammation and fibrosis are aggravated in Faim2-knockout mice and alleviated in mice with AAV8-mediated FAIM2 overexpression. Furthermore, in hepatocytes, FAIM2 knockout increases the expression of genes related to fatty acid synthesis, while overexpressing FAIM2 exhibits the opposite effect. Mechanistically, FAIM2 directly interacts with CREB-regulated transcription coactivator 2 (CRTC2), a prominent regulator of lipid metabolism, and mediates its degradation through autophagy. Specifically, we find that the N terminus of FAIM2, which interacts with CRTC2 and LC3, is required for autophagic degradation of CRTC2. Collectively, our findings reveal that FAIM2 acts as a fatty acid synthesis inhibitor in MAFLD by promoting the autophagic degradation of CRTC2 and that FAIM2-CRTC2 may be a promising therapeutic target.