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

Lysosomal membrane proteins (LMPs) 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), an LMP, is previously 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 catalyzing K48-linked ubiquitination. High-fat or high-fat and high-cholesterol diet-induced hepatic steatosis, inflammation and fibrosis was aggravated in FAIM2 knockout (KO) mice and alleviated in FAIM2 overexpressing mice. Furthermore, in hepatocytes, FAIM2 KO increased the expression of genes related to fatty acid synthesis, whereas over-expressing FAIM2 exhibits the opposite effect. Mechanistically, FAIM2 directly interacts with CREB-regulated transcription coactivator 2 (CRTC2), a prominent regulator of lipid metabolism, and medicates its degradation through autophagy. Specifically, we find that the N-terminus of FAIM2 which interacts with CRCT2 and LC3B is required for autophagic CRTC2 degradation. Collectively, our findings reveal that FAIM2 acts as a fatty acid synthesis inhibitor in MAFLD by promoting the autophagic degradation of CRTC2, and FAIM2-CRTC2 may be a promising therapeutic target.