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

## TL;DR

FAIM2 reduces liver fat and inflammation in MAFLD by breaking down a protein called CRTC2 through autophagy.

## Contribution

FAIM2 is identified as a novel inhibitor of fatty acid synthesis and a potential therapeutic target for MAFLD.

## Key findings

- FAIM2 levels are decreased in MAFLD and its degradation is mediated by NEDD4L.
- FAIM2 interacts with CRTC2 and promotes its autophagic degradation to suppress fatty acid synthesis.
- Overexpression of FAIM2 in mice alleviates hepatic steatosis, inflammation, and fibrosis.

## Abstract

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.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common liver condition affecting many people worldwide. Researchers are looking for new ways to treat MAFLD. A recent study explored the role of a protein called FAIM2 in MAFLD. They found that FAIM2 levels are lower in people with MAFLD, and this protein helps reduce fat buildup in the liver. Researchers used mice and primary hepatocytes to study the function of FAIM2. They discovered that, when FAIM2 is missing, fat and inflammation in the liver increase. However, increasing FAIM2 levels can reduce these issues. FAIM2 works by interacting with another protein, CRTC2, and helps break it down through a process called autophagy. The study suggests that boosting FAIM2 could be a new way to treat MAFLD by reducing fat buildup in the liver.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.