SIMPLE Is an Endosomal Regulator That Protects Against NAFLD by Targeting the Lysosomal Degradation of EGFR

Background and Aims NAFLD has become a tremendous burden for public health; however, there is no drug for NAFLD therapy at present. Impaired endo‐lysosome‐mediated protein degradation is observed in a variety of metabolic disorders, such as atherosclerosis, type 2 diabetes mellitus, and NAFLD. Small integral membrane protein of lysosome/late endosome (SIMPLE) is a regulator of endosome‐to‐lysosome trafficking and cell signaling, but the role that SIMPLE plays in NAFLD progression remains unknown. Here we investigated SIMPLE function in NAFLD development and sophisticated mechanism therein. Approach and Results This study found that in vitro knockdown of SIMPLE significantly aggravated lipid accumulation and inflammation in hepatocytes treated with metabolic stimulation. Consistently, in vivo experiments showed that liver‐specific Simple‐knockout (Simple‐HKO) mice exhibited more severe high‐fat diet (HFD)–induced, high‐fat‐high‐cholesterol diet (HFHC)–induced, and methionine‐choline‐deficient diet (MCD)–induced steatosis, glucose intolerance, inflammation, and fibrosis than those fed with normal chow (NC) diet. Meanwhile, RNA‐sequencing demonstrated the up‐regulated signaling pathways and signature genes involved in lipid metabolism, inflammation, and fibrosis in Simple‐HKO mice compared with control mice under metabolic stress. Mechanically, we found SIMPLE directly interact with epidermal growth factor receptor (EGFR). SIMPLE deficiency results in dysregulated degradation of EGFR, subsequently hyperactivated EGFR phosphorylation, thus exaggerating NAFLD development. Moreover, we demonstrated that using EGFR inhibitor or silencing EGFR expression could ameliorate lipid accumulation induced by the knockdown of SIMPLE. Conclusions SIMPLE ameliorated NASH by prompting EGFR degradation and can be a potential therapeutic candidate for NASH.