Jingjing Song1,2, Yupeng Liu1,2, Juan Wan3, Guang-Nian Zhao4, Jian-Cheng Wang5, Zhifei Dai6, Sha Hu3, Ling Yang3, Zhen Liu3, Yi Fu7, Erdan Dong8,9, Yi-Da Tang1,2,9. 1. Department of Cardiology, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 2. Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 3. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China. 4. Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China. 5. Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China. 6. Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China. 7. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China. 8. The Institute of Cardiovascular Sciences, Peking University, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China. 9. Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China.
Abstract
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.
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.