Song Jingjing, Liu Yupeng, Wan Juan, Zhao Guang-Nian, Wang Jian-Cheng, Dai Zhifei, Hu Sha, Yang Ling, Liu Zhen, Fu Yi, Dong Erdan, Tang Yi-Da
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.
Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Hepatology. 2021 Dec;74(6):3091-3109. doi: 10.1002/hep.32075. Epub 2021 Nov 2.
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.
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.
SIMPLE ameliorated NASH by prompting EGFR degradation and can be a potential therapeutic candidate for NASH.
非酒精性脂肪性肝病（NAFLD）已成为公共卫生的巨大负担；然而，目前尚无用于NAFLD治疗的药物。在多种代谢紊乱中，如动脉粥样硬化、2型糖尿病和NAFLD，均观察到内吞溶酶体介导的蛋白质降解受损。溶酶体/晚期内体小整合膜蛋白（SIMPLE）是内体到溶酶体运输和细胞信号传导的调节因子，但SIMPLE在NAFLD进展中的作用尚不清楚。在此，我们研究了SIMPLE在NAFLD发展中的功能及其复杂机制。
本研究发现，在体外敲低SIMPLE可显著加重经代谢刺激处理的肝细胞中的脂质积累和炎症。同样，体内实验表明，肝脏特异性敲除Simple（Simple-HKO）小鼠比喂食正常饲料（NC）的小鼠表现出更严重的高脂饮食（HFD）诱导、高脂高胆固醇饮食（HFHC）诱导和蛋氨酸-胆碱缺乏饮食（MCD）诱导的脂肪变性、葡萄糖不耐受、炎症和纤维化。同时，RNA测序显示，与代谢应激下的对照小鼠相比，Simple-HKO小鼠中参与脂质代谢、炎症和纤维化的信号通路和特征基因上调。从机制上讲，我们发现SIMPLE直接与表皮生长因子受体（EGFR）相互作用。SIMPLE缺乏导致EGFR降解失调，随后EGFR磷酸化过度激活，从而加剧NAFLD的发展。此外，我们证明使用EGFR抑制剂或沉默EGFR表达可改善敲低SIMPLE诱导的脂质积累。
SIMPLE通过促进EGFR降解改善非酒精性脂肪性肝炎（NASH），可成为NASH的潜在治疗候选药物。
