RNA helicase DEAD‐box protein 5 alleviates nonalcoholic steatohepatitis progression via tethering TSC complex and suppressing mTORC1 signaling

作者：Yanqiu Zhang, Shengtao Ye, Wei-Jia Lu, Jiawen Zhong, Yingrong Leng, Ting Yang, Jun Luo, Wen‐Jun Xu, Hao Zhang, Ling‐Yi Kong · 发表于：Hepatology · 年份：2022 · DOI：10.1002/hep.32651 · 被引用次数：36 · 研究领域：RNA Research and Splicing、PI3K/AKT/mTOR signaling in cancer、Liver Disease Diagnosis and Treatment

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease and its progressive form, nonalcoholic steatohepatitis (NASH), are rapidly becoming the top causes of hepatocellular carcinoma (HCC). Currently, there are no approved therapies for the treatment of NASH. DEAD-box protein 5 (DDX5) plays important roles in different cellular processes. However, the precise role of DDX5 in NASH remains unclear. APPROACH AND RESULTS: DDX5 expression was downregulated in patients with NASH, mouse models with diet-induced NASH (high-fat diet [HFD], methionine- and choline-deficient diet, and choline-deficient HFD), mouse models with NASH-HCC (diethylnitrosamine with HFD), and palmitic acid-stimulated hepatocytes. Adeno-associated virus-mediated DDX5 overexpression ameliorates hepatic steatosis and inflammation, whereas its deletion worsens such pathology. The untargeted metabolomics analysis was carried out to investigate the mechanism of DDX5 in NASH and NASH-HCC, which suggested the regulatory effect of DDX5 on lipid metabolism. DDX5 inhibits mechanistic target of rapamycin complex 1 (mTORC1) activation by recruiting the tuberous sclerosis complex (TSC)1/2 complex to mTORC1, thus improving lipid metabolism and attenuating the NACHT-, leucine-rich-repeat (LRR)-, and pyrin domain (PYD)-containing protein 3 inflammasome activation. We further identified that the phytochemical compound hyperforcinol K directly interacted with DDX5 and prevented its ubiquitinated degradation mediated by ubiquitin l...