Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines , School of Traditional Chinese Pharmacy , China Pharmaceutical University , Nanjing , China.
Hepatology. 2023 May 1;77(5):1670-1687. doi: 10.1002/hep.32651. Epub 2023 Apr 17.
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.
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 ligase (E3) tripartite motif protein 5, thereby significantly reducing lipid accumulation and inflammation in a NASH mouse model.
These findings provide mechanistic insight into the role of DDX5 in mTORC1 regulation and NASH progression, as well as suggest a number of targets and a promising lead compound for therapeutic interventions against NASH.
非酒精性脂肪性肝病及其进展形式，即非酒精性脂肪性肝炎（NASH），正在迅速成为肝细胞癌（HCC）的首要病因。目前，尚无批准用于治疗 NASH 的疗法。 DEAD-box 蛋白 5（DDX5）在不同的细胞过程中发挥着重要作用。然而，DDX5 在 NASH 中的确切作用尚不清楚。
在 NASH 患者、饮食诱导的 NASH 小鼠模型（高脂肪饮食[HFD]、蛋氨酸和胆碱缺乏饮食、胆碱缺乏 HFD）、NASH-HCC 小鼠模型（二乙基亚硝胺加 HFD）和棕榈酸刺激的肝细胞中，DDX5 的表达下调。腺相关病毒介导的 DDX5 过表达可改善肝脂肪变性和炎症，而其缺失则使此类病理加重。进行了非靶向代谢组学分析以研究 DDX5 在 NASH 和 NASH-HCC 中的作用机制，这表明 DDX5 对脂质代谢具有调节作用。DDX5 通过募集结节性硬化复合物（TSC）1/2 复合物到 mTORC1 来抑制雷帕霉素复合物 1（mTORC1）的激活，从而改善脂质代谢并减轻 NACHT、富含亮氨酸重复（LRR）和吡喃结构域（PYD）的包含蛋白 3 炎症小体的激活。我们进一步发现，植物化学化合物 hyperforcinol K 与 DDX5 直接相互作用，并防止其被泛素连接酶（E3）三联体基序蛋白 5 介导的泛素化降解，从而在 NASH 小鼠模型中显著减少脂质积累和炎症。
这些发现为 DDX5 在 mTORC1 调节和 NASH 进展中的作用提供了机制上的见解，并为针对 NASH 的治疗干预提出了多个靶点和有前途的先导化合物。
