DEAD‐Box Helicase 17 exacerbates non‐alcoholic steatohepatitis via transcriptional repression of cyp2c29, inducing hepatic lipid metabolism disorder and eliciting the activation of M1 macrophages

• Published in: Clinical and translational medicine 2024-02, Vol.14 (2), p.e1529-n/a
• Main Authors: Ning, Deng, Jin, Jie, Fang, Yuanyuan, Du, Pengcheng, Yuan, Chaoyi, Chen, Jin, Huang, Qibo, Cheng, Kun, Mo, Jie, Xu, Lei, Guo, Hui, Yang, Mia Jiming, Chen, Xiaoping, Liang, Huifang, Zhang, Bixiang, Zhang, Wanguang
• Format: Article
• Language: English
• Subjects: 14,15‐EET; Animals; CTCF; Cyp2c29; DDX17; DDX5; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; Diet; Diet, High-Fat - adverse effects; Disease Progression; Fibrosis; Gene Expression; Humans; Inflammation; Lipid Metabolism - genetics; Lipid Metabolism Disorders - genetics; Lipids; Liver cancer; Luciferases - metabolism; Macrophages - metabolism; Male; Metabolism; Mice; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - pathology; non‐alcoholic steatohepatitis; Plasmids; RNA polymerase
• ISSN: 2001-1326; 2001-1326
• DOI: 10.1002/ctm2.1529

Objective Our study was to elucidate the role of RNA helicase DEAD‐Box Helicase 17 (DDX17) in NAFLD and to explore its underlying mechanisms. Methods We created hepatocyte‐specific Ddx17‐deficient mice aim to investigate the impact of Ddx17 on NAFLD induced by a high‐fat diet (HFD) as well as methionine and choline‐deficient l‐amino acid diet (MCD) in adult male mice. RNA‐seq and lipidomic analyses were conducted to depict the metabolic landscape, and CUT&Tag combined with chromatin immunoprecipitation (ChIP) and luciferase reporter assays were conducted. Results In this work, we observed a notable increase in DDX17 expression in the livers of patients with NASH and in murine models of NASH induced by HFD or MCD. After introducing lentiviruses into hepatocyte L02 for DDX17 knockdown or overexpression, we found that lipid accumulation induced by palmitic acid/oleic acid (PAOA) in L02 cells was noticeably weakened by DDX17 knockdown but augmented by DDX17 overexpression. Furthermore, hepatocyte‐specific DDX17 knockout significantly alleviated hepatic steatosis, inflammatory response and fibrosis in mice after the administration of MCD and HFD. Mechanistically, our analysis of RNA‐seq and CUT&Tag results combined with ChIP and luciferase reporter assays indicated that DDX17 transcriptionally represses Cyp2c29 gene expression by cooperating with CCCTC binding factor (CTCF) and DEAD‐Box Helicase 5 (DDX5). Using absolute quantitative lipidomics analysis, we identified a hepatocyte‐specific DDX17 deficiency that decreased lipid accumulation and altered lipid composition in the livers of mice after MCD administration. Based on the RNA‐seq analysis, our findings suggest that DDX17 could potentially have an impact on the modulation of lipid metabolism and the activation of M1 macrophages in murine NASH models. Conclusion These results imply that DDX17 is involved in NASH development by promoting lipid accumulation in hepatocytes, inducing the activation of M1 macrophages, subsequent inflammatory responses and fibrosis through the transcriptional repression of Cyp2c29 in mice. Therefore, DDX17 holds promise as a potential drug target for the treatment of NASH. DDX17 expression is elevated in the livers of patients with NASH. DDX17 accelerates NASH development by promoting lipid accumulation in hepatocytes. DDX17 alters lipid composition in murine NASH model. Hepatocyte DDX17 induces the activation of M1 macrophages and subsequent inflammatory response and fibrosis th