Gasdermin D plays a key role as a pyroptosis executor of non-alcoholic steatohepatitis in humans and mice

• Published in: Journal of hepatology 2018-04, Vol.68 (4), p.773-782
• Main Authors: Xu, Bing, Jiang, Mingzuo, Chu, Yi, Wang, Weijie, Chen, Di, Li, Xiaowei, Zhang, Zhao, Zhang, Di, Fan, Daiming, Nie, Yongzhan, Shao, Feng, Wu, Kaichun, Liang, Jie
• Format: Article
• Language: English
• Subjects: Choline; Disease; Fatty liver; Fibrosis; Gangrene; GSDMD; GSDMD-N; High fat diet; IL-1β; Inflammation; Lipogenesis; Liver cancer; Liver diseases; Medical diagnosis; Methionine; Monocyte chemoattractant protein 1; N protein; NF-ĸB; Non-alcoholic steatohepatitis; Pathogenesis; Pyroptosis; Signal transduction; Steatosis; Tumor necrosis factor-α
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2017.11.040

[Display omitted] •Hepatic N-terminal cleavage fragments of GSDMD (GSDMD-N) are associated with lobular inflammation and hepatic ballooning.•GSDMD-N is a potential biomarker for the diagnosis of non-alcoholic steatohepatitis.•GSDMD plays a key role in steatohepatitis by mediating macrophage infiltration, NF-ĸB activation and lipogenesis. Gasdermin D (GSDMD)-executed programmed necrosis is involved in inflammation and controls interleukin (IL)-1β release. However, the role of GSDMD in non-alcoholic steatohepatitis (NASH) remains unclear. We investigated the role of GSDMD in the pathogenesis of steatohepatitis. Human liver tissues from patients with non-alcoholic fatty liver disease (NAFLD) and control individuals were obtained to evaluate GSDMD expression. Gsdmd knockout (Gsdmd−/−) mice, obese db/db mice and their wild-type (WT) littermates were fed with methionine-choline deficient (MCD) or control diet to induce steatohepatitis. The Gsdmd−/− and WT mice were also used in a high-fat diet (HFD)-induced NAFLD model. In addition, Alb-Cre mice were administered an adeno-associated virus (AAV) vector that expressed the gasdermin-N domain (AAV9-FLEX-GSDMD-N) and were fed with either MCD or control diet for 10 days. GSDMD and its pyroptosis-inducing fragment GSDMD-N were upregulated in liver tissues of human NAFLD/NASH. Importantly, hepatic GSDMD-N protein levels were significantly higher in human NASH and correlated with the NAFLD activity score and fibrosis. GSDMD-N remained a potential biomarker for the diagnosis of NASH. MCD-fed Gsdmd−/− mice exhibit decreased severity of steatosis and inflammation compared with WT littermates. GSDMD was associated with the secretion of pro-inflammatory cytokines (IL-1β, TNF-α, and MCP-1 [CCL2]) and persistent activation of the NF-ĸB signaling pathway. Gsdmd−/− mice showed lower steatosis, mainly because of reduced expression of the lipogenic gene Srebp1c (Srebf1) and upregulated expression of lipolytic genes, including Pparα, Aco [Klk15], Lcad [Acadl], Cyp4a10 and Cyp4a14. Alb-Cre mice administered with AAV9-FLEX-GSDMD-N showed significantly aggravated steatohepatitis when fed with MCD diet. As an executor of pyroptosis, GSDMD plays a key role in the pathogenesis of steatohepatitis, by controlling cytokine secretion, NF-ĸB activation, and lipogenesis. Non-alcoholic fatty liver disease has become one of the most feared chronic liver diseases, because it is the most rapidly growing indication for adult liver transplantation an