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

J Hepatol. 2018 Apr;68(4):773-782. doi: 10.1016/j.jhep.2017.11.040. Epub 2017 Dec 20.


Background & aims: 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.

Methods: 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.

Results: 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.

Conclusion: As an executor of pyroptosis, GSDMD plays a key role in the pathogenesis of steatohepatitis, by controlling cytokine secretion, NF-ĸB activation, and lipogenesis.

Lay summary: 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 and a major cause of hepatocellular carcinoma. However, the mechanisms involved in the transformation of simple steatosis to steatohepatitis remain unclear. Herein, we show that gasdermin D driven pyroptosis is prominent in patients with non-alcoholic steatohepatitis (NASH), and gasdermin-N domain remains a potential biomarker for the diagnosis of NASH. Gasdermin D plays a key role in the pathogenesis of NASH by regulating lipogenesis, the inflammatory response, and the NF-ĸB signaling pathway, revealing potential treatment targets for NASH in humans.

Keywords: GSDMD; GSDMD-N; NF-ĸB; Non-alcoholic steatohepatitis; Pyroptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / physiology*
  • Cells, Cultured
  • Cytokines / biosynthesis
  • Diet, High-Fat
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Lipolysis
  • Liver / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / physiology
  • Neoplasm Proteins / physiology*
  • Non-alcoholic Fatty Liver Disease / etiology*
  • Non-alcoholic Fatty Liver Disease / pathology
  • Phosphate-Binding Proteins
  • Pyroptosis*


  • Apoptosis Regulatory Proteins
  • Cytokines
  • GSDMD protein, human
  • Gsdmd protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • Neoplasm Proteins
  • Phosphate-Binding Proteins