Highlights
- •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.
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.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: December 19, 2017
Accepted:
November 24,
2017
Received in revised form:
November 22,
2017
Received:
June 6,
2017
See Editorial, pages 643–645Identification
Copyright
© 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
