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Gasdermin D Plays A Key Role As A Pyroptosis Executor Of Non-alcoholic Steatohepatitis

Posted on:2019-05-02Degree:DoctorType:Dissertation
Country:ChinaCandidate:B XuFull Text:PDF
GTID:1364330563955811Subject:Internal medicine (digestive diseases)
Abstract/Summary:PDF Full Text Request
Background:Non-alcoholic fatty liver disease(NAFLD)and its pathologically more severe form non-alcoholic steatohepatitis(NASH)has become one of the most feared chronic liver diseases,because NASH is the most rapidly growing indication for adult liver transplantation and a major cause of hepatocellular carcinoma.However,the mechanisms involved in the pathogenesis of NAFLD/NASH remain unclear.Toxic lipid accumulation in the liver,and their interactions with inflammatory responses,oxidative stress, endoplasmic reticulum stress,autophagy are crucial in the development and progression of NAFLD/NASH.It is important to note that inflammation in the liver is believed to be the compelling feature in steatohepatitis,perpetuating hepatocellular injury and subsequent cell death,and promoting liver fibrosis.Gasdermin D(GSDMD)-executed programmed necrosis is involved in inflammation.However,the role of GSDMD in NASH remains unclear.Aims:To investigate the role of GSDMD in the pathogenesis of NAFLD/NASH and to evaluate its clinical significance of NASH.Moreover,to find out the potential signal pathways that GSDMD may participate in and to intervene to investigate whether GSDMD-mediated pyroptosis may provide a new target for the treatment of NASH.Methods:Human liver tissues from patients with NAFLD and control individuals were obtained to evaluate GSDMD expression and to investigate the relationship between the clinicopathological parameters of NAFLD/NASH patients and GSDMD/GSDMD-N 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-/-mice 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(NAS)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)and persistent activation of the NF-?B signaling pathway.GSDMD-/-mice showed lower steatosis,mainly because of reduced expression of the lipogenic gene SREBP-1c and upregulated expression of lipolytic genes,including PPARα,ACO,LCAD,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-?B activation,and lipogenesis.
Keywords/Search Tags:GSDMD, GSDMD-N, Non-alcoholic steatohepatitis, Pyroptosis, NF-?B
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