Abstract
Background and Aims: Activation of the inflammasome NLRP3 (NOD-, LRR- and pyrin domain containing 3) contributes to the development of non-alcoholic fatty liver disease (NAFLD) and progression to non-alcoholic steatohepatitis (NASH). Therefore, this study explored the therapeutic effects of a novel and selective NLRP3 antagonist in a murine dietary model of NASH.Methods: Groups of 12-week-old ApoE -/- mice were fed ad lib for 7 weeks with a methionine/choline deficient (MCD) and western diet (WD). After 3 weeks of diet-induced injury, mice were injected i. p. with the NLRP3 antagonist IFM-514 (100 mg/kg body weight) or vehicle (0.5% carmellose) every day, 5 days/week for a further 4 weeks. Several markers of inflammation, fibrosis and steatosis were evaluated. Whole transcriptome sequencing and panel RNA expression analysis (NanoString) were performed.Results: IFM-514 inhibited IL-1β production in mice challenged with 20 mg/kg lipopolysaccharide, and in mouse and human inflammatory cells in vitro. IFM-514 inhibited hepatic inflammation in the in vivo non-alcoholic steatohepatitis model assessed by H&E staining and in the hepatic gene expression of inflammasome-related proinflammatory cytokines. This effect was associated with significant reduction in caspase-1 activation. Similarly, IFM-514 was efficacious in vivo in MDC-fed ApoE -/- mice, markedly reducing portal pressure, Sirius red staining and 4-hydroxyproline content compared to vehicle-treated mice. Moreover, IFM-514 significantly reduced hepatic steatosis in MCD-fed ApoE -/- mice, as evidenced by NAFLD scores, oil red O staining, hepatic triglycerides and gene expression. In WD treated animals, similar trends in inflammation and fibrosis were observed, although not sufficient IFM-514 levels were reached.Conclusion: Overall, IFM-514 reduced liver inflammation and fibrosis, with mild effects on liver steatosis in experimental murine NASH. Blocking of NLRP3 may be an attractive therapeutic approach for NASH patients.
Highlights
Non-alcoholic fatty liver disease (NAFLD), characterized by fat accumulation in the liver in the absence of chronic alcohol use, is a common and emerging cause of chronic liver disease (Williams et al, 2011; Rinella, 2015)
nonalcoholic steatohepatitis (NASH) represents the severe and dangerous form of NAFLD characterized by hepatocyte injury, inflammation and fibrosis - the most critical outcome in NASH, that may result from inflammasome activation (Ganz et al, 2015)
Since this approach lacks specificity and is likely to produce many offtarget effects (Bahia et al, 2015), this study tested a novel selective NOD-like receptor protein 3 (NLRP3) antagonist for therapeutic effects in murine models of NASH. Since both NASH and NLRP3 have been linked to metabolic syndrome we have chosen murine models for which we have previously demonstrated that it is suitable for investigation of liver of metabolic syndrome (Schierwagen et al, 2015, 2016)
Summary
Non-alcoholic fatty liver disease (NAFLD), characterized by fat accumulation in the liver (steatosis) in the absence of chronic alcohol use, is a common and emerging cause of chronic liver disease (Williams et al, 2011; Rinella, 2015). Several members of the NLR family (nucleotide-binding and oligomerization domain and leucine-rich-repeat-containing proteins), including the NOD-like receptor protein 3 (NLRP3), have been linked to the pathophysiology of NASH (Abstract diagram). This has inspired strategies to block inflammasome activation by pharmacological targeting of NLRP3 (Próchnicki et al, 2016). Inhibition of NLRP3 can be achieved by limiting Toll-like receptor- and tumor necrosis factor-mediated increases in NLRP3 expression Since this approach lacks specificity and is likely to produce many offtarget effects (Bahia et al, 2015), this study tested a novel selective NLRP3 antagonist for therapeutic effects in murine models of NASH. This study explored the therapeutic effects of a novel and selective NLRP3 antagonist in a murine dietary model of NASH
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