Inhibition of the NLRP3 inflammasome in a mouse model of NASH reduces hepatic inflammation and liver fibrosis, according to new research published in the Journal of Hepatology.

Credit: Laura Marshall/Macmillan Publishers Limited

Excess hepatic levels of lipotoxic lipids, such as ceramides, diacylglycerols and free fatty acids, have been suggested as key molecules promoting progression of NAFLD to NASH. In the past few years, other lipid species have also been investigated. “We and several other groups have found evidence to support free cholesterol as the lipotoxin,” explains author Geoffrey Farrell. “In the atherosclerosis literature, it has been shown that cholesterol crystals ... provoke activation of the NLRP3 inflammasome.” Hepatic NLRP3 inflammasome activation, which promotes caspase-1-dependent IL-1β production, occurs in patients with NASH, and evidence from knockout mouse models suggests activation of the inflammasome is important in NAFLD progression.

To probe the role of the NLRP3 inflammasome in NASH, Farrell and colleagues treated an overnutrition mouse model of NASH with a selective small molecule NLRP3 inhibitor, MCC950, or a control solution for 8 weeks. Mice treated with the control solution had upregulated levels of hepatic NLRP3, IL-1β and active caspase 1, in addition to NASH pathology and cholesterol crystal accumulation in the liver. By contrast, MCC950 prevented increased expression of these proteins and reduced levels of plasma inflammatory markers.

Despite no treatment effect on body weight, hepatic steatosis extent and cholesterol crystal levels, NASH severity was reduced in treated mice, primarily as a result of reduced histologically assessed liver inflammation and hepatocyte ballooning. Liver fibrosis progression over the 8 weeks was also lessened in mice treated with MCC950. In vitro, Kupffer cells and macrophages were activated by cholesterol crystals, releasing IL-1β. Treatment with MCC950 inhibited this activation and associated neutrophil chemotaxis, suggesting that the treatment suppresses cholesterol-crystal- mediated immune activation.

“By using an intervention in whole animals that specifically blocks NLRP3, these results are the most powerful to date that indicate a key role for NLRP3 activation in the liver for NASH pathogenesis,” Farrell concludes. “We now plan to study more rigorously, using a longer time course, the extent to which NLRP3 blockade (using MCC950 as our tool compound) can reverse liver fibrosis in established NASH in our mouse model.”