LACK OF NLRP3-INFLAMMASOME LEADS TO GUT-LIVER AXIS DERANGEMENT AND INCREASES HEPATIC INJURY IN A MOUSE MODEL OF NON-ALCOHOLIC FATTY LIVER DISEASE

Background and Aims: Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common form of chronic liver disease. The NLRP3- inflammasome can elicit a pro-inflammatory response when activated but also regulates intestinal homeostasis and gut microbiota composition. The NLRP3-inflammasome has been implicated in the pathogenesis of obesity, diabetes and in the progression of chronic liver injury, but its role in NAFLD is controversial. Therefore, the aim of this study was to investigate the role of NLRP3-inflammasome in NAFLD. Methods: Nlrp3-/- and wild-type (WT) C57BL/6 micewere fed with a high-fat diet with fructose in drinking water (HFHC), or a chow diet, for 12 weeks. Results:Nlrp3-/- HFHC showed reduced energyexpenditure and this lead to increased body weight, higher fat mass and adipose tissue TNF-?expression.Nlrp3-/-HFHC developed more hepatic steatosis, measured by triglyceride content, compared to WT HFHC because of augmented SCD-1 activity (a regulator of hepatic lipogenesis) and PPAR?2 expression (that regulates lipid uptake and storage). Increased mitochondrial fatty acid oxidation and reduced expression of NRF2, the"master regulator"of antioxidant response, led to increased superoxide production in Nlrp3-/- HFHC. After HFHC,lack of NLRP3-inflammasome was associated with significantly alteration in intestinal microbiota (higher Firmicutes/Bacteroidetes ratio, and increased levels of mucus-degrading bacteria Akkermansia and Desulfovibrio) which was associated to a"leaky" intestinalbarrier. Concomitantly, hepatic TLR4 and TLR9 expression, inflammatory macrophages in the liver, and NAS score were increased in Nlrp3-/-HFHC mice, indicating increased inflammatory response and liver injury. Gut decontamination by antibiotics reduced body weight, bacterial translocation and liver injury in Nlrp3-/-HFHC mice. Conclusions: Lack of NLRP3-inflammasome is linked to severe metabolic alterations and development of NASH possibly due to translocation of bacterial products.