NLRP3 Deficiency in Nonimmune Cells Averts Obesity-Induced Fatty Liver Disease

Abstract

Obesity predisposes to metabolic dysfunction-associated fatty liver disease (MAFLD), cardiovascular disease, and type 2 diabetes. Accumulating evidence suggests a complex role of NLR family pyrin domain containing 3 (NLRP3) inflammasome function in multiple manifestations of the metabolic syndrome, with contradictory results. Its broad expression and pleiotropic functions during obesity led us to investigate the contribution of its expression in nonimmune versus immune cells to the development of obesity and MAFLD. Bone marrow chimerism was used to target NLRP3 deficiency to immune (ImmuneΔNlrp3) versus nonimmune (NonimmuneΔNlrp3) cells. Irradiated WT mice reconstituted with WT bone marrow served as controls. Mice were fed a 60% high-fat diet for 16 weeks. NonimmuneΔNlrp3 mice gained less weight and displayed reduced liver and epididymal white adipose tissue (epiWAT) mass. They also exhibited reduced adipocyte hypertrophy and increased epiWAT adipogenesis and lipolysis. Notable was the diminished hepatic steatosis in NonimmuneΔNlrp3 livers, which persisted even following equilibration of their body weight to that of the control. This was accompanied by a decline in liver triglycerides and in expression of transcriptional modules involved with lipid uptake, storage, and de novo lipogenesis. Thermogenic pathways in brown adipose tissue were comparable to control mice, but an elevation was observed in the genes encoding for lipid transporters and fatty acid oxidation. In contrast, deletion of NLRP3 in the immune cell compartment had limited effects on obesity and hepatic steatosis. Collectively, our results outline a prominent role for NLRP3 in nonimmune cells in facilitating MAFLD during constant energy surplus.