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NLRP3 Deficiency in Nonimmune Cells Averts Obesity-Induced Fatty Liver Disease
Lilah Margalit Grigg1, Bander Abu Shrkihe2, Irina Efimova2
1The Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel; The Microsurgery and Plastic Surgery Lab, Department of Plastic and Reconstructive Surgery, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
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.
Insights
NLRP3 inflammasome in nonimmune cells drives obesity and metabolic dysfunction-associated fatty liver disease (MAFLD). Targeting NLRP3 in these cells reduces weight gain and liver fat accumulation, highlighting a key role in metabolic health.
Area of Science:
- Metabolic disease research
- Inflammasome biology
- Obesity and liver disease mechanisms
Background:
- Obesity is linked to metabolic dysfunction-associated fatty liver disease (MAFLD), cardiovascular disease, and type 2 diabetes.
- The NLR family pyrin domain containing 3 (NLRP3) inflammasome has a complex, debated role in metabolic syndrome.
- NLRP3's widespread expression necessitates understanding its cell-specific contributions to obesity and MAFLD.
Purpose of the Study:
- To investigate the distinct roles of NLRP3 inflammasome in immune versus nonimmune cells in obesity and MAFLD development.
- To determine if NLRP3 deficiency in specific cell types impacts metabolic parameters and liver steatosis.
Main Methods:
- Utilized bone marrow chimerism to create mice with NLRP3 deficiency specifically in immune (ImmuneΔNlrp3) or nonimmune (NonimmuneΔNlrp3) cells.
- Administered a high-fat diet (60%) for 16 weeks to all experimental groups, including controls (WT mice reconstituted with WT bone marrow).
- Assessed body weight, tissue mass (liver, epididymal white adipose tissue), adipocyte morphology, gene expression, and hepatic steatosis.
Main Results:
- NonimmuneΔNlrp3 mice exhibited reduced weight gain, liver, and epididymal white adipose tissue (epiWAT) mass compared to controls.
- These mice showed decreased adipocyte hypertrophy, increased adipogenesis and lipolysis in epiWAT, and significantly diminished hepatic steatosis.
- NLRP3 deletion in immune cells had minimal impact on obesity and hepatic steatosis, underscoring the role of nonimmune NLRP3.
Conclusions:
- NLRP3 inflammasome in nonimmune cells plays a critical role in promoting MAFLD under conditions of sustained energy surplus.
- Targeting NLRP3 in nonimmune cells represents a potential therapeutic strategy for managing obesity-related fatty liver disease.
- Cell-specific functions of NLRP3 are crucial for understanding and treating metabolic disorders.
