1619-P: Redox Immunometabolism—NADPH Oxidase 4 (NOX4) Alleviates Stat6-Deficiency–Related MASLD in Mice

by sugaradmin



Introduction and Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by a set of metabolic abnormalities, such as pathological adipose tissue (WAT) accumulation, dyslipidemia and type 2 diabetes mellitus (T2D). Two major components linking pathological WAT function and MASLD to T2D are perturbed cellular redox homeostasis and the onset of chronic deregulation of inflammatory cell functions. NADPH oxidases (NOXs) produce oxidants that control redox homeostasis and cytokine signaling in inflammatory cells. NOX4 modulates signal transduction of the transcription factor, Stat6 that relays anti-inflammatory actions of IL-4 and IL-13. Mice deficient in Stat6 display a predisposition towards the development of MASLD. The goal of our study was to investigate the effect of NOX4-mediated signaling in IL-4/IL-13-related processes in MASLD.Methods: We created mice with double knock-out for NOX4 and Stat6 (DKO) and compared their metabolic phenotype to littermates with single NOX4 deletion (NOX4KO) upon 13-week high-fat diet feeding. Glucose and insulin sensitivity was determined by intra-peritoneal glucose and insulin tolerance tests. Whole body metabolism was assessed in metabolic cages. Organs were processed for protein and gene expression analysis.Results: DKO and NOX4KO mice displayed similar food intake. By contrast, DKO mice displayed reduced adiposity compared to NOX4KO mice due to lower energy efficiency. DKO mice shifted lipid deposition away from the WAT and enhanced lipid storage in the liver. DKO mice displayed similar fed and starved glucose levels with no alterations in glucose tolerance. Gene expression analysis confirmed a less inflammatory state of both WAT and liver of DKO mice.Conclusion: Our results demonstrate that anti-inflammatory signaling is modulated by NOX4-derived oxidants in vivo in mice. In addition, they show that the interaction between NOX4 and IL-4/IL-13 is a critical component in the onset of MASLD.

Disclosure

I. Szanto: None.

Funding

Insuleman Foundation, Geneva, Switzarland (ISZ-1) Foundation for the Innovation in Research in Cancer and BiologicalSciences, Geneva, Switzerland (ISZ-1)



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