Chronic stress-secreted glucocorticoids induce NAFLD-like changes in male rats: oxidative stress/NLRP3 inflammasome signalling.

Abstract

Graphical abstract:

Abstract: The aim of this study was to investigate the mechanism by which chronic stress (CS) induces non-alcoholic fatty liver disease (NAFLD)-like changes, and the role of oxidative stress and the NLRP3 inflammasome in this mechanism. Transcriptomic data extracted from the Sequence Read Archive (SRA) at the NCBI were employed to identify the molecular targets of CS-induced NAFLD. Fifty 8-week-old healthy male Wistar rats were divided into five groups (n = 10 each) as follows: control, CS, CS + mifepristone (CS + Mif), CS + metyrapone (CS + Met), and corticosterone (Cort). The CS, CS + Mif, and CS + Met groups underwent restraint stress training. Rats in the CS + Mif, CS + Met, and Cort groups were administered mifepristone, metyrapone, and corticosterone for 8 weeks. Data showed that CS induced NAFLD-like liver damage via increased glucocorticoids (GCs). Moreover, CS increased malonaldehyde (MDA) levels and decreased superoxide dismutase (SOD) activity in liver and serum samples, suggesting the occurrence of oxidative stress. Furthermore, CS activated various inflammatory pathways via the NLRP3 inflammasome (NLRP3, ASC, caspase-1), which enhanced cytokine levels (IL-1β, IL-6, TNF-α) in liver tissue. Notably, treatment with metyrapone or mifepristone alleviated liver lesions induced by CS, which implies that the GC signalling pathway may be an important mediator of stress-induced liver inflammation. We conclude that GC mediates the development of oxidative stress and inflammation in the liver, and inhibition of GC signalling may be a new therapeutic strategy in NAFLD.