SPHK2 inhibition alleviates chronic intermittent hypoxia-induced inflammation in adipose tissue by decreasing endoplasmic reticulum stress

Abstract

Obstructive Sleep Apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is a prevalent disorder that significantly elevates the risk of cardiovascular and metabolic complications. Lipid metabolism disturbances, a common comorbidity in OSA, are closely associated with CIH-induced adipose tissue inflammation, yet the underlying mechanisms remain poorly defined. In this study, we established a CIH mouse model to investigate the roles of Sphingosine Kinase 2 (SPHK2) and endoplasmic reticulum stress (ERS) in CIH-induced lipid metabolic disturbances. Mice were exposed to normal air (NA) or CIH for 4 or 12 weeks. Serum triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) were measured to assess systemic lipid metabolism. CIH group significantly elevated SPHK2 expression and activated the PERK-ATF4-CHOP signaling pathway in epididymal (eWAT) and subcutaneous white adipose tissue (scWAT), leading to increased NLRP3 inflammasome accumulation, oxidative stress, and adipocyte apoptosis. Administration of the SPHK2 inhibitor ABC294640, opaganib, attenuated these effects, reducing ERS activation and restoring lipid homeostasis. Further, treatment with the ERS inhibitor 4-BPA suppressed oxidative stress and inflammatory cytokines, alleviating CIH-induced adipose tissue inflammation. In contrast, ERS activation by thapsigargin reversed the protective effects of SPHK2 inhibition, exacerbating metabolic and inflammatory dysregulation. In summary, our findings highlight the critical role of SPHK2 and ERS in CIH-induced adipose tissue inflammation and lipid metabolic disturbances. Pharmacological inhibition of SPHK2 represents a promising therapeutic approach for mitigating OSA-related lipid metabolic disturbances.