Long-term intermittent hypoxia in mice induces inflammatory pathways implicated in sleep apnea and steatohepatitis in humans

ABSTRACT: Obstructive Sleep Apnea (OSA) engenders repetitive desaturation-reoxygenation sequences called intermittent hypoxia (IH), now widely accepted as an independent risk factor for the occurrence and progression of non-alcoholic fatty liver disease (NAFLD). The specific molecular mechanisms linking IH and the development and progression of NAFLD remain elusive. NAFLD pathogenesis is multifactorial including immune cell-driven inflammation as a key mechanism in the transition from fatty liver to steatohepatitis (NASH). The overall goal of this study was to identify the specific impact of IH on liver inflammation in the absence of major confounders frequently encountered in OSA clinical research (i.e., obesity, diabetes, reduced physical activity). We employed a model of lean mice exposed to long-term IH (16 weeks) and a cohort of lean OSA patients free of comorbidities (n=71) coupled with high-throughput hepatic transcriptomics, lipidomics and targeted serum proteomics. For the first time, we have demonstrated that long-term IH is an independent “hit” sufficient by itself to induce the NASH molecular signatures found in human steatohepatitis transcriptomic datasets.We identified a unique set of biomarkers in mice and humans (PPARs, NRFs, arachidonic acid, IL16, IL20, IFNB and TNFa) associated with early hepatic and systemic inflammation. This molecular connection between IH, sleep apnea and steatohepatitis warrants further investigation in clinical trials and support the systematic implementation of sleep apnea diagnosis in liver disease phenotyping. Our original signatures could allow the identification of potential diagnostic and treatment response markers, as well as therapeutic targets in the comorbid association between NAFLD and OSA.

ORGANISM(S): Mus musculus

PROVIDER: GSE242668 | GEO | 2024/02/14

REPOSITORIES: GEO