Chronic intermittent hypoxia promotes the development of experimental non-alcoholic steatohepatitis by modulating Treg/Th17 differentiation.

The present study aims to characterize the effect of chronic intermittent hypoxia and HIF1α on the non-alcoholic steatohepatitis (NASH) process in mice, and to explore the role of the Treg/Th17 balance in the formation of NASH inflammation and fibrosis. To achieve this purpose, simple steatosis was induced in mice by high-fat diet administration. Subsequently, chronic intermittent hypoxia was simulated by intraperitoneally injecting sodium nitrite. The changes of inflammation, fibrosis, and Treg/Th17 balance in the liver were quantified under chronic intermittent hypoxia condition and after tail vein injection of HIF1α-siRNA. In addition, T cells were cultured in vitro, and HIF1α expression was either blocked or overexpressed under chronic intermittent hypoxia or normal conditions. Then, the changes of Treg/Th17 balance, inflammatory factors, and cell pathways were measured in each group. Our results demonstrated that chronic intermittent hypoxia accelerates the NASH process, while tail vein injection of HIF1α-siRNA improves liver histology and function. Chronic intermittent hypoxia alters the ratio of Th17 and Treg cells through HIF1α and mTOR signaling, and increases the expressions of NF-κB, IL-6, and IL-17, but decreases IL-10 expression. Inhibition of the mTOR-HIF1α-TLR4-IL-6 pathway increases the ratio of Treg/Th17. Thus, chronic intermittent hypoxia modulates the Treg/Th17 balance by inducing HIF1α, resulting in the activation of the mTOR-HIF1α-TLR4-IL-6 pathway, which accelerates the formation of NASH and fibrosis.