Chronic intermittent hypoxia promotes the development of experimental non-alcoholic steatohepatitis by modulating Treg/Th17 differentiation.
ACTA BIOCHIMICA ET BIOPHYSICA SINICA(2018)
摘要
The present study aims to characterize the effect of chronic intermittent hypoxia and HIF1 alpha 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 HIF1 alpha-siRNA. In addition, T cells were cultured in vitro, and HIF1 alpha 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 HIF1 alpha-siRNA improves liver histology and function. Chronic intermittent hypoxia alters the ratio of Th17 and Treg cells through HIF1 alpha and mTOR signaling, and increases the expressions of NF-kappa B, IL-6, and IL-17, but decreases IL-10 expression. Inhibition of the mTOR-HIF1 alpha-TLR4-IL-6 pathway increases the ratio of Treg/Th17. Thus, chronic intermittent hypoxia modulates the Treg/Th17 balance by inducing HIF1 alpha, resulting in the activation of the mTOR-HIF1 alpha-TLR4-IL-6 pathway, which accelerates the formation of NASH and fibrosis.
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关键词
chronic intermittent hypoxia,non-alcoholic steatohepatitis,Treg/Th17 balance
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