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

Abstract

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.

• Authors: Jiang Liu, Weiping Li, Weihua Zhu, Weimei He, Hui Zhao, Yu Xiang, Chunyan Liu, Wei Wu
• Journal: Acta biochimica et biophysica Sinica (Acta Biochim Biophys Sin (Shanghai)) Vol. 50 Issue 12 Pg. 1200-1210 (Dec 01 2018) ISSN: 1745-7270 [Electronic] China
• PMID: 30379980 (Publication Type: Journal Article)

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• Interleukin-6
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• mTOR protein, mouse
• TOR Serine-Threonine Kinases

Topics

• Animals
• Cell Differentiation
• Cells, Cultured
• Chronic Disease
• Hypoxia
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Interleukin-6 (genetics, metabolism)
• Liver (metabolism, pathology)
• Mice, Inbred C57BL
• Non-alcoholic Fatty Liver Disease (genetics, metabolism)
• RNA Interference
• Signal Transduction (genetics)
• T-Lymphocytes, Regulatory (metabolism)
• TOR Serine-Threonine Kinases (genetics, metabolism)
• Th17 Cells (metabolism)
• Toll-Like Receptor 4 (genetics, metabolism)