Chronic intermittent hypoxia accelerates liver fibrosis in rats with combined hypoxia and nonalcoholic steatohepatitis via angiogenesis rather than endoplasmic reticulum stress.

In the present study, we aimed to investigate the role of endoplasmic reticulum stress (ERS) and its related inflammation and angiogenesis in liver fibrosis in a rat model of combined hypoxia and nonalcoholic steatohepatitis (NASH) and to confirm whether the intervention of hypoxia-inducible factor 1 (HIF1) can improve fibrosis. Liver histological changes and biochemical indices, HIF1, inflammatory factors, ERS-related parameters (GRP78, CHOP, caspase-3, and caspase-12), and angiogenesis indices (VEGFA, VEGFR2, and CD34) were evaluated. Compared with the control rats, the liver tissue of rats with hypoxia and NASH had obvious NASH characteristics and hepatic fibrosis was significantly aggravated, including bridging fibrosis in some rats. The mRNA expression levels of HIF1, VEGFA, and VEGFR2 and total immunohistochemical staining scores of VEGFR2 and CD34 were significantly increased. In addition, HIF1 silencing significantly decreased HIF1, biochemical indices (ALT, AST, and TG), inflammatory factors (TNF, IL6, and IL1), and angiogenesis indices (CD34 and VEGFR2), consequently, improved the hepatic fibrosis score in the rat model of combined hypoxia and NASH. Taken together, chronic intermittent hypoxia accelerates liver fibrosis in rats with combined hypoxia and NASH via angiogenesis rather than ERS and HIF1 intervention can improve liver fibrosis, angiogenesis, inflammatory factors, and biochemical indices. Therefore, HIF1 is a key regulatory factor of liver fibrosis in rats with combined hypoxia and NASH.