Obstructive sleep apnea (OSA) is associated with insulin resistance, lipid dysregulation, and hepatic steatosis and fibrosis in nonalcoholic fatty liver disease (NAFLD). We have previously shown that hepatocyte hypoxia inducible factor-1 (HIF-1) mediates the development of liver fibrosis in a mouse model of NAFLD. We hypothesized that intermittent hypoxia (IH) modeling OSA would worsen hepatic steatosis and fibrosis in murine NAFLD, via HIF-1. Mice with hepatocyte-specific deletion of Hif1a () and wild-type () controls were fed a high -fat diet to induce NAFLD with steatohepatitis. Half from each group were exposed to IH, and the other half to intermittent air. Glucose tolerance test was performed prior to sacr... More
Obstructive sleep apnea (OSA) is associated with insulin resistance, lipid dysregulation, and hepatic steatosis and fibrosis in nonalcoholic fatty liver disease (NAFLD). We have previously shown that hepatocyte hypoxia inducible factor-1 (HIF-1) mediates the development of liver fibrosis in a mouse model of NAFLD. We hypothesized that intermittent hypoxia (IH) modeling OSA would worsen hepatic steatosis and fibrosis in murine NAFLD, via HIF-1. Mice with hepatocyte-specific deletion of Hif1a () and wild-type () controls were fed a high -fat diet to induce NAFLD with steatohepatitis. Half from each group were exposed to IH, and the other half to intermittent air. Glucose tolerance test was performed prior to sacrifice. Liver collagen and triglycerides were determined. Mitochondrial efficiency was assessed in fresh liver tissue at sacrifice. Hepatic malondialdehyde concentration and pro-inflammatory cytokine levels were assessed, and genes of collagen and fatty acid metabolism were queried. mice gained less weight than mice (-2.3 grams, p=0.029). There was also a genotype-independent effect of IH on body weight, with less weight gain in IH (p=0.003). Fasting glucose, HOMA-IR, and glucose tolerance test were all improved in mice. Liver collagen was increased in IH (p=0.033), and reduced in mice (p<0.001), without any significant exposure/genotype interaction. Liver TNF-α and IL-1β were significantly increased in IH, and decreased in . We conclude that HIF-1 signaling worsens the metabolic profile and hastens NAFLD progression, and that IH may worsen liver fibrosis. These effects are plausibly mediated by hepatic inflammatory stress.
