title: Intermittent hypoxia upregulates hepatic heme oxygenase-1 and ferritin-1, thereby limiting hepatic pathogenesis in rats fed a high-fat diet.
abstract: Non-alcoholic fatty liver disease (NAFLD) is prevalent in patients with sleep apnea syndrome (SAS). Intermittent hypoxia (IH) and a high-fat diet (HFD) reproduce SAS and NAFLD, respectively, in rodents. In this study, rats were fed either an HFD or a standard diet (SD) for 2 weeks, and breathed either IH air or normoxic air for 4 days (early phase) or 6 weeks (late phase), with the same diets maintained during the exposure. HFD increased hepatic lipid accumulation, as detected by oil-red staining and triglyceride content. However, IH exposure reversed the hepatic steatosis at the late phase in these HFD-rats. IH exposure also increased hepatic expression of HO-1 and iron-binding protein ferritin-1 at the late phase, in association with increase in serum iron, bilirubin, and hepatic levels of lipid peroxides, such as 4-hydroxy-2-nonenal (HNE). IH exposure increased serum levels of hemoglobin (Hb) at the early phase and immunofluorescence of Hb and HO-1 in CD68-positive Kupffer cells (KCs) at the late phase. These findings support that IH induces erythrocytosis, erythro-phagocytosis, and generation of Hb in the KCs. The Hb promotes HO-1 expression in KCs, thereby produces iron, bilirubin, and carbon monoxide (CO). The iron would be either sequestrated by ferritin-1, transferred to the bone marrow for erythropoiesis, or would produce hydroxyradicals and HNE in the liver of rats fed an HFD. HNE might also contribute to the upregulation of HO-1, transferrin-1, and IκB, thereby limiting hepatic steatosis and inflammation via inhibition of nuclear factor κB (NFκB) activation.
authors.affiliation: a Department of Forensic Medicine , Tokyo Medical University , Shinjyuku-ku , Tokyo , Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Maeda
authors.affiliation: a Department of Forensic Medicine , Tokyo Medical University , Shinjyuku-ku , Tokyo , Japan.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology*; D059305:Diet, High-Fat; D005293:Ferritins / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
chemical_list: D005293:Ferritins; D051547:Heme Oxygenase-1
keywords: Heme oxygenase; high-fat diet; intermittent hypoxia; non-alcoholic fatty liver disease; sleep apnea syndrome