title: Hypoxanthine induces cholesterol accumulation and incites atherosclerosis in apolipoprotein E-deficient mice and cells.
abstract: Reactive oxygen species (ROS) generation during purine metabolism is associated with xanthine oxidase and uric acid. However, the direct effect of hypoxanthine on ROS generation and atherosclerosis has not been evaluated. Smoking and heavy drinking are associated with elevated levels of hypoxanthine. In this study, we investigated the role of hypoxanthine on cholesterol synthesis and atherosclerosis development, particularly in apolipoprotein E (APOE)-deficient mice. The effect of hypoxanthine on the regulation of cholesterol synthesis and atherosclerosis were evaluated in Apoe knockout (KO) mice and cultured HepG2 cells. Hypoxanthine markedly increased serum cholesterol levels and the atherosclerotic plaque area in Apoe KO mice. In HepG2 cells, hypoxanthine increased intracellular ROS production. Hypoxanthine increased cholesterol accumulation and decreased APOE and ATP-binding cassette transporter A1 (ABCA1) mRNA and protein expression in HepG2 cells. Furthermore, H2O2also increased cholesterol accumulation and decreased APOE and ABCA1 expression. This effect was partially reversible by treatment with the antioxidant N-acetyl cysteine and allopurinol. Hypoxanthine and APOE knockdown using APOE-siRNA synergistically induced cholesterol accumulation and reduced APOE and ABCA1 expression. Hypoxanthine induces cholesterol accumulation in hepatic cells through alterations in enzymes that control lipid transport and induces atherosclerosis in APOE-deficient cells and mice. These effects are partially mediated through ROS produced in response to hypoxanthine.
authors.affiliation: Division of Nephrology and Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.|Cell and Matrix Research Institute, Kyungpook National University, Daegu, Korea.
authors.forename: Hye-Myung
authors.initials: HM
authors.lastname: Ryu
authors.affiliation: Division of Nephrology and Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.|BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Korea.|Cell and Matrix Research Institute, Kyungpook National University, Daegu, Korea.
authors.forename: You-Jin
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Division of Nephrology and Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.|Cell and Matrix Research Institute, Kyungpook National University, Daegu, Korea.
authors.forename: Eun-Joo
authors.initials: EJ
authors.lastname: Oh
authors.affiliation: Division of Nephrology and Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.|BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Korea.|Cell and Matrix Research Institute, Kyungpook National University, Daegu, Korea.
authors.forename: Se-Hyun
authors.initials: SH
authors.lastname: Oh
authors.affiliation: Division of Nephrology and Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Choi
authors.affiliation: Division of Nephrology and Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.
authors.forename: Jang-Hee
authors.initials: JH
authors.lastname: Cho
authors.affiliation: Division of Nephrology and Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.|Cell and Matrix Research Institute, Kyungpook National University, Daegu, Korea.
authors.forename: Chan-Duck
authors.initials: CD
authors.lastname: Kim
authors.affiliation: Division of Nephrology and Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.|Cell and Matrix Research Institute, Kyungpook National University, Daegu, Korea.
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Park
authors.affiliation: Division of Nephrology and Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea. ylkim@knu.ac.kr.|BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Korea. ylkim@knu.ac.kr.|Cell and Matrix Research Institute, Kyungpook National University, Daegu, Korea. ylkim@knu.ac.kr.
authors.forename: Yong-Lim
authors.initials: YL
authors.lastname: Kim
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000378:metabolism; D050197:Atherosclerosis / Q000097:blood / Q000473:pathology*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D056945:Hep G2 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D006937:Hypercholesterolemia / Q000473:pathology; D019271:Hypoxanthine / Q000494:pharmacology*; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D058226:Plaque, Atherosclerotic / Q000097:blood / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001057:Apolipoproteins E; D019271:Hypoxanthine; D000493:Allopurinol; D002784:Cholesterol; D006861:Hydrogen Peroxide; D000111:Acetylcysteine
keywords: APOE; ROS; atherosclerosis; cholesterol; hypoxanthine