Hypoxanthine induces cholesterol accumulation and incites atherosclerosis in apolipoprotein E‐deficient mice and cells

• Published in: Journal of cellular and molecular medicine 2016-11, Vol.20 (11), p.2160-2172
• Main Authors: Ryu, Hye‐Myung, Kim, You‐Jin, Oh, Eun‐Joo, Oh, Se‐Hyun, Choi, Ji‐Young, Cho, Jang‐Hee, Kim, Chan‐Duck, Park, Sun‐Hee, Kim, Yong‐Lim
• Format: Article
• Language: English
• Subjects: ABCA1 protein; Accumulation; Acetylcysteine - pharmacology; Alcohol use; Allopurinol; Allopurinol - pharmacology; Animals; Antioxidants; APOE; Apolipoprotein E; Apolipoproteins; Apolipoproteins E - deficiency; Apolipoproteins E - metabolism; Arteriosclerosis; Atherosclerosis; Atherosclerosis - blood; Atherosclerosis - pathology; ATP-binding protein; Cholesterol; Cholesterol - blood; Cholesterol - metabolism; Coronary vessels; Diet; Down-Regulation - drug effects; Down-Regulation - genetics; Drinking behavior; Enzymes; Gene expression; Hemodialysis; Hep G2 Cells; Humans; Hydrogen peroxide; Hydrogen Peroxide - toxicity; Hypercholesterolemia - pathology; Hypoxanthine; Hypoxanthine - pharmacology; Laboratory animals; Lipids; Lipogenesis - drug effects; Lipogenesis - genetics; Liver; Male; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; mRNA; Original; Oxidative stress; Plaque, Atherosclerotic - blood; Plaque, Atherosclerotic - metabolism; Plaque, Atherosclerotic - pathology; Reactive oxygen species; ROS; siRNA; Smoking; Up-Regulation - drug effects; Uric acid; Xanthine oxidase
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.12916

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, H2O2 also 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.