title: Hyperglycemia accelerates ATP-binding cassette transporter A1 degradation via an ERK-dependent pathway in macrophages.
abstract: An elevation in blood glucose concentration leads to increased risk of developing diabetes-associated atherosclerotic cardiovascular disease due to an excessive accumulation of cholesterol in arterial macrophages. ATP-binding cassette transporter A1 (ABCA1) is an atheroprotective protein that mediates the export of cholesterol from macrophages. The present study aims to investigate the effect of hyperglycemia on the regulation of ABCA1 expression and to explore its underlying mechanisms of regulation in macrophages. Our results show that high glucose activates the extracellular signal-regulated kinases (ERK) signaling pathway via reactive oxygen species (ROS) production, which in turn down-regulates ABCA1 mRNA and protein expression. This down-regulation is mediated by accelerating ABCA1 mRNA and protein degradation in macrophages exposed to high concentrations of glucose. Our results provide evidence for the first time that hyperglycemia inhibits ABCA1 expression by ERK-modulated ABCA1 mRNA and protein stability. Overall, these results provide a mechanism for hyperglycemia-induced reduction in ABCA1 expression, which suggests a promising strategy for the treatment of diabetes-associated atherosclerosis.
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yu-Cheng
authors.initials: YC
authors.lastname: Chang
authors.forename: Wayne H-H
authors.initials: WH
authors.lastname: Sheu
authors.forename: Yi-Shen
authors.initials: YS
authors.lastname: Chien
authors.forename: Pei-Chi
authors.initials: PC
authors.lastname: Tseng
authors.forename: Wen-Jane
authors.initials: WJ
authors.lastname: Lee
authors.forename: An-Na
authors.initials: AN
authors.lastname: Chiang
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D015870:Gene Expression; D005947:Glucose / Q000502:physiology; D006943:Hyperglycemia / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D055550:Protein Stability; D059748:Proteolysis; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D064286:ATP Binding Cassette Transporter 1; D002784:Cholesterol; D005947:Glucose; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C577833:Abca1 protein, mouse