A2b adenosine receptor regulates hyperlipidemia and atherosclerosis.
A2b adenosine receptor regulates hyperlipidemia and atherosclerosis.
复制标题
A2b 腺苷受体调节高脂血症和动脉粥样硬化。
DOI：
10.1161/circulationaha.111.057596
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发表时间：
2012
期刊：
影响因子：
37.8
通讯作者：
Ravid,Katya
中科院分区：
文献类型：
--
作者：
Koupenova,Milka;Johnston-Cox,Hillary;Vezeridis,Alexander;Gavras,Haralambos;Yang,Dan;Zannis,Vassilis;Ravid,Katya
BackgroundThe cAMP-elevating A2badenosine receptor (A2bAR) controls inflammation via its expression in bone marrow cells.Methods and ResultsAtherosclerosis induced by a high-fat diet in apolipoprotein E–deficient mice was more pronounced in the absence of the A2bAR. Bone marrow transplantation experiments indicated that A2bAR bone marrow cell signals alone were not sufficient to elicit this effect. Intriguingly, liver expression of the A2bAR in wild-type mice was vastly augmented by a high-fat diet, raising the possibility that this upregulation is of functional significance. A2bAR genetic ablation led to elevated levels of liver and plasma cholesterol and triglycerides and to fatty liver pathology typical of steatosis, assessed by enzymatic assays and analysis of liver sections. Western blotting and quantitative polymerase chain reaction revealed elevated expression of the following molecules in the liver of A2bAR-null mice: the transcription factor sterol regulatory element binding protein-1 (SREBP-1) and its 2 downstream targets and regulators of lipogenesis, acetyl CoA carboxylase and fatty acid synthase. Pharmacological activation or inhibition of A2bAR in primary hepatocytes confirmed the regulation of SREBP-1 by this receptor. A2bAR-mediated changes in cAMP were found to regulate levels of the transcriptionally active form of SREBP-1. Finally, adenovirally mediated restoration of the A2bAR in the liver of A2bAR-null mice reduced the lipid profile and atherosclerosis. Similarly, in vivo administration of the A2bAR ligand BAY 60-6853 in control mice on a high-fat diet reduced the lipid profile and atherosclerosis.ConclusionThis study provides the first evidence that the A2bAR regulates liver SREBP-1, hyperlipidemia, and atherosclerosis, suggesting that this receptor may be an effective therapeutic target.
