Background: The cAMP-elevating A2b adenosine receptor (A2bAR) controls inflammation via its expression in bone marrow cells.

Methods and Results: Atherosclerosis induced by high fat diet (HFD) 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 HFD, 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 qPCR revealed elevated expression of the following molecules in the liver of A2bAR null mice: the transcription factor SREBP-1 and its downstream targets, and two 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, adenoviral-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 HFD reduced lipid profile and atherosclerosis.

Conclusions: This 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.

Read more »