title: A2b adenosine receptor regulates hyperlipidemia and atherosclerosis.
abstract: BACKGROUND
  The cAMP-elevating A(2b) adenosine receptor (A(2b)AR) controls inflammation via its expression in bone marrow cells.
  
  
  RESULTS
  Atherosclerosis induced by a high-fat diet in apolipoprotein E-deficient mice was more pronounced in the absence of the A(2b)AR. Bone marrow transplantation experiments indicated that A(2b)AR bone marrow cell signals alone were not sufficient to elicit this effect. Intriguingly, liver expression of the A(2b)AR in wild-type mice was vastly augmented by a high-fat diet, raising the possibility that this upregulation is of functional significance. A(2b)AR 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 A(2b)AR-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 A(2b)AR in primary hepatocytes confirmed the regulation of SREBP-1 by this receptor. A(2b)AR-mediated changes in cAMP were found to regulate levels of the transcriptionally active form of SREBP-1. Finally, adenovirally mediated restoration of the A(2b)AR in the liver of A(2b)AR-null mice reduced the lipid profile and atherosclerosis. Similarly, in vivo administration of the A(2b)AR ligand BAY 60-6853 in control mice on a high-fat diet reduced the lipid profile and atherosclerosis.
  
  
  CONCLUSIONS
  This study provides the first evidence that the A(2b)AR regulates liver SREBP-1, hyperlipidemia, and atherosclerosis, suggesting that this receptor may be an effective therapeutic target.
authors.affiliation: Department of Medicine, Boston University School of Medicine, 700 Albany St, CVI, W-601, Boston, MA 02118, USA.
authors.forename: Milka
authors.initials: M
authors.lastname: Koupenova
authors.forename: Hillary
authors.initials: H
authors.lastname: Johnston-Cox
authors.forename: Alexander
authors.initials: A
authors.lastname: Vezeridis
authors.forename: Haralambos
authors.initials: H
authors.lastname: Gavras
authors.forename: Dan
authors.initials: D
authors.lastname: Yang
authors.forename: Vassilis
authors.initials: V
authors.lastname: Zannis
authors.forename: Katya
authors.initials: K
authors.lastname: Ravid
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000209:etiology*; D004041:Dietary Fats / Q000008:administration & dosage; D006949:Hyperlipidemias / Q000209:etiology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D043704:Receptor, Adenosine A2B / Q000502:physiology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000032:analysis
chemical_list: D001057:Apolipoproteins E; D004041:Dietary Fats; D043704:Receptor, Adenosine A2B; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1