Macrophage Mal1 Deficiency Suppresses Atherosclerosis in Low-Density Lipoprotein Receptor–Null Mice by Activating Peroxisome Proliferator-Activated Receptor-γ–Regulated Genes
| Autor: | Daping Fan, Robert P. Runner, Vladimir R. Babaev, Cem Z. Görgün, Huan Tao, Youmin Zhang, MacRae F. Linton, Gökhan S. Hotamisligil, Ebru Erbay, Sergio Fazio, Lei Ding |
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| Rok vydání: | 2011 |
| Předmět: |
CD36 Antigens
Apolipoprotein E CCR2 PPARγ chemokine receptor CCR2 CD36 Peroxisome proliferator-activated receptor Antigens CD36 PPAR Mice Chemokine receptor CD36 antigen cell count chemistry.chemical_classification article food and beverages chemokine receptor peroxisome proliferator activated receptor gamma atherogenesis protein function low density lipoprotein receptor Lipids unclassified drug Neoplasm Proteins medicine.anatomical_structure priority journal monocyte lipids (amino acids peptides and proteins) Female wild type Cardiology and Cardiovascular Medicine lipid diet medicine.medical_specialty Receptors CCR2 animal experiment macrophage Biology Fatty Acid-Binding Proteins Article animal tissue Internal medicine medicine Animals controlled study protein expression mouse nonhuman fatty acid binding protein 5 animal model Macrophages Monocyte cholesterol Atherosclerosis PPAR gamma carrier protein aorta Endocrinology Gene Expression Regulation Receptors LDL chemistry aorta atherosclerosis LDL receptor biology.protein CC chemokine receptors |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology |
| ISSN: | 1524-4636 1079-5642 |
| Popis: | Objective— The adipocyte/macrophage fatty acid-binding proteins aP2 (FABP4) and Mal1 (FABP5) are intracellular lipid chaperones that modulate systemic glucose metabolism, insulin sensitivity, and atherosclerosis. Combined deficiency of aP2 and Mal1 has been shown to reduce the development of atherosclerosis, but the independent role of macrophage Mal1 expression in atherogenesis remains unclear. Methods and Results— We transplanted wild-type (WT), Mal1 −/− , or aP2 −/− bone marrow into low-density lipoprotein receptor–null (LDLR −/− ) mice and fed them a Western diet for 8 weeks. Mal1 −/− →LDLR −/− mice had significantly reduced (36%) atherosclerosis in the proximal aorta compared with control WT→LDLR −/− mice. Interestingly, peritoneal macrophages isolated from Mal1-deficient mice displayed increased peroxisome proliferator-activated receptor-γ (PPARγ) activity and upregulation of a PPARγ-related cholesterol trafficking gene, CD36. Mal1 −/− macrophages showed suppression of inflammatory genes, such as COX2 and interleukin 6. Mal1 −/− →LDLR −/− mice had significantly decreased macrophage numbers in the aortic atherosclerotic lesions compared with WT→LDLR −/− mice, suggesting that monocyte recruitment may be impaired. Indeed, blood monocytes isolated from Mal1 −/− →LDLR −/− mice on a high-fat diet had decreased CC chemokine receptor 2 gene and protein expression levels compared with WT monocytes. Conclusion— Taken together, our results demonstrate that Mal1 plays a proatherogenic role by suppressing PPARγ activity, which increases expression of CC chemokine receptor 2 by monocytes, promoting their recruitment to atherosclerotic lesions. |
| Databáze: | OpenAIRE |
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