Macrophage Mal1 deficiency suppresses atherosclerosis in low-density lipoprotein receptor-null mice by activating peroxisome proliferator-activated receptor-γ-regulated genes.

Abstract

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.

• Authors: Vladimir R Babaev, Robert P Runner, Daping Fan, Lei Ding, Youmin Zhang, Huan Tao, Ebru Erbay, Cem Z Görgün, Sergio Fazio, Gökhan S Hotamisligil, MacRae F Linton
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 31 Issue 6 Pg. 1283-90 (Jun 2011) ISSN: 1524-4636 [Electronic] United States
• PMID: 21474828 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CD36 Antigens
• Ccr2 protein, mouse
• Fabp4 protein, mouse
• Fabp5 protein, mouse
• Fatty Acid-Binding Proteins
• Lipids
• Neoplasm Proteins
• PPAR gamma
• Receptors, CCR2
• Receptors, LDL

Topics

• Animals
• Atherosclerosis (prevention & control)
• CD36 Antigens (physiology)
• Fatty Acid-Binding Proteins (physiology)
• Female
• Gene Expression Regulation
• Lipids (blood)
• Macrophages (physiology)
• Mice
• Neoplasm Proteins (physiology)
• PPAR gamma (physiology)
• Receptors, CCR2 (genetics)
• Receptors, LDL (physiology)