Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis.
The adipocyte fatty-acid-binding protein, aP2, has an important role in regulating systemic insulin resistance and lipid metabolism. Here we demonstrate that aP2 is also expressed in macrophages, has a significant role in their biological responses and contributes to the development of atherosclerosis. Apolipoprotein E (ApoE)-deficient mice also deficient for aP2 showed protection from atherosclerosis in the absence of significant differences in serum lipids or insulin sensitivity. aP2-deficient macrophages showed alterations in inflammatory cytokine production and a reduced ability to accumulate cholesterol esters when exposed to modified lipoproteins. Apoe-/- mice with Ap2+/+ adipocytes and Ap2-/- macrophages generated by bone-marrow transplantation showed a comparable reduction in atherosclerotic lesions to those with total aP2 deficiency, indicating an independent role for macrophage aP2 in atherogenesis. Through its distinct actions in adipocytes and macrophages, aP2 provides a link between features of the metabolic syndrome and could be a new therapeutic target for the prevention of atherosclerosis.
Makowski
Liza
L
Division of Biological Sciences and Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
Boord
Jeffrey B
JB
Departments of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Maeda
Kazuhisa
K
Division of Biological Sciences and Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
Babaev
Vladimir R
VR
Departments of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Uysal
K Teoman
KT
Division of Biological Sciences and Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
Morgan
Maureen A
MA
Bristol-Myers Squibb PRI, Department of Metabolic Research, Princeton, New Jersey, USA.
Parker
Rex A
RA
Bristol-Myers Squibb PRI, Department of Metabolic Research, Princeton, New Jersey, USA.
Suttles
Jill
J
Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky, USA.
Fazio
Sergio
S
Departments of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Hotamisligil
Gökhan S
GS
Division of Biological Sciences and Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
Linton
MacRae F
MF
Departments of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
D017667:Adipocytes / Q000502:physiology*; D000818:Animals; D001011:Aorta / Q000166:cytology; D001057:Apolipoproteins E / Q000378:metabolism*; D001161:Arteriosclerosis / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D016026:Bone Marrow Transplantation; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002788:Cholesterol Esters / Q000378:metabolism; D004032:Diet; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005260:Female; D005487:Foam Cells / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D001057:Apolipoproteins E; D002352:Carrier Proteins; D002788:Cholesterol Esters; C107608:FABP7 protein, human; C082667:Fabp5 protein, mouse; C086936:Fabp7 protein, mouse; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D007328:Insulin; D007375:Interleukin-1; D015850:Interleukin-6; D008055:Lipids; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D005947:Glucose