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. 2002 Jan 8;99(1):407-12.
doi: 10.1073/pnas.012587699. Epub 2001 Dec 18.

The ATP binding cassette transporter A1 (ABCA1) modulates the development of aortic atherosclerosis in C57BL/6 and apoE-knockout mice

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The ATP binding cassette transporter A1 (ABCA1) modulates the development of aortic atherosclerosis in C57BL/6 and apoE-knockout mice

Charles W Joyce et al. Proc Natl Acad Sci U S A. .

Abstract

Identification of mutations in the ABCA1 transporter (ABCA1) as the genetic defect in Tangier disease has generated interest in modulating atherogenic risk by enhancing ABCA1 gene expression. To investigate the role of ABCA1 in atherogenesis, we analyzed diet-induced atherosclerosis in transgenic mice overexpressing human ABCA1 (hABCA1-Tg) and spontaneous lesion formation in hABCA1-Tg x apoE-knockout (KO) mice. Overexpression of hABCA1 in C57BL/6 mice resulted in a unique anti-atherogenic profile characterized by decreased plasma cholesterol (63%), cholesteryl ester (63%), free cholesterol (67%), non-high density lipoprotein (HDL)-cholesterol (53%), and apolipoprotein (apo) B (64%) but markedly increased HDL-cholesterol (2.8-fold), apoA-I (2.2-fold), and apoE (2.8-fold) levels. These beneficial changes in the lipid profile led to significantly lower (65%) aortic atherosclerosis in hABCA1-Tg mice. In marked contrast, ABCA1 overexpression had a minimal effect on the plasma lipid profile of apoE-KO mice and resulted in a 2- to 2.6-fold increase in aortic lesion area. These combined results indicate that overexpression of ABCA1 in C57BL/6 mice on a high cholesterol diet results in an atheroprotective lipoprotein profile and decreased atherosclerosis, and thus provide previously undocumented in vivo evidence of an anti-atherogenic role for the ABCA1 transporter. In contrast, overexpression of ABCA1 in an apoE-KO background led to increased atherosclerosis, further substantiating the important role of apoE in macrophage cholesterol metabolism and atherogenesis. In summary, these results establish that, in the presence of apoE, overexpression of ABCA1 modulates HDL as well as apoB-containing lipoprotein metabolism and reduces atherosclerosis in vivo, and indicate that pharmacological agents that will increase ABCA1 expression may reduce atherogenic risk in humans.

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Figures

Figure 1
Figure 1
Analyses of the plasma lipoproteins in hABCA1-Tg and C57BL/6 control mice maintained on the atherogenic diet. (A) The distribution of cholesterol after separation of the plasma lipoproteins present in pooled plasma from female C57BL/6 (■; n = 5) and hABCA1-Tg (○; n = 5) mice by FPLC. ApoA-I, apoA-II, and apoB present in FPLC fractions corresponding to VLDL (lanes 1), IDL/LDL (lanes 2), and HDL (lanes 3) elution volumes (15, 21, and 29 ml, respectively) were determined by immunoblot analysis (Inset). (B) Two microliters of plasma from C57BL/6 (C) and hABCA1-Tg (Tg) mice were analyzed by native agarose gel electrophoresis followed by staining with fat red B. (C) Detection of apoA-I by immunoblotting after two-dimensional gel electrophoresis of plasma from C57BL/6 and hABCA1-Tg mice.
Figure 2
Figure 2
Analyses of aortic atherosclerosis in C57BL/6 (■; n = 11) and hABCA1-Tg (○; n = 18) mice maintained for 15 weeks on an atherogenic diet.
Figure 3
Figure 3
Analyses of the plasma lipoproteins in hABCA1-Tg × apoE-KO and apoE-KO mice maintained on a regular chow diet. (A) The distribution of cholesterol in different FPLC elution fractions was analyzed after separation of the plasma lipoproteins present in pooled plasma from female apoE-KO (■; n = 5) and hABCA1-Tg × apoE-KO (○; n = 5) mice by FPLC. ApoA-I, apoA-II, and apoB present in FPLC fractions corresponding to VLDL (lanes 1 and 2), IDL/LDL (lanes 3), and HDL (lanes 4) elution volumes (16, 17, 22.5, and 31 ml, respectively) were determined by immunoblot analysis (Inset). (B) Two microliters of plasma from C57BL/6 (C), apoE-KO (E-KO), and hABCA1-Tg × apoE-KO (E-KO × hABCA1-Tg) mice were analyzed by native agarose gel electrophoresis followed by staining with fat red B. (C) Detection of apoA-I by immunoblotting after two-dimensional gel electrophoresis of plasma from apoE-KO and hABCA1-Tg × apoE-KO mice.
Figure 4
Figure 4
Analyses of aortic atherosclerosis in apoE-KO (■; male n = 15 and female n = 20) and hABCA1-Tg × apoE-KO (○; male n = 16 and female n = 26) mice maintained for 15 weeks on an atherogenic diet.

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