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High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1.

ABSTRACT: Recently, the human ATP-binding cassette transporter-1 (ABC1) gene has been demonstrated to be mutated in patients with Tangier disease. To investigate the role of the ABC1 protein in an experimental in vivo model, we used gene targeting in DBA-1J embryonic stem cells to produce an ABC1-deficient mouse. Expression of the murine Abc1 gene was ablated by using a nonisogenic targeting construct that deletes six exons coding for the first nucleotide-binding fold. Lipid profiles from Abc1 knockout (-/-) mice revealed an approximately 70% reduction in cholesterol, markedly reduced plasma phospholipids, and an almost complete lack of high density lipoproteins (HDL) when compared with wild-type littermates (+/+). Fractionation of lipoproteins by FPLC demonstrated dramatic alterations in HDL cholesterol (HDL-C), including the near absence of apolipoprotein AI. Low density lipoprotein (LDL) cholesterol (LDL-C) and apolipoprotein B were also significantly reduced in +/- and -/- compared with their littermate controls. The inactivation of the Abc1 gene led to an increase in the absorption of cholesterol in mice fed a chow or a high-fat and -cholesterol diet. Histopathologic examination of Abc1-/- mice at ages 7, 12, and 18 mo demonstrated a striking accumulation of lipid-laden macrophages and type II pneumocytes in the lungs. Taken together, these findings demonstrate that Abc1-/- mice display pathophysiologic hallmarks similar to human Tangier disease and highlight the capacity of ABC1 transporters to participate in the regulation of dietary cholesterol absorption.

SUBMITTER: McNeish J

PROVIDER: S-EPMC18215 | biostudies-literature | 2000 Apr

REPOSITORIES: biostudies-literature

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High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1.

McNeish J J Aiello R J RJ Guyot D D Turi T T Gabel C C Aldinger C C Hoppe K L KL Roach M L ML Royer L J LJ de Wet J J Broccardo C C Chimini G G Francone O L OL

Proceedings of the National Academy of Sciences of the United States of America 20000401 8

Recently, the human ATP-binding cassette transporter-1 (ABC1) gene has been demonstrated to be mutated in patients with Tangier disease. To investigate the role of the ABC1 protein in an experimental in vivo model, we used gene targeting in DBA-1J embryonic stem cells to produce an ABC1-deficient mouse. Expression of the murine Abc1 gene was ablated by using a nonisogenic targeting construct that deletes six exons coding for the first nucleotide-binding fold. Lipid profiles from Abc1 knockout (- ...[more]

PMID: 10760292

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Project description:Transplantation studies suggest that bone marrow cell ATP-binding cassette transporter A1 protects against atherosclerosis development. However, the in vivo effect of macrophage ATP-binding cassette transporter A1 expression on atherogenesis is not fully understood because bone marrow contains other leukocytes and hematopoietic stem and progenitor cells. Myeloid-specific ATP-binding cassette transporter A1 knockout mice in the low-density lipoprotein (LDL) receptor knockout C57BL/6 background were developed to address this question.Chow-fed myeloid-specific ATP-binding cassette transporter A1 knockout/LDL receptor knockout (double knockout [DKO]) versus LDL receptor knockout (single knockout [SKO]) mice had similar plasma lipid concentrations, but atherogenic diet (AD)-fed DKO mice had reduced plasma very-LDL (VLDL)/LDL concentrations resulting from decreased hepatic VLDL triglyceride secretion. Resident peritoneal macrophages from AD-fed DKO versus SKO mice had significantly higher cholesterol content but similar proinflammatory gene expression. Atherosclerosis extent was similar between genotypes after 10 to 16 weeks of AD but increased modestly in DKO mice by 24 weeks of AD. Lesional macrophage content was similar, likely because of the higher monocyte flux through aortic root lesions in DKO versus SKO mice. After transplantation of DKO or SKO bone marrow into SKO mice and 16 weeks of AD feeding, atherosclerosis extent was similar and plasma apolipoprotein B lipoproteins were reduced in mice receiving DKO bone marrow. When differences in plasma VLDL/LDL concentrations were minimized by maintaining mice on chow for 24 weeks, DKO mice had modest, but significantly more, atherosclerosis compared with SKO mice.Myeloid cell ATP-binding cassette transporter A1 increases hepatic VLDL triglyceride secretion and plasma VLDL/LDL concentrations in AD-fed LDL receptor knockout mice, offsetting its atheroprotective role in decreasing macrophage cholesterol content, resulting in a minimal increase in atherosclerosis.

Dataset Information

High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1.

Publications

High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1.

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