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

Recently, the human ATP binding cassette transporter-1 (ABC1) gene has been demonstrated to be mutated in patients with Tangier disease. To investigat e the role of the ABC1 protein in an experimental in vivo model, we used ge ne targeting in DBA-1J embryonic stem cells to produce an ABC1-deficient mo use. 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 appr oximate to 70% reduction in cholesterol, markedly reduced plasma phospholip ids, and an almost complete lack of high density lipoproteins (HDL) when co mpared with wild-type littermates (+/+), Fractionation of lipoproteins by F PLC demonstrated dramatic alterations in HDL cholesterol (HDL-C), including the near absence of apolipoprotein Al. Low density lipoprotein (LDL) chole sterol (LDL-C) and apolipoprotein B were also significantly reduced in +/- and -/- compared with their littermate controls. The inactivation of the Ab c1 gene led to an increase in the absorption of cholesterol in mice fed a c how or a high-fat and -cholesterol diet. Histopathologic examination of Abc 1-/- mice at ages 7, 12, and 18 mo demonstrated a striking accumulation of lipid-laden macrophages and type II pneumocytes in the lungs. Taken togethe r, these findings demonstrate that Abc1-/- mice display pathophysiologic ha llmarks similar to human Tangier disease and highlight the capacity of Asci transporters to participate in the regulation of dietary cholesterol absor ption.