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 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.
McNeish
J
J
Central Research Division, Pfizer Incorporated, Eastern Point Road, Groton, CT 06340, USA.
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
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D002784:Cholesterol / Q000097:blood; D017931:DNA Primers; D005487:Foam Cells / Q000166:cytology*; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D017931:DNA Primers; D006023:Glycoproteins; D008075:Lipoproteins, HDL; D002784:Cholesterol