Abca7 null mice retain normal macrophage phosphatidylcholine and cholesterol efflux activity despite alterations in adipose mass and serum cholesterol levels.
Mutations in the A class of ATP-binding cassette transporters (ABCA) are causally implicated in three human diseases: Tangier disease (ABCA1), Stargadt's macular degeneration (ABCA4), and neonatal respiratory failure (ABCA3). Both ABCA1 and ABCA4 have been shown to transport lipids across cellular membranes, and ABCA3 may play a similar role in transporting pulmonary surfactant. Although the functions of the other 10 ABCA class transporters identified in the human genome remain obscure, ABCA7-transfected cells have been shown to efflux lipids in response to stimulation by apolipoprotein A-I. In an effort to elucidate the physiologic role of ABCA7, we generated mice lacking this transporter (Abca7-/- mice). Homozygous null mice were produced from intercrosses of heterozygous null mice at the expected Mendelian frequency and developed normally without any obvious phenotypic abnormalities. Cholesterol and phospholipid efflux stimulated by apolipoprotein A-I from macrophages isolated from wild type and Abca7-/- mice did not differ, suggesting that these activities may not be central to the physiological role of the transporter in vivo. Abca7-/- females, but not males, had significantly less visceral fat and lower total serum and high density lipoprotein cholesterol levels than wild type, gender-matched littermates. ABCA7 expression was detected in hippocampal and cortical neurons by in situ hybridization and in brain and white adipose tissue by Western blotting. Induction of adipocyte differentiation from 3T3 fibroblasts in culture led to a marked increase in ABCA7 expression. These studies suggest that ABCA7 plays a novel role in lipid and fat metabolism that Abca7-/- mice can be used to elucidate.
Kim
Woojin Scott
WS
Lipid Metabolism Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Fitzgerald
Michael L
ML
Kang
Kihwa
K
Okuhira
Kei-ichiro
K
Bell
Susan A
SA
Manning
Jennifer J
JJ
Koehn
Stephanie L
SL
Lu
Naifang
N
Moore
Kathryn J
KJ
Freeman
Mason W
MW
D016475:3T3 Cells; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood / Q000378:metabolism*; D005247:Feeding Behavior; D005260:Female; D015870:Gene Expression; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010713:Phosphatidylcholines / Q000378:metabolism*; D015430:Weight Gain
D018528:ATP-Binding Cassette Transporters; C485856:Abca7 protein, mouse; D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D010713:Phosphatidylcholines