Abca7 Null Mice Retain Normal Macrophage Phosphatidylcholine and Cholesterol Efflux Activity despite Alterations in Adipose Mass and Serum Cholesterol Levels

Woojin Scott Kim,Michael L Fitzgerald,Kihwa Kang,Kei-Ichiro Okuhira,Susan A Bell,Jennifer J Manning,Stephanie L Koehn,Naifang Lu,Kathryn J Moore,Mason W Freeman

doi:10.1074/jbc.m412602200

Woojin Scott Kim, Michael L Fitzgerald + Show 8 more

Open Access

https://doi.org/10.1074/jbc.m412602200

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Abstract

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.

Highlights

ATP-binding cassette (ABC)1 transporters form a large and ancient gene family, many members of which have been linked to genetic diseases in humans [1]
Cholesterol and Phospholipid Efflux Assays—Studies of cholesterol and phospholipid efflux were performed in bone marrow-derived macrophages or 293 and 293-EBNA T cells transfected with ABCA7 or ABCA1 cDNAs as we have described previously [22]
ABCA7 is of considerable interest because it is a member of the A class of lipid transporters that have been shown to be causally implicated in three human genetic diseases: Tangier disease (ABCA1), Stargadt’s macular degeneration (ABCA4), and neonatal respiratory failure (ABCA3) (9 – 12,15)

Summary

Introduction

ATP-binding cassette (ABC) transporters form a large and ancient gene family, many members of which have been linked to genetic diseases in humans [1]. The significance of the lipid efflux measured in ABCA7transfected cells is uncertain, and the physiologic role of the transporter is unknown To explore this function, we generated Abca7Ϫ/Ϫ null mice and performed an initial characterization of their phenotype. ABCA7 Null Mice total serum and HDL cholesterol levels These serum lipid differences were much less profound than those seen in comparisons of wild type and Abca1Ϫ/Ϫ mice. We found no disruption in macrophage efflux of phosphatidylcholine or cholesterol efflux to apoA-I, as might have been predicted from the published ABCA7 cell transfection experiments These results indicate that ABCA7 does not recapitulate ABCA1 function but rather has distinct activities that will require further investigation of wild type and null mice to elucidate

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