Abca7 null mice retain normal macrophage phosphatidyleholine and cholesterol efflux activity despite alterations in adipose mass and serum cholesterol levels
Abca7 null mice retain normal macrophage phosphatidyleholine and cholesterol efflux activity despite alterations in adipose mass and serum cholesterol levels
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DOI：
10.1074/jbc.m412602200
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发表时间：
2005-02-04
影响因子：
4.8
通讯作者：
Freeman, MW
中科院分区：
文献类型：
--
作者：
Kim, WS;Fitzgerald, ML;Freeman, MW
A类ATP结合盒转运蛋白（ABCA）的突变与三种人类疾病有因果关系：丹吉尔病（ABCA 1）、Stargadt黄斑变性（ABCA 4）和新生儿呼吸衰竭（ABCA 3）。ABCA 1和ABCA 4都被证明可以跨细胞膜转运脂质，ABCA 3可能在转运肺表面活性物质方面发挥类似的作用。虽然在人类基因组中鉴定的其他10种ABCA类转运蛋白的功能仍然不清楚，但ABCA 7转染的细胞已显示出响应载脂蛋白A-I的刺激而流出脂质。为了阐明ABCA 7的生理作用，我们产生了缺乏ABCA 7的小鼠。这种转运蛋白（Abca 7（-/-）小鼠）。纯合子无效小鼠是由杂合子无效小鼠以预期的孟德尔频率杂交产生的，并且发育正常，没有任何明显的表型异常。从野生型和Abca 7（-/-）小鼠分离的巨噬细胞中的载脂蛋白A-1刺激的胆固醇和磷脂流出没有差异，表明这些活动可能不是体内转运蛋白生理作用的核心。与野生型、性别匹配的同窝出生仔相比，Abca 7（-/-）雌性动物（而非雄性动物）的内脏脂肪显著减少，血清总胆固醇和高密度脂蛋白胆固醇水平显著降低。原位杂交检测海马和皮质神经元中ABCA 7的表达，Western印迹检测脑和白色脂肪组织中ABCA 7的表达。从培养的3 T3成纤维细胞诱导脂肪细胞分化导致ABCA 7表达的显著增加。这些研究表明，ABCA 7在脂质和脂肪代谢中起着新的作用，Abca 7（-/-）小鼠可以用来阐明。
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-1 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.