Department of Pathology/Section on Lipid Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Circulation. 2011 Oct 11;124(15):1663-72. doi: 10.1161/CIRCULATIONAHA.111.025445. Epub 2011 Sep 19.
Adipose tissue (AT) is the body's largest free cholesterol reservoir and abundantly expresses ATP binding cassette transporter A1 (ABCA1), a key cholesterol transporter for high-density lipoprotein (HDL) biogenesis. However, the extent to which AT ABCA1 expression contributes to HDL biogenesis in vivo is unknown.
Adipocyte-specific ABCA1 knockout mice (ABCA1(-A/-A)) were generated by crossing ABCA1(floxed) mice with aP2Cre transgenic mice. AT from ABCA1(-A/-A) mice had <10% of wild-type ABCA1 protein expression but normal hepatic and intestinal expression. Deletion of adipocyte ABCA1 resulted in a significant decrease in plasma HDL cholesterol (approximately 15%) and apolipoprotein A-I (approximately 13%) concentrations. AT from ABCA1(-A/-A) mice had a 2-fold increase in free cholesterol content compared with wild-type mice and failed to efflux cholesterol to apolipoprotein A-I. However, cholesterol efflux from AT to plasma HDL was similar for both genotypes of mice. Incubation of wild-type AT explants with apolipoprotein A-I resulted in the formation of multiple discrete-sized nascent HDL particles ranging in diameter from 7.1 to 12 nm; similar incubations with ABCA1(-A/-A) AT explants resulted in nascent HDL <8 nm. Plasma decay and tissue uptake of wild-type (125)I-HDL tracer were similar in both genotypes of recipient mice, suggesting that adipocyte ABCA1 deficiency reduces plasma HDL concentrations solely by reducing nascent HDL particle formation.
We provide in vivo evidence that AT ABCA1-dependent cholesterol efflux and nascent HDL particle formation contribute to systemic HDL biogenesis and that AT ABCA1 expression plays an important role in adipocyte cholesterol homeostasis.
脂肪组织（AT）是体内最大的游离胆固醇库，大量表达 ATP 结合盒转运体 A1（ABCA1），这是高密度脂蛋白（HDL）生成的关键胆固醇转运蛋白。然而，脂肪组织 ABCA1 表达在体内对 HDL 生成的贡献程度尚不清楚。
通过将 ABCA1（floxed）小鼠与 aP2Cre 转基因小鼠杂交，生成了脂肪细胞特异性 ABCA1 敲除小鼠（ABCA1（-A/-A））。ABCA1（-A/-A）小鼠的脂肪组织 ABCA1 蛋白表达水平仅为野生型的<10%，但肝和肠表达正常。脂肪细胞 ABCA1 的缺失导致血浆 HDL 胆固醇（约 15%）和载脂蛋白 A-I（约 13%）浓度显著降低。与野生型小鼠相比，ABCA1（-A/-A）小鼠的脂肪组织游离胆固醇含量增加了 2 倍，并且无法将胆固醇外排至载脂蛋白 A-I。然而，两种基因型小鼠的脂肪组织向血浆 HDL 的胆固醇外排是相似的。用载脂蛋白 A-I 孵育野生型 AT 外植体可形成多种不同大小的新生 HDL 颗粒，直径范围从 7.1 到 12nm；用 ABCA1（-A/-A）AT 外植体进行类似孵育可导致新生 HDL<8nm。两种基因型接受小鼠的血浆（125）I-HDL 示踪剂的衰变和组织摄取相似，表明脂肪细胞 ABCA1 缺乏通过减少新生 HDL 颗粒形成来降低血浆 HDL 浓度。
我们提供了体内证据表明，AT ABCA1 依赖性胆固醇外排和新生 HDL 颗粒形成有助于全身 HDL 生成，并且 AT ABCA1 表达在脂肪细胞胆固醇稳态中起着重要作用。
