Department of Medicine, UBC James Hogg Research Centre, Heart and Lung Institute, St, Paul's Hospital, Vancouver, British Columbia, Canada.
BMC Biochem. 2012 Jan 16;13:1. doi: 10.1186/1471-2091-13-1.
ATP-binding cassette transporter A1 (ABCA1) mediates the lipidation of exchangeable apolipoproteins, the rate-limiting step in the formation of high density lipoproteins (HDL). We previously demonstrated that HDL oxidized ex vivo by peroxidase-generated tyrosyl radical (tyrosylated HDL, tyrHDL) increases the availability of cellular cholesterol for efflux and reduces the development of atherosclerosis when administered to apolipoprotein E-deficient mice as compared to treatment with control HDL.
In the current study we determined that tyrHDL requires functional ABCA1 for this enhanced activity. Like lipid-free apolipoprotein A-I (apoA-I), tyrHDL increases total and cell surface ABCA1, inhibits calpain-dependent and -independent proteolysis of ABCA1, and can be bound by cell surface ABCA1 in human skin fibroblasts. Additionally, tyrHDL apoproteins are susceptible to digestion by enteropeptidase like lipid-free apoA-I, but unlike lipid-bound apoA-I on HDL, which is resistant to proteolysis.
These results provide the first evidence that lipid-bound apolipoproteins on the surface of spherical HDL particles can behave like lipid-free apoA-I to increase ABCA1 protein levels and activity.
三磷酸腺苷结合盒转运体 A1（ABCA1）介导可交换载脂蛋白的脂质化，这是高密度脂蛋白（HDL）形成的限速步骤。我们之前的研究表明，与对照 HDL 相比，过氧化物酶产生的酪氨酸自由基（酪氨酸化 HDL，tyrHDL）体外氧化的 HDL 增加了细胞胆固醇流出的可利用性，并减少了载脂蛋白 E 缺陷小鼠动脉粥样硬化的发展。
在本研究中，我们确定 tyrHDL 需要功能性 ABCA1 才能发挥这种增强的活性。与无脂质载脂蛋白 A-I（apoA-I）一样，tyrHDL 增加了总和细胞表面 ABCA1，抑制钙蛋白酶依赖性和非依赖性 ABCA1 蛋白水解，并可与人皮肤成纤维细胞表面的 ABCA1 结合。此外，tyrHDL 载脂蛋白易受肠肽酶消化，与 HDL 上结合脂质的 apoA-I 不同，后者不易发生蛋白水解。
这些结果首次提供了证据，表明球形 HDL 颗粒表面的脂质结合载脂蛋白可以像无脂质 apoA-I 一样，增加 ABCA1 蛋白水平和活性。
