Nanjee M N, Crouse J R, King J M, Hovorka R, Rees S E, Carson E R, Morgenthaler J J, Lerch P, Miller N E
Department of Cardiovascular Biochemistry, St Bartholomew's Hospital Medical College, London, UK.
Arterioscler Thromb Vasc Biol. 1996 Sep;16(9):1203-14. doi: 10.1161/01.atv.16.9.1203.
Apolipoprotein (apo) A-I is the principal protein component of the plasma high density lipoproteins (HDLs). Tissue culture studies have suggested that lipid-free apo A-I may, by recruiting phospholipids (PLs) and unesterified cholesterol from cell membranes, initiate reverse cholesterol transport and provide a nidus for the formation, via lipid-poor, pre-beta-migrating HDLs, of spheroidal alpha-migrating HDLs. Apo A-I has also been shown to inhibit hepatic lipase (HL) and lipoprotein lipase (LPL) in vitro. To further study its functions and fate in vivo, we gave lipid-free apo A-I intravenously on a total of 32 occasions to six men with low HDL cholesterol (30 to 38 mg/dL) by bolus injection (25 mg/kg) and/or by infusion over 5 hours (1.25, 2.5, 5.0, and 10.0 mg.kg-1.h-1). The procedure was well tolerated: there were no clinical, biochemical, or hematologic changes, and there was no evidence of allergic, immunologic, or acute-phase responses. The 5-hour infusions increased plasma total apo A-I concentration in a dose-related manner by 10 to 50 mg/dL after which it decreased, with a half-life of 15 to 54 hours. Coinfusion of Intralipid reduced the clearance rate. The apparent volume of distribution exceeded the known extracellular space in humans, suggesting extensive first-pass clearance by one or more organs. No apo A-I appeared in the urine. Increases in apo A-I mass were confined to the pre-beta region on crossed immunoelectrophoresis of plasma and to HDL-size particles on size exclusion chromatography. Increases were recorded in HDL PL, but not in HDL unesterified or esterified cholesterol. Increases also occurred in LDL PL and in very low density lipoprotein cholesterol, triglycerides, and PL but not in plasma total apo B concentration. These results can all be explained by combined inhibition of HL and LPL activities. Owing to the effects that this would have had on HDL metabolism, no conclusions can be drawn from these data about the role of lipid-free apo A-I in the removal of PL and cholesterol from peripheral tissues in humans. The kinetic data suggest that the fractional catabolic rate of lipid-free apo A-I exceeds that of spheroidal HDLs and is reduced in the presence of surplus PL.
载脂蛋白（apo）A-I是血浆高密度脂蛋白（HDL）的主要蛋白质成分。组织培养研究表明，无脂apo A-I可能通过从细胞膜募集磷脂（PL）和未酯化胆固醇，启动逆向胆固醇转运，并通过贫脂的前β迁移HDL形成球状α迁移HDL的核心。体外研究还表明，apo A-I可抑制肝脂酶（HL）和脂蛋白脂酶（LPL）。为了进一步研究其在体内的功能和转归，我们对6名HDL胆固醇水平较低（30至38mg/dL）的男性，共32次静脉给予无脂apo A-I，给药方式为静脉推注（25mg/kg）和/或5小时持续输注（1.25、2.5、5.0和10.0mg·kg-1·h-1）。该过程耐受性良好：无临床、生化或血液学变化，也无过敏、免疫或急性期反应的证据。5小时输注使血浆总apo A-I浓度以剂量相关方式升高10至50mg/dL，之后下降，半衰期为15至54小时。同时输注脂肪乳可降低清除率。分布表观容积超过人类已知的细胞外间隙，提示一个或多个器官存在广泛的首过清除。尿中未出现apo A-I。血浆交叉免疫电泳显示apo A-I质量增加局限于前β区，尺寸排阻色谱显示增加局限于HDL大小的颗粒。HDL PL增加，但HDL未酯化或酯化胆固醇未增加。LDL PL以及极低密度脂蛋白胆固醇、甘油三酯和PL也增加，但血浆总apo B浓度未增加。这些结果均可通过HL和LPL活性的联合抑制来解释。由于这可能对HDL代谢产生影响，因此无法从这些数据得出关于无脂apo A-I在人类外周组织中清除PL和胆固醇作用的结论。动力学数据表明，无脂apo A-I的分解代谢率分数超过球状HDL，且在PL过剩时降低。
