KineMed, Inc, Emeryville, CA (S.T., J.V., A.G., S.K., J.D., H.M., E.M., J.L., M.A.).
J Am Heart Assoc. 2012 Aug;1(4):e001826. doi: 10.1161/JAHA.112.001826. Epub 2012 Aug 24.
Reverse cholesterol transport from peripheral tissues is considered the principal atheroprotective mechanism of high-density lipoprotein, but quantifying reverse cholesterol transport in humans in vivo remains a challenge. We describe here a method for measuring flux of cholesterol though 3 primary components of the reverse cholesterol transport pathway in vivo in humans: tissue free cholesterol (FC) efflux, esterification of FC in plasma, and fecal sterol excretion of plasma-derived FC.
A constant infusion of [2,3-(13)C(2)]-cholesterol was administered to healthy volunteers. Three-compartment SAAM II (Simulation, Analysis, and Modeling software; SAAM Institute, University of Washington, WA) fits were applied to plasma FC, red blood cell FC, and plasma cholesterol ester (13)C-enrichment profiles. Fecal sterol excretion of plasma-derived FC was quantified from fractional recovery of intravenous [2,3-(13)C(2)]-cholesterol in feces over 7 days. We examined the key assumptions of the method and evaluated the optimal clinical protocol and approach to data analysis and modeling. A total of 17 subjects from 2 study sites (n=12 from first site, age 21 to 75 years, 2 women; n=5 from second site, age 18 to 70 years, 2 women) were studied. Tissue FC efflux was 3.79±0.88 mg/kg per hour (mean ± standard deviation), or ≍8 g/d. Red blood cell-derived flux into plasma FC was 3.38±1.10 mg/kg per hour. Esterification of plasma FC was ≍28% of tissue FC efflux (1.10±0.38 mg/kg per hour). Recoveries were 7% and 12% of administered [2,3-(13)C(2)]-cholesterol in fecal bile acids and neutral sterols, respectively.
Three components of systemic reverse cholesterol transport can be quantified, allowing dissection of this important function of high-density lipoprotein in vivo. Effects of lipoproteins, genetic mutations, lifestyle changes, and drugs on these components can be assessed in humans. (J Am Heart Assoc. 2012;1:e001826 doi: 10.1161/JAHA.112.001826.).
从外周组织的胆固醇逆向转运被认为是高密度脂蛋白的主要抗动脉粥样硬化机制，但在人体内定量检测胆固醇逆向转运仍然是一个挑战。我们在这里描述了一种在人体内测量胆固醇通过胆固醇逆向转运途径的 3 个主要成分的通量的方法：组织游离胆固醇（FC）流出、FC 在血浆中的酯化以及血浆源性 FC 的粪便固醇排泄。
向健康志愿者输注[2,3-(13)C(2)]-胆固醇恒速。应用三房室 SAAM II（模拟、分析和建模软件；华盛顿大学 SAAM 研究所）拟合来拟合血浆 FC、红细胞 FC 和血浆胆固醇酯（13)C-丰度谱。通过静脉内[2,3-(13)C(2)]-胆固醇在粪便中 7 天的分数回收来定量测定血浆源性 FC 的粪便排泄。我们检查了该方法的关键假设，并评估了最佳的临床方案以及数据分析和建模方法。共有来自 2 个研究地点的 17 名受试者（第 1 个地点 12 名，年龄 21 至 75 岁，2 名女性；第 2 个地点 5 名，年龄 18 至 70 岁，2 名女性）接受了研究。组织 FC 流出为 3.79±0.88mg/kg/小时（平均值±标准差），或约 8g/d。红细胞衍生的 FC 进入血浆的通量为 3.38±1.10mg/kg/小时。FC 的酯化率约为组织 FC 流出量的 28%（1.10±0.38mg/kg/小时）。粪便胆汁酸和中性固醇中分别回收了给予的[2,3-(13)C(2)]-胆固醇的 7%和 12%。
可以定量测定系统胆固醇逆向转运的 3 个组成部分，从而可以在体内剖析高密度脂蛋白的这一重要功能。可以在人体中评估脂蛋白、基因突变、生活方式改变和药物对这些成分的影响。
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