强效选择性过氧化物酶体增殖物激活受体α（PPAR-α）激动剂LY518674可上调代谢综合征患者载脂蛋白A-I（ApoA-I）的生成及分解代谢。
Potent and selective PPAR-alpha agonist LY518674 upregulates both ApoA-I production and catabolism in human subjects with the metabolic syndrome.
作者信息
Millar John S, Duffy Danielle, Gadi Ramprasad, Bloedon LeAnne T, Dunbar Richard L, Wolfe Megan L, Movva Rajesh, Shah Ashish, Fuki Ilia V, McCoy Mary, Harris Cynthia J, Wang Ming-Dauh, Howey Daniel C, Rader Daniel J
机构信息
Departments of Pharmacology, University of Pennsylvania, 652 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104, USA.
出版信息
Arterioscler Thromb Vasc Biol. 2009 Jan;29(1):140-6. doi: 10.1161/ATVBAHA.108.171223. Epub 2008 Nov 6.
OBJECTIVE
The study of PPAR-alpha activation on apoA-I production in humans has been limited to fibrates, relatively weak PPAR-alpha agonists that may have other molecular effects. We sought to determine the effect of a potent and highly specific PPAR-alpha agonist, LY518674, on apoA-I, apoA-II, and apoB-100 kinetics in humans with metabolic syndrome and low levels of HDL cholesterol (C).
METHODS AND RESULTS
Subjects were randomized to receive LY518674 (100 microg) once daily (n=13) or placebo (n=15) for 8 weeks. Subjects underwent a kinetic study using a deuterated leucine tracer to measure apolipoprotein production and fractional catabolic rates (FCR) at baseline and after treatment. LY518674 significantly reduced VLDL-C (-38%, P=0.002) and triglyceride (-23%, P=0.002) levels whereas LDL-C and HDL-C levels were unchanged. LY518674 significantly reduced VLDL apoB-100 (-12%, P=0.01) levels, attributable to an increased VLDL apoB-100 FCR with no change in VLDL apoB-100 production. IDL and LDL apoB-100 kinetics were unchanged. LY518674 significantly increased the apoA-I production rate by 31% (P<0.0001), but this was accompanied by a 33% increase in the apoA-I FCR (P=0.002), resulting in no change in plasma apoA-I. There was a 71% increase in the apoA-II production rate (P<0.0001) accompanied by a 25% increase in the FCR (P<0.0001), resulting in a significant increase in plasma apoA-II.
CONCLUSIONS
Activation of PPAR-alpha with LY518674 (100 microg) in subjects with metabolic syndrome and low HDL-C increased the VLDL apoB-100 FCR consistent with enhanced lipolysis of plasma triglyceride. Significant increases in the apoA-I and apoA-II production rates were accompanied by increased FCRs resulting in no change in HDL-C levels. These data indicate a major effect of LY518674 on the production and clearance of apoA-I and HDL despite no change in the plasma concentration. The effect of these changes on reverse cholesterol transport remains to be determined.
目的
关于过氧化物酶体增殖物激活受体α（PPAR-α）激活对人体载脂蛋白A-I（apoA-I）生成的研究仅限于贝特类药物，这类相对较弱的PPAR-α激动剂可能还有其他分子效应。我们试图确定一种强效且高度特异性的PPAR-α激动剂LY518674对代谢综合征且高密度脂蛋白胆固醇（HDL-C）水平低的人体中apoA-I、apoA-II和载脂蛋白B-100（apoB-100）动力学的影响。
方法与结果
将受试者随机分为两组，一组每天接受一次LY518674（100微克，n = 13），另一组接受安慰剂（n = 15），为期8周。受试者在基线和治疗后使用氘代亮氨酸示踪剂进行动力学研究，以测量载脂蛋白的生成和分数分解代谢率（FCR）。LY518674显著降低了极低密度脂蛋白胆固醇（VLDL-C）水平（-38%，P = 0.002）和甘油三酯水平（-23%，P = 0.002），而低密度脂蛋白胆固醇（LDL-C）和HDL-C水平未改变。LY518674显著降低了VLDL apoB-100水平（-12%，P = 0.01），这归因于VLDL apoB-100的FCR增加，而VLDL apoB-100的生成没有变化。中间密度脂蛋白（IDL）和LDL apoB-100的动力学未改变。LY518674使apoA-I的生成率显著增加了31%（P < 0.0001），但同时apoA-I的FCR增加了33%（P = 0.002），导致血浆apoA-I水平没有变化。apoA-II的生成率增加了71%（P < 0.0001），同时FCR增加了25%（P < 0.0001），导致血浆apoA-II显著增加。
结论
在代谢综合征且HDL-C低的受试者中，用LY518674（100微克）激活PPAR-α可增加VLDL apoB-100的FCR，这与血浆甘油三酯脂解增强一致。apoA-I和apoA-II生成率的显著增加伴随着FCR的增加，导致HDL-C水平没有变化。这些数据表明，尽管血浆浓度没有变化，但LY518674对apoA-I和HDL的生成及清除有主要影响。这些变化对逆向胆固醇转运的影响仍有待确定。
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