University of Pennsylvania, Depts. of Medicine and Pharmacology, 652 BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104, United States.
Atherosclerosis. 2010 May;210(1):35-40. doi: 10.1016/j.atherosclerosis.2009.11.010. Epub 2009 Dec 14.
Metabolic syndrome, diabetes and obesity are frequently associated with hypertriglyceridemia, hypercholesterolemia and low HDL levels, a phenotype known as atherogenic dyslipidemia. Atherogenic dyslipidemia and hypertriglyceridemia are frequently treated with fibric acid derivatives which activate the nuclear receptor PPAR-alpha leading to reduce plasma triglycerides and an increase in HDL cholesterol levels. The mechanism by which activation of PPAR-alpha with fibrates improves the plasma lipid profile in patients with atherogenic dyslipidemia and hypertriglyceridemia has been examined in several small studies measuring lipoprotein kinetics. The results of these studies indicate that the changes in lipoprotein metabolism observed in response to fibrate treatment vary according to lipoprotein phenotype. In general, fibrates act to reduce VLDL apoB-100 through enhanced fractional catabolism (clearance) of VLDL apoB-100 with additional effects on reducing VLDL apoB-100 production. LDL apoB-100 levels generally decrease in response to fibrates due to increased LDL fractional catabolism except in those patients with high to very high plasma triglyceride levels (>400mg/dL). Fibrates also increase HDL apoA-I and apoA-II levels by enhancing apoA-I and apoA-II production, although this is partially counteracted by increasing fractional catabolism of these apolipoproteins. The potent and specific PPAR-alpha agonist LY518674, reduced VLDL apoB-100 levels through enhanced fractional catabolism similar to what is seen with fibrates. In contrast to fibrates, LY518674 did not change HDL apoA-I levels in response to due to an increased turnover of apoA-I where an increased fractional catabolic rate entirely counteracted the increase in apoA-I production. The changes in apoB metabolism in response to PPAR-alpha activation with fibrates and specific PPAR-alpha agonists would be expected to reduce the risk of cardiovascular disease. However, the benefit of the enhanced turnover of HDL apoA-I in response to PPAR-alpha activation remains to be determined.
代谢综合征、糖尿病和肥胖症常伴有高甘油三酯血症、高胆固醇血症和低 HDL 水平，这种表型被称为致动脉粥样硬化性血脂异常。致动脉粥样硬化性血脂异常和高甘油三酯血症常采用纤维酸衍生物治疗，这些药物可激活核受体 PPAR-α，从而降低血浆甘油三酯并增加 HDL 胆固醇水平。纤维酸衍生物激活 PPAR-α可改善致动脉粥样硬化性血脂异常和高甘油三酯血症患者的血浆脂质谱，这一机制已在几项测量脂蛋白动力学的小型研究中进行了检验。这些研究的结果表明，纤维酸衍生物治疗引起的脂蛋白代谢变化因脂蛋白表型而异。一般来说，纤维酸衍生物通过增强 VLDL apoB-100 的部分分解代谢（清除）来减少 VLDL apoB-100，同时还可减少 VLDL apoB-100 的产生。由于 LDL 部分分解代谢增加，除了那些血浆甘油三酯水平高至非常高（>400mg/dL）的患者外，LDL apoB-100 水平通常会因纤维酸衍生物而降低。纤维酸衍生物还通过增加 apoA-I 和 apoA-II 的产生来增加 HDL apoA-I 和 apoA-II 水平，尽管这部分被这些载脂蛋白的部分分解代谢增加所抵消。强效且特异的 PPAR-α激动剂 LY518674 通过增强 VLDL apoB-100 的部分分解代谢来降低 VLDL apoB-100 水平，这与纤维酸衍生物的作用相似。与纤维酸衍生物不同，由于 apoA-I 的周转率增加，LY518674 并未因增加而改变 HDL apoA-I 水平apoA-I 的产生完全抵消了apoA-I 分解代谢率的增加。纤维酸衍生物和特异的 PPAR-α激动剂激活 PPAR-α 后，apoB 代谢的变化预计将降低心血管疾病的风险。然而，PPAR-α 激活后 HDL apoA-I 周转率增加的益处仍有待确定。
