他汀类药物对代谢综合征混合性血脂异常脂蛋白亚群作用的双重性：随时间变化的量变与质变及 CETP 的影响。

Duality of statin action on lipoprotein subpopulations in the mixed dyslipidemia of metabolic syndrome: Quantity vs quality over time and implication of CETP.

机构信息

National Institute for Health and Medical Research (INSERM), Pitié-Salpêtrière University Hospital, Paris, France; Department of Endocrinology-Metabolism, Pitié-Salpêtrière University Hospital, Paris, France; Pierre et Marie Curie University-Paris 6, Paris, France.

National Institute for Health and Medical Research (INSERM), Pitié-Salpêtrière University Hospital, Paris, France; Service de Biochimie, AP-HP, HUPS, Bicetre University Hospital, Le Kremlin Bicetre, France.

出版信息

J Clin Lipidol. 2018 May-Jun;12(3):784-800.e4. doi: 10.1016/j.jacl.2018.02.001. Epub 2018 Feb 9.

DOI:10.1016/j.jacl.2018.02.001

PMID:29574070

Abstract

BACKGROUND

Statins impact the metabolism, concentrations, composition, and function of circulating lipoproteins.

OBJECTIVE

We evaluated time course relationships between statin-mediated reduction in atherogenic apolipoprotein B (ApoB)-containing particles and dynamic intravascular remodeling of ApoAI-containing lipoprotein subpopulations in the mixed dyslipidemia of metabolic syndrome.

METHODS

Insulin-resistant, hypertriglyceridemic, hypercholesterolemic, obese males (n = 12) were treated with pitavastatin (4 mg/d) and response evaluated at 6, 42, and 180 days.

RESULTS

Reduction in low-density lipoprotein (LDL) cholesterol, ApoB, and triglycerides (TGs) was essentially complete at 42 days (-38%, -32%, and -35%, respectively); rapid reduction equally occurred in remnant cholesterol, ApoCII, CIII, and E levels (day 6; -35%, -50%, -23%, and -26%, respectively). Small dense LDLs (LDL4 and LDL5 subpopulations) predominated at baseline and were markedly reduced on treatment (-29% vs total LDL mass). Cholesteryl ester (CE) transfer protein activity and mass decreased progressively (-18% and -16%, respectively); concomitantly, TG depletion (up to -49%) and CE enrichment occurred in all high-density lipoprotein (HDL) particle subpopulations with normalization of CE/TG mass ratio at 180 days. ApoAI was redistributed from LpAI to LpAI:AII particles in HDL2a and HDL3a subpopulations; ApoCIII was preferentially depleted from LpAI:AII-rich particles on treatment.

CONCLUSION

Overall, statin action exhibits duality in mixed dyslipidemia, as CE transfer protein-mediated normalization of the HDL CE/TG core lags markedly behind subacute reduction in elevated levels of atherogenic ApoB-containing lipoproteins. Normalization of the HDL neutral lipid core is consistent with enhanced atheroprotective function. The HDL CE/TG ratio constitutes a metabolomic marker of perturbed HDL metabolism in insulin-resistant states, equally allowing monitoring of statin impact on HDL metabolism, structure, and function.

摘要

背景

他汀类药物会影响循环脂蛋白的代谢、浓度、组成和功能。

目的

我们评估了他汀类药物降低致动脉粥样硬化载脂蛋白 B (ApoB) 载脂蛋白的时间过程与代谢综合征混合性血脂异常中载脂蛋白 AI 载脂蛋白脂蛋白亚群的血管内重塑之间的关系。

方法

胰岛素抵抗、高三酰甘油血症、高胆固醇血症、肥胖男性（n = 12）接受匹伐他汀（4 mg/d）治疗，并在第 6、42 和 180 天进行评估。

结果

低密度脂蛋白 (LDL) 胆固醇、ApoB 和三酰甘油 (TG) 的降低在第 42 天基本完全（分别降低 38%、32%和 35%）；残留胆固醇、ApoCII、CIII 和 E 水平的快速降低发生在第 6 天（分别降低 35%、50%、23%和 26%）。小而密的 LDL（LDL4 和 LDL5 亚群）在基线时占主导地位，并在治疗时显著减少（-29%与总 LDL 质量）。胆固醇酯（CE）转移蛋白活性和质量逐渐降低（分别降低 18%和 16%）；同时，所有高密度脂蛋白（HDL）颗粒亚群中的 TG 耗竭（高达-49%）和 CE 富集发生，CE/TG 质量比在 180 天内恢复正常。ApoAI 在 HDL2a 和 HDL3a 亚群中从 LpAI 重新分布到 LpAI:AII 颗粒；在治疗过程中，ApoCIII 优先从富含 LpAI:AII 的颗粒中被消耗。

结论

总之，他汀类药物在混合性血脂异常中的作用具有双重性，因为 CE 转移蛋白介导的 HDL CE/TG 核心的正常化明显滞后于亚急性降低升高的致动脉粥样硬化 ApoB 载脂蛋白。HDL 中性脂质核心的正常化与增强的抗动脉粥样硬化功能一致。HDL CE/TG 比值是胰岛素抵抗状态下 HDL 代谢紊乱的代谢组学标志物，同样可以监测他汀类药物对 HDL 代谢、结构和功能的影响。