Atherosclerosis, Cardiovascular Diseases, Merck Research Laboratories, RY80T-A100, 126 E. Lincoln Ave, Rahway, NJ 07065, USA.
J Cardiovasc Transl Res. 2011 Dec;4(6):801-10. doi: 10.1007/s12265-011-9309-8. Epub 2011 Aug 6.
Lecithin:cholesterol acyltransferase (LCAT) is the key circulating enzyme responsible for high-density lipoprotein (HDL) cholesterol esterification, HDL maturation, and potentially reverse cholesterol transport. To further explore LCAT's mechanism of action on lipoprotein metabolism, we employed adeno-associated viral vector (AAV) serotype 8 to achieve long-term (32-week) high level expression of human LCAT in hCETP;Ldlr(+/-) mice, and characterized the lipid profiles in detail. The mice had a marked increase in HDL cholesterol, HDL particle size, and significant reduction in low-density lipoprotein (LDL) cholesterol, plasma triglycerides, and plasma apoB. Plasma LCAT activity significantly increased with humanized substrate specificity. HDL cholesteryl esters increased in a fashion that fits human LCAT specificity. HDL phosphatidylcholines trended toward decrease, with no change observed for HDL lysophosphatidylcholines. Triglycerides reduction appeared to reside in all lipoprotein particles (very low-density lipoprotein (VLDL), LDL, and HDL), with HDL triglycerides composition highly reflective of VLDL, suggesting that changes in HDL triglycerides were primarily driven by the altered triglycerides metabolism in VLDL. In summary, in this human-like model for lipoprotein metabolism, AAV8-mediated overexpression of human LCAT resulted in profound changes in plasma lipid profiles. Detailed lipid analyses in the lipoprotein particles suggest that LCAT's beneficial effect on lipid metabolism includes not only enhanced HDL cholesterol esterification but also improved metabolism of apoB-containing particles and triglycerides. Our findings thus shed new light on LCAT's mechanism of action and lend support to its therapeutic potential in treating dyslipidemia.
卵磷脂胆固醇酰基转移酶（LCAT）是负责高密度脂蛋白（HDL）胆固醇酯化、HDL 成熟和潜在的胆固醇逆向转运的关键循环酶。为了进一步探讨 LCAT 对脂蛋白代谢的作用机制，我们采用腺相关病毒载体（AAV）血清型 8 在 hCETP；Ldlr(+/-)小鼠中实现了人 LCAT 的长期（32 周）高水平表达，并详细描述了其脂质谱特征。与野生型小鼠相比，这些小鼠的 HDL 胆固醇、HDL 颗粒大小显著增加，LDL 胆固醇、血浆甘油三酯和载脂蛋白 B 显著减少。血浆 LCAT 活性显著增加，并具有人源化的底物特异性。HDL 胆固醇酯的增加符合人类 LCAT 的特异性。HDL 磷脂酰胆碱呈下降趋势，而 HDL 溶血磷脂酰胆碱没有变化。甘油三酯的减少似乎存在于所有脂蛋白颗粒（极低密度脂蛋白（VLDL）、LDL 和 HDL）中，HDL 甘油三酯的组成与 VLDL 高度相似，表明 HDL 甘油三酯的变化主要是由 VLDL 中甘油三酯代谢的改变引起的。综上所述，在这个类似人类的脂蛋白代谢模型中，AAV8 介导的人 LCAT 过表达导致了血浆脂质谱的显著变化。对脂蛋白颗粒中的详细脂质分析表明，LCAT 对脂质代谢的有益影响不仅包括增强 HDL 胆固醇酯化，还包括改善载脂蛋白 B 含有的颗粒和甘油三酯的代谢。我们的研究结果因此为 LCAT 的作用机制提供了新的见解，并为其在治疗血脂异常方面的治疗潜力提供了支持。
