IN VIVO EXPRESSION AND GENE/GENE INTERACTION OF GENES MODULATING HDL METABOLISM

HDL是主要的抗动脉粥样硬化脂蛋白，可能在 胆固醇逆向转运是一个复杂的过程， 多种酶、转运蛋白和受体的结合。LCAT、CETP和HL 对脂类的酯化、交换和水解至关重要 存在于HDL中并调节血浆HDL浓度、异质性和 新陈代谢.通过它们对HDL的作用，这3种蛋白质也可能发挥作用。 在动脉粥样硬化的发展中起主要作用。为了研究 我们利用LCAT、CETP和HL基因-基因相互作用 重组腺病毒在转基因小鼠中表达人HL和CETP 过表达人LCAT，血浆水平比对照高100倍 小鼠与对照动物相比，LCAT转基因小鼠的生长速度加快， 血浆TC、CE和HDL-C浓度以及标记的HDL 异质性与人类不同，小鼠缺乏CETP活性， 因此，在这些动物中，CETP介导的HDL和apoB之间的脂质交换 含有脂蛋白的情况不会发生。 腺病毒介导的HL在对照和LCAT转基因小鼠中的表达 导致肝素后血浆HL活性为24482+7440和27549+9755 nmol/m/ml，血浆TC降低约50-60%， PL和HDL。与对照动物相比， 转基因小鼠导致富含apoE的HDL优先水解 以及异质HDL谱的标准化， 建立这两种酶在调节HDL中的协调作用 颗粒不均匀性 腺病毒介导的CETP在对照和LCAT中的表达 转基因小鼠的血浆CETP活性分别为80 ± 4和74 ± 5%/5 ul/18 h，并增加血浆apoB脂蛋白以及 HDL浓度降低，这是一种脂蛋白模式， 这表明CETP介导的CE从HDL的有效转移。 与对照动物相比，LCAT转基因小鼠中CETP的表达 导致了一个更具保护性的脂蛋白谱，从而建立了 CETP和LCAT在HDL代谢中的协调作用。

HDL, the major antiatherogenic lipoprotein, may play an important role in reverse cholesterol transport, a complex process modulated by the action of multiple enzymes, transfer proteins and receptors. LCAT, CETP and HL are essential for the esterification, exchange and hydrolysis of lipids present in HDL and modulate plasma HDL concentrations, heterogeneity and metabolism. Through their action on HDL, these 3 proteins may also play a major role in the development of atherosclerosis. In order to investigate the LCAT, CETP and HL gene-gene interaction in vivo we have utilized recombinant adenovirus to express human HL and CETP in transgenic mice overexpressing human LCAT at plasma levels 100 fold higher than control mice. Compared to control animals, LCAT transgenic mice have increased plasma TC, CE and HDL-C concentrations as well as marked HDL heterogeneity. Unlike humans, mice are deficient in CETP activity and thus, in these animals CETP-mediated lipid exchange between HDL and apoB containing lipoproteins does not occur. Adenovirus-mediated expression of HL in control and LCAT transgenic mice resulted in post-heparin plasma HL activity of 24482+7440 and 27549+9755 nmol/m/ml, respectively and approximately 50-60% reduction in plasma TC, PL and HDL in both groups. Compared to control animals, HL expression in transgenic mice resulted in preferential hydrolysis of the apoE-rich HDL as well as normalization of the heterogeneous HDL profile thus establishing a coordinate role for these two enzymes in modulating HDL particle heterogeneity. Adenovirus-mediated expression of CETP in control and LCAT transgenic mice resulted in plasma CETP activity of 80+4 and 74+5 %/5 ul/l8h, respectively and increased plasma apoB lipoproteins as well as decreased HDL concentrations, a lipoprotein pattern reminiscent of human profiles which indicates effective CETP-mediated transfer of CE from HDL. Compared to control animals, expression of CETP in LCAT transgenic mice resulted in a more protective lipoprotein profile, thus establishing the coordinate role of CETP and LCAT in HDL metabolism.