Hayek T, Azrolan N, Verdery R B, Walsh A, Chajek-Shaul T, Agellon L B, Tall A R, Breslow J L
Laboratory of Biochemical Genetics and Metabolism, Rockefeller University, New York 10021-6399.
J Clin Invest. 1993 Sep;92(3):1143-52. doi: 10.1172/JCI116683.
Several types of transgenic mice were used to study the influence of hypertriglyceridemia and cholesteryl ester transfer protein (CETP) expression on high density lipoprotein (HDL) levels, particle sizes, and metabolism. The presence of the CETP transgene in hypertriglyceridemic human apo CIII transgenic mice lowered HDL-cholesterol (HDL-C) 48% and apolipoprotein (apo) A-I 40%, decreased HDL size (particle diameter from 9.8 to 8.8 nm), increased HDL cholesterol ester (CE) fractional catabolic rate (FCR) 65% with a small decrease in HDL CE transport rate (TR) and increased apo A-I FCR 15% and decreased apo A-I TR 29%. The presence of the CETP transgene in hypertriglyceridemic mice with human-like HDL, human apo A-I apo CIII transgenic mice, lowered HDL-C 61% and apo A-I 45%, caused a dramatic diminution of HDL particle size (particle diameters from 10.3 and 9.1 to 7.6 nm), increased HDL CE FCR by 107% without affecting HDL CE TR, and increased apo A-I FCR 35% and decreased apo A-I TR 48%. Moreover, unexpectedly, hypertriglyceridemia alone in the absence of CETP was also found to cause lower HDL-C and apo A-I levels primarily by decreasing TRs. Decreased apo A-I TR was confirmed by an in vivo labeling study and found to be associated with a decrease in intestinal but not hepatic apo A-I mRNA levels. In summary, the introduction of the human apo A-I, apo CIII, and CETP genes into transgenic mice produced a high-triglyceride, low-HDL-C lipoprotein phenotype. Human apo A-I gene overexpression caused a diminution of mouse apo A-I and a change from monodisperse to polydisperse HDL. Human apo CIII gene overexpression caused hypertriglyceridemia with a significant decrease in HDL-C and apo A-I levels primarily due to decreased HDL CE and apo A-I TR but without a profound change in HDL size. In the hypertriglyceridemic mice, human CETP gene expression further reduced HDL-C and apo A-I levels, primarily by increasing HDL CE and apo A-I FCR, while dramatically reducing HDL size. This study provides insights into the genes that may cause the high-triglyceride, low-HDL-C phenotype in humans and the metabolic mechanisms involved.
使用了几种类型的转基因小鼠来研究高甘油三酯血症和胆固醇酯转运蛋白（CETP）表达对高密度脂蛋白（HDL）水平、颗粒大小和代谢的影响。高甘油三酯血症的人载脂蛋白CIII转基因小鼠中存在CETP转基因，使HDL胆固醇（HDL-C）降低48%，载脂蛋白（apo）A-I降低40%，HDL大小减小（颗粒直径从9.8纳米降至8.8纳米），HDL胆固醇酯（CE）分解代谢率（FCR）增加65%，HDL CE转运率（TR）略有下降，apo A-I FCR增加15%，apo A-I TR降低29%。在具有类人HDL的高甘油三酯血症小鼠、人apo A-I载脂蛋白CIII转基因小鼠中存在CETP转基因，使HDL-C降低61%，apo A-I降低45%，导致HDL颗粒大小显著减小（颗粒直径从10.3和9.1纳米降至7.6纳米），HDL CE FCR增加107%，而不影响HDL CE TR，apo A-I FCR增加35%，apo A-I TR降低48%。此外，出乎意料的是，在没有CETP的情况下，单独的高甘油三酯血症也被发现主要通过降低转运率导致HDL-C和apo A-I水平降低。体内标记研究证实了apo A-I TR的降低，并发现其与肠道而非肝脏apo A-I mRNA水平的降低有关。总之，将人apo A-I、apo CIII和CETP基因导入转基因小鼠产生了高甘油三酯、低HDL-C脂蛋白表型。人apo A-I基因的过度表达导致小鼠apo A-I减少，HDL从单分散变为多分散。人apo CIII基因的过度表达导致高甘油三酯血症，HDL-C和apo A-I水平显著降低，主要是由于HDL CE和apo A-I TR降低，但HDL大小没有显著变化。在高甘油三酯血症小鼠中，人CETP基因的表达进一步降低了HDL-C和apo A-I水平，主要是通过增加HDL CE和apo A-I FCR，同时显著减小HDL大小。这项研究为可能导致人类高甘油三酯、低HDL-C表型的基因以及所涉及的代谢机制提供了见解。
