一、低密度脂蛋白受体
LDL受体通过识别脂蛋白表面的ApoB和E而介导脂蛋白的清除。将人类LDL-R基因在小鼠体内增强表达后,标有同位素的LDL清除加快十倍以上,血浆ApoB和ApoE水平则下降90%。LDL的快速清除主要通过肝脏完成。当用高胆固醇饲料喂养这种动物后,血浆IDL和LDL不被诱导上升,仅仅VLDL的水平轻度升高。
近年来,LDL-R基因剔除的小鼠模型被研制成功。这种LDL-R缺乏的小鼠即使在普通饲料饲养条件下,血浆总胆固醇也高出正常2~3倍,而IDL和LDL含量则可上升8倍以上,IDL和VLDL-C浓度更明显剧增。这种LDL-R缺乏的动物被用来作基因治疗的对象,将装载有人类LDL-R基因的腺病毒载体注射到这种小鼠循环系统内,肝组织很快出现LDL-R的表达和活性。VLDL和LDL的清除速度随之加快,血浆IDL和VLDL含量明显降低。LDL-R基因剔除的小鼠被公认为是人类家族性高胆固醇血症的良好模型。
二、LDL受体相关蛋白
LRP可能是乳糜微粒残粒的相应受体。若将LRP基因剔除后,纯合子型动物不能生存,而杂合子型动物表现正常,因此,LRP在乳糜微粒残粒代谢中的作用尚不能肯定。
上述各个因素表达的变化对血脂及脂蛋白的主要影响效果概略归纳如下,见表14-1。由于在多数情况下这些变化对动脉粥样硬化的影响未有详细观察和报道,因此动脉粥样硬化发病的相应变化没有归纳于表14-1内。
表14-1 抑扬基因表达引起血脂及脂蛋白特征性变化一览表
基因名称 | 基因表达 的变化 | 血脂及脂蛋白特征性变化 |
ApoAⅠ | ↑ | HDL-C↓ |
↓ | HDL-C↓ | |
ApoAⅠ | ↑ | 部分HDL颗粒变小,HDL-C不变 |
ApoAⅣ | ↑ | 无明显变化 |
ApoB | ↑ | 总胆固醇水平↑,LDL-C↑ |
↓ | 总胆固醇水平↓,ApoAⅠ↓ | |
HDL-C↓,VLDL-C,LDL-C↓ | ||
ApoCⅠ | ↑ | 甘油三酯水平↑,VLDL-C↑ |
ApoCⅡ | ↑ | 甘油三酯水平↑,VLDL-C↑ |
ApoCⅢ | ↑ | 甘油三酯水平↑,VLDL-C↑,VLDL颗粒变大 |
ApoE | ↑ | 总胆固醇水平↓,LDL-C↓,VLDL-C↓ |
↓ | 总胆固醇水平↑,VLDL-C↑,IDL-C↑ | |
Apo(a) | ↑ | 无明显异常 |
CETP | ↑ | HDL-C↓,HDL颗粒变小, LDL-C↑,VLDL-C↑ |
LPL | ↑ | 甘油三酯水平↓,HDL-C↑ |
HL | ↑ | 甘油三酯水平↓,HDL-C↓ HDL2→HDL3转变 |
LCAT | ↑ | HDL颗粒增大, HDL-CE↑,LDL-CE↑,VLDL-CE↑ |
LDL-R | ↑ | 总胆固醇水平↓,LDL-C↓,VLDL-C↓ |
↓ | 总胆固醇水平↑,LDL-C↑,VLDL-C↑,IDL-C↑ | |
CRP | ↑ | 无明显变化 |
(周明月)
参考文献
1.Breslow JL.Lipoprotein metabolism and atherosclerosis susceptibility in transgenic mice.Curr Opin Lipido,1994,5:175-184
2.Applebaum-Bowden D.Lipase and lecithin :cholesterol acyltransferase in the control of lipoprotein metabolism.Curr Opin Lipidw,1995,6:130-135
3.Plump A S,and Breslow J L.Apolipoprotein E and the apolipoprotein E-deficient mouse .Annu Rev Nutr,1995,15:495-518
4.Williamson R Lee D,Hagaman J,et al .Marked reduction of high density lipoprotein cholesterol in mice genetically modifid to lack apolipoprotein A-I.Proc Natl Acad Sci ,USA 1992,89:7134-7138
5.Li H,Reddick ,R L,Maeda N.Lack ApoAI is not associated with increased susceptibility to atherosclerosis in mice .Arterioscler Thromb 1993,13:1814-1821
6.Linton M F,Farese R V ,Chiesa G,et al. Transgenic mice expressing high plasma concentration of human apolipoprotein B100 and lipoprotein (a).J Clin Invest,1993,3029-3037
7.Homanics C E,Smith T J,Zhandg S H,et al .Targeted modification of the apolipoprotein B gene results in hypop-betalipoproteinemia and developmental abnormalities in mice Proc Natl Acad Sci USA,1993,90:2389-2392
8.Shimada M,Shimano H,Gotoda T,et al .Overexpression of human lipprotein lipase in transgenic mice.J Biol Chem,1993,268:17924-17929
9.Ishibashi S,Brown M S,Goldstein J L,et al.Hypercholesterolemia in low density lipoprotein receptor knockout mice in its reversal by adenovirus-mediated gene delievery.J Clin Invest .1993,92:883-893
10.Fan J.Wang J.Bensadoun A,et al.Overexpression of hepatic lipase in transgenic rabbits leads to a marded reduction of plasma high density lipoprotein and intermediate density lipoprotein.Proc Natl Acad Sci UAS,1994,91:8724-8728
, 百拇医药