Mahley R W, Huang Y, Rall S C
Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94141-9100, USA.
J Lipid Res. 1999 Nov;40(11):1933-49.
Type III hyperlipoproteinemia (HLP) is a genetic disorder characterized by accumulation of remnant lipoproteins in the plasma and development of premature atherosclerosis. Although receptor binding-defective forms of apolipoprotein (apo) E are the common denominator in this disorder, a number of apparent paradoxes concerning its pathogenesis still exist. However, studies in transgenic animals are resolving the mechanisms underlying this disorder. PARADOX I: Defective apoE (commonly apoE2) is essential but not sufficient to cause overt type III HLP. In fact, most apoE2 homozygotes are hypolipidemic. Studies in apoE2 transgenic models have demonstrated the impact of other genes or hormones in converting the hypolipidemia to hyperlipidemia. PARADOX II: Among apoE2 homozygotes, men are more susceptible than women to type III HLP. Transgenic studies have shown that estrogen affects both LDL receptor expression and lipolytic processing, explaining the resistance of women to this disorder until after menopause. PARADOX III: ApoE deficiency is associated with hypercholesterolemia, whereas the type III HLP phenotype is characterized by both hypercholesterolemia and hypertriglyceridemia. The hypercholesterolemia is caused by impaired receptor-mediated clearance, whereas the hypertriglyceridemia is caused primarily by impaired lipolytic processing of remnants and increased VLDL production associated with increased levels of apoE. PARADOX IV: ApoE2 is associated with recessive inheritance of this disorder, whereas other defective apoE variants are associated with dominant inheritance. Determinants of the mode of inheritance are the differential binding of apoE variants to the LDL receptor versus the HSPG/LRP complex and the preference of certain apoE variants for specific lipoproteins. Thus, the pathogenesis of this sometimes mysterious disorder has been clarified.
III型高脂蛋白血症（HLP）是一种遗传性疾病，其特征是血浆中残留脂蛋白的积累和早发性动脉粥样硬化的发展。尽管载脂蛋白（apo）E的受体结合缺陷形式是该疾病的共同特征，但关于其发病机制仍存在一些明显的矛盾之处。然而，对转基因动物的研究正在揭示该疾病的潜在机制。矛盾之一：缺陷型apoE（通常为apoE2）是导致明显的III型HLP所必需的，但并不充分。事实上，大多数apoE2纯合子血脂水平较低。对apoE2转基因模型的研究表明，其他基因或激素在将低脂血症转变为高脂血症方面具有影响。矛盾之二：在apoE2纯合子中，男性比女性更容易患III型HLP。转基因研究表明，雌激素会影响低密度脂蛋白受体的表达和脂解过程，这解释了女性在绝经前对该疾病具有抵抗力的原因。矛盾之三：apoE缺乏与高胆固醇血症有关，而III型HLP的表型特征是高胆固醇血症和高甘油三酯血症。高胆固醇血症是由受体介导的清除功能受损引起的，而高甘油三酯血症主要是由残留脂蛋白的脂解过程受损以及与apoE水平升高相关的极低密度脂蛋白（VLDL）生成增加所导致的。矛盾之四：apoE2与该疾病的隐性遗传有关，而其他缺陷型apoE变体与显性遗传有关。遗传方式的决定因素是apoE变体与低密度脂蛋白受体和硫酸乙酰肝素蛋白聚糖/低密度脂蛋白受体相关蛋白（HSPG/LRP）复合物的差异结合，以及某些apoE变体对特定脂蛋白的偏好。因此，这种有时神秘的疾病的发病机制已经得到阐明。
