REGULATION OF APOLIPOPROTEIN METABOLISM--A TURTLE MODEL

肝脏卵黄蛋白原和其他卵黄前体的合成 非哺乳动物物种中的载脂蛋白涉及大量的动员和 为研究脂类的转运提供了良好的模型系统 激素在脂蛋白代谢中的作用。尽管哺乳动物不会 合成卵黄蛋白原本身，其他蛋白质组成非 哺乳动物的卵黄生成复合体，如载脂蛋白B，可能还有载脂蛋白A1， 都是人工合成的，可能受到类似的内分泌控制。近期 人类载脂蛋白B和人类载脂蛋白B序列相似性的证据 脊椎动物卵黄蛋白原提示这些蛋白可能是 属于一个基因超家族。我们认为哺乳动物的肝脂蛋白 合成及其激素控制在系统发育上源于它们的 爬行动物的祖先，在这一背景下可能更好地理解。这是 尤其与冠心病有关，在这种疾病中， 明确的性别偏见，目前还没有协调的研究计划， 考虑到了系统发育史。特别值得关注的是， 一方面，雌激素对肝脏的影响，以及孕酮和 在另一种情况下，睾丸素与 爬行动物卵黄蛋白原的合成为研究卵黄蛋白原提供了一个模型 同种激素对合成代谢的调节作用 在哺乳动物中的载脂蛋白。这些脂质转运的变化 蛋白质与性别和易感性密切相关。 人类的心血管疾病。我们建议1.隔离和 鉴定循环中的主要载脂蛋白并开发抗体 用于定量分析和建立与哺乳动物的同源性 载脂蛋白。2.记录这些人的血浆水平的变化 男性和女性中的蛋白质以及(仅在女性中)作为 在年度周期中的生殖状况和荷尔蒙状况。3. 阐明调节载脂蛋白复合体的激素机制 体内，特别注意黄体酮和雄激素对 雌二醇。4.在体外评估雌激素和雌激素的直接相互作用 其他激素对肝脏载脂蛋白合成的影响。5.使用抗体和 异源卵黄蛋白原和/或载脂蛋白抗体和cDNA探针， 鉴定同源爬行动物克隆，并获得爬行动物基因 实验中的交叉杂交，以及未来的机理研究。6. 爬行动物抗体和cDNA探针在常规蛋白质印迹中的应用 和杂交实验，鉴定相关的哺乳动物肝脏蛋白 并表达了基因。

The hepatic synthesis of vitellogenin and other yolk precursor apolipoproteins in non-mammalian species involves massive mobilization and transport of lipids and provides an excellent model system for the study of the role of hormones in lipoprotein metabolism. Although mammals do not synthesize vitellogenin per se, other proteins which form part of the non- mammalian vitellogenic complex, such as apo-protein B, and possibly apo A1, are synthesized and may be subject to similar endocrine controls. Recent evidence of sequence similarities between human apo-protein B and vertebrate vitellogenins suggests that these proteins may be the products of a gene superfamily. We suggest that mammalian hepatic lipoprotein synthesis and its hormonal controls are phylogenetically derived from their reptilian ancestors and may be better understood in this context. This is of particular relevance for coronary heart disease in which there is a clear sex bias yet for which no co-ordinated research program exists which takes into account the phylogenetic history. Of particular interest, the hepatic effects of estrogen on the one hand, and progesterone and testosterone on the other, which are in opposition with regard to vitellogenin synthesis in reptiles, provide a model for investigation of the regulatory effects of the same hormones on the synthesis and metabolism of apolipoproteins in mammals. Changes in these lipid transporting proteins are closely associated with sex and susceptibility to cardiovascular disease in the human. We propose to 1. Isolate and characterize the major circulating apolipoproteins and develop antibodies for quantitative analyses and for establishing homologies with mammalian apolipoproteins. 2. Document variations in the plasma levels of these proteins in males vs females and (in females only) as a correlate of reproductive condition and hormonal status during the annual cycle. 3. Elucidate hormonal mechanisms which regulate the apolipoprotein complex in vivo, with special attention to the roles of progesterone and androgen vs estradiol. 4. Evaluate, in vitro, the direct interactions of estrogens and other hormones on hepatic apolipoprotein synthesis. 5. Use antibodies and heterologous vitellogenin and/or apolipoprotein antibody and cDNA probes, to identify homologous reptilian clones, and obtain reptilian cDNAs for crosshybridization in experiments, and future mechanistic studies. 6. Using reptilian antibody and cDNA probes in conventional protein blotting and hybridization experiments, identify related mammalian hepatic proteins and expressed genes.