REGULATION OF APOLIPOPROTEIN METABOLISM--A TURTLE MODEL

卵黄蛋白原及其他卵黄前体的肝脏合成 非哺乳动物物种中的载脂蛋白涉及大规模动员， 脂质的运输，并提供了一个很好的模型系统， 激素在脂蛋白代谢中的作用。 虽然哺乳动物没有 合成卵黄蛋白原本身，其他蛋白质，形成部分的非 哺乳动物卵黄发生复合物，如载脂蛋白B，可能还有载脂蛋白A1， 是合成的，可能受到类似的内分泌控制。 最近 人载脂蛋白B和人载脂蛋白B之间序列相似性的证据 脊椎动物卵黄蛋白原表明，这些蛋白质可能是产品 一个基因超家族。 我们认为哺乳动物肝脂蛋白 合成及其激素控制是由它们的 爬行动物的祖先，并可能在此背景下更好地理解。 这是 特别是对于冠心病， 明确的性别偏见，但没有协调的研究计划存在， 考虑了系统发育史。 特别值得注意的是， 雌激素对肝脏的影响，孕激素和 另一方面是睾丸激素，它们与 在爬行动物卵黄蛋白原的合成，提供了一个模型， 相同激素对合成和代谢的调节作用 哺乳动物的载脂蛋白。 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。分离和 表征主要循环载脂蛋白并产生抗体 用于定量分析和用于建立与哺乳动物的同源性 载脂蛋白 2.记录这些药物的血浆水平变化 男性与女性的蛋白质和（仅女性）作为 生殖条件和荷尔蒙状态在年度周期。 3. 阐明调节载脂蛋白复合物的激素机制， 体内，特别注意孕酮和雄激素与 雌二醇 4.在体外评价雌激素和 其他激素对肝载脂蛋白合成的影响。 5.使用抗体， 异源卵黄蛋白原和/或载脂蛋白抗体和cDNA探针， 以鉴定同源的爬行动物克隆，并获得爬行动物的cDNA， 实验中的交叉杂交和未来的机制研究。 6. 利用爬行动物抗体和cDNA探针进行常规蛋白质印迹 和杂交实验，鉴定相关的哺乳动物肝蛋白 和表达的基因。

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.