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.
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