Tang J J, Srivastava R A, Krul E S, Baumann D, Pfleger B A, Kitchens R T, Schonfeld G
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110.
J Lipid Res. 1991 Oct;32(10):1571-85.
We tested the hypothesis that testosterone and estrogen modulate apoA-I gene expression and metabolism by different mechanisms that may be influenced by genetic factors. Male and female C3H/HeJ (atherosclerosis-resistant) and C57BL/6J (atherosclerosis-susceptible) mice (n = 5/group) were castrated (Placebo). Castrates were given 17 beta-estradiol (E2) at 0.16 microgram/g (E2L) or 5 micrograms/g (E2H) body weight per day, or testosterone (Testo) 1 microgram/g per day, 14 days after surgery, for 14 days. Plasma total cholesterol concentrations (TC) were higher in male Placebo mice than in females. Testosterone altered TC and high density lipoprotein (HDL) cholesterol by gender and strain; however (HDL-C)/TC ratios and apoA-I concentrations were unaltered. Testosterone did reduce HDL particle diameters in both genders of C3H mice only. Low density lipoprotein-cholesterol (LDL-C)/TC ratios remained constant and apoB increased in males only. E2L and E2H decreased TC, HDL-C/TC ratios, and apoA-I. Decrements varied by strain. HDL diameters decreased in both genders in C3H mice only; however, HDL size distributions were altered in both strains. LDL-C/TC ratios increased in all groups. E2L mice showed variable responses of apoB, but apoB rose uniformly in all E2H groups. Testosterone increased and E2H decreased hepatic apoA-I synthesis. ApoA-I mRNA concentrations remained stable in both Testo and E2 groups. ApoA-I gene transcription varied by strain and gender, but all changes were less than twofold. Testosterone did not affect hepatic apoB or LDL receptor mRNA, however, E2H increased both mRNAs in males but not in females. On Western blotting of liver membranes, E2H had little effect on mouse LDL receptor protein mass; by contrast, E2H increased LDL receptor approximately threefold in rats. In summary, responsiveness of mouse lipids to testosterone and E2 vary by strain and gender. Testosterone and E2 differ in their regulation of apoA-I production mainly at the level of translation. Hormones operate at several levels of gene regulation, suggesting that complex mechanisms are involved. Mice differ from rats and rabbits in their LDL receptor responsiveness to estradiol treatment.
睾酮和雌激素通过可能受遗传因素影响的不同机制调节载脂蛋白A-I（apoA-I）的基因表达和代谢。对雄性和雌性C3H/HeJ（抗动脉粥样硬化）和C57BL/6J（易患动脉粥样硬化）小鼠（每组n = 5只）进行去势（安慰剂组）。术后14天，给去势小鼠每天按体重0.16微克/克（E2L）或5微克/克（E2H）给予17β-雌二醇（E2），或每天按体重1微克/克给予睾酮（Testo），持续14天。雄性安慰剂组小鼠的血浆总胆固醇浓度（TC）高于雌性。睾酮根据性别和品系改变TC和高密度脂蛋白（HDL）胆固醇；然而，（HDL-C）/TC比值和apoA-I浓度未改变。仅在C3H小鼠的两性中，睾酮确实降低了HDL颗粒直径。低密度脂蛋白胆固醇（LDL-C）/TC比值保持恒定，且仅在雄性中载脂蛋白B（apoB）增加。E2L和E2H降低了TC、HDL-C/TC比值和apoA-I。降低程度因品系而异。仅在C3H小鼠的两性中HDL直径减小；然而，在两个品系中HDL大小分布均发生改变。所有组的LDL-C/TC比值均升高。E2L小鼠的apoB反应不一，但在所有E2H组中apoB均一致升高。睾酮增加而E2H降低肝脏apoA-I的合成。在Testo组和E2组中，apoA-I mRNA浓度均保持稳定。apoA-I基因转录因品系和性别而异，但所有变化均小于两倍。睾酮不影响肝脏apoB或低密度脂蛋白受体（LDL受体）mRNA，然而，E2H增加了雄性小鼠的这两种mRNA，但雌性小鼠未增加。在肝细胞膜的蛋白质免疫印迹分析中，E2H对小鼠LDL受体蛋白量影响不大；相比之下，E2H使大鼠的LDL受体增加了约三倍。总之，小鼠血脂对睾酮和E2的反应因品系和性别而异。睾酮和E2在调节apoA-I产生方面主要在翻译水平存在差异。激素在基因调控的多个水平上起作用，这表明涉及复杂的机制。小鼠在LDL受体对雌二醇治疗的反应性方面与大鼠和兔子不同。
