PROLACTIN AND BILE SECRETORY FUNCTION

描述（由申请人提供）：哺乳是一种生理状态，其特征是能量需求增加4-5倍，食物消耗增加2-3倍以满足这种需求。我们已经证明，在哺乳期间，大鼠肝脏钠/牛磺胆酸共转运体（ntcp）和胆盐输出泵（bsep）以及肠顶端钠依赖性胆汁酸转运体（asbt）的表达协同上调。在哺乳期间，胆汁酸池的大小也增加了3倍。我们假设，这些增加的功能，以提高饲料脂的吸收，以满足能量需求的哺乳动物和纳入牛奶。然而，当胆固醇合成胆汁酸的主要调控酶Cyp7a1表达降低，ntcp表达增加时，胆汁酸池就会增加。我们将检验以下假设：1)在胆汁酸池最大扩张时，肝脏中参与胆汁酸替代合成途径的酶的表达增加；2)胆汁酸池的扩大导致FXR的激活，bsep和SHP在肝脏的表达增加；3)当SHP的表达增加导致Cyp7a1的抑制时，催乳素介导的Jak2/Stat5信号转导通路的激活激活了ntcp并覆盖了SHP介导的抑制。为了验证这些假设，我们将在产后不同时间使用雌性和哺乳期大鼠作为对照，以表征1)胆汁酸池的大小和组成以及脂质和胆固醇的吸收；2)胆汁酸转运蛋白及胆固醇合成胆汁酸关键酶的表达及表达；3)调节胆汁酸合成和运输的信号通路。哺乳期的雌性在高能量需求方面是独一无二的；该模型的研究为进一步了解应激条件下胆固醇和胆汁酸稳态的调节提供了机会。除了需要了解哺乳妇女可能发生的变化外，该模型还可以识别其他方式未观察到的新调节途径，并可用于治疗目的。与高胆固醇相关的疾病的高负担使这成为一个非常重要和引人注目的机会。

DESCRIPTION (provided by applicant): Lactation is a physiological state characterized by a 4-5-fold increase in energy demand and a 2-3-fold increase in food consumption to meet this demand. We have demonstrated a coordinated up-regulation of expression of the hepatic sodium/taurocholate cotransporter (ntcp) and bile salt export pump (bsep) and of the intestinal apical sodium-dependent bile acid transporter (asbt) during lactation in the rat. There is also a 3-fold increase in the size of the bile acid pool during lactation. We postulate that these increases function to enhance absorption of dietary lipids to meet the energy demands of the lactating dam and for incorporation into milk. However, the increased bile acid pool occurs at times when expression of Cyp7a1, the major regulated enzyme in the synthesis of bile acids from cholesterol, is decreased and ntcp expression is increased. We will test the following hypotheses: 1) hepatic expression of enzymes involved in the alternate bile acid synthesis pathway is increased at the time of maximal expansion of the bile acid pool; 2) the expanded bile acid pool leads to activation of FXR and increased hepatic expression of bsep and SHP; and 3) while increased expression of SHP leads to repression of Cyp7a1, prolactin-mediated activation of the Jak2/Stat5 signal transduction pathway activates ntcp and overrides SHP-mediated repression. Specific Aims designed to test these hypotheses will use control female and lactating rats at various times postpartum to characterize 1) the size and composition of the bile acid pool and in lipid and cholesterol absorption; 2) expression of bile acid transporters and key enzymes in the synthesis of bile acids from cholesterol and expression; 3) signaling pathways that regulate bile acid synthesis and transport. The lactating female is unique in terms of the high-energy demands; investigation in this model offers an opportunity for increased understanding of the regulation of cholesterol and bile acid homeostasis under stressful conditions. In addition to the need to understand the changes that potentially occur in nursing women, this model may enable identification of new regulatory pathways not otherwise observed, and which may be exploited for therapeutic purposes. The high burden of disease related to elevated cholesterol makes this a highly significant and compelling opportunity.