PROLACTIN AND BILE SECRETORY FUNCTION

描述（由申请人提供）：哺乳是一种生理状态，其特征在于能量需求增加4-5倍，食物消耗增加2-3倍以满足该需求。我们已经证明了哺乳期大鼠肝脏钠/牛磺胆酸协同转运蛋白（ntcp）和胆盐输出泵（bsep）以及小肠顶端钠依赖性胆汁酸转运蛋白（asbt）表达的协同上调。在哺乳期间，胆汁酸池的大小也增加了3倍。我们推测，这些增加的功能，以提高膳食脂质的吸收，以满足能量需求的哺乳母鼠和纳入牛奶。然而，增加的胆汁酸池发生在Cyp 7a 1（从胆固醇合成胆汁酸的主要调节酶）的表达降低和ntcp表达增加时。我们将检验以下假设：1）在胆汁酸库最大扩增时，参与胆汁酸合成途径的酶的肝脏表达增加; 2）胆汁酸库扩增导致FXR活化和bsep和SHP的肝脏表达增加;和3）虽然SHP表达增加导致Cyp 7a 1的抑制，但催乳素介导的Jak 2/Stat 5信号转导途径的激活激活ntcp并克服SHP介导的抑制。旨在检验这些假设的特定目的将使用对照雌性和哺乳期大鼠在产后不同时间表征1）胆汁酸池的大小和组成以及脂质和胆固醇吸收; 2）胆汁酸转运蛋白和关键酶在胆固醇合成胆汁酸中的表达和表达; 3）调节胆汁酸合成和转运的信号传导途径。哺乳期女性在高能量需求方面是独特的;在该模型中的研究为增加对压力条件下胆固醇和胆汁酸稳态调节的理解提供了机会。除了需要了解哺乳期妇女可能发生的变化外，该模型还可以识别未观察到的新的调节途径，并且可以用于治疗目的。与胆固醇升高相关的高疾病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.