PROLACTIN AND BILE SECRETORY FUNCTION

描述(申请人提供)：哺乳期是一种生理状态，其特征是能量需求增加4-5倍，食物消耗增加2-3倍，以满足这一需求。在大鼠哺乳期，肝脏钠/牛磺胆酸盐协同转运体(NTCP)、胆盐输出泵(BSEP)和肠尖钠依赖性胆汁酸转运体(ASBT)的表达协同上调。哺乳期间胆酸池的大小也增加了3倍。我们推测，这些增加的功能是促进膳食脂肪的吸收，以满足哺乳母牛的能量需求并将其并入牛奶中。然而，胆汁酸池的增加发生在Cyp7a1表达减少和ntcp表达增加的时候。Cyp7a1是胆固醇合成胆汁酸的主要调节酶。我们将检验以下假设：1)在胆酸池最大扩张时，参与交替胆汁酸合成途径的酶的肝脏表达增加；2)扩张的胆酸池导致FXR激活，bsep和SHP的表达增加；3)当SHP表达增加导致Cyp7a1抑制时，催乳素介导的JAK2/Stat5信号转导通路的激活激活NTCP并覆盖SHP介导的抑制。为了验证这些假说，我们将在产后不同时间用对照雌鼠和哺乳大鼠来描述1)胆酸池的大小和组成以及脂肪和胆固醇的吸收；2)胆汁酸转运体和胆固醇合成胆汁酸的关键酶的表达和表达；3)调节胆汁酸合成和运输的信号通路。哺乳期女性在高能需求方面是独一无二的；对该模型的研究提供了一个机会，以增加对压力条件下胆固醇和胆汁酸稳态调节的理解。除了需要了解哺乳妇女可能发生的变化外，这个模型还可以识别以其他方式没有观察到的新的调节途径，这些途径可能被用于治疗目的。与高胆固醇相关的高疾病负担使这是一个非常重要和令人信服的机会。

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.