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.
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