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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK046923-11
Application #
7268952
Study Section
Special Emphasis Panel (ZRG1-DIG-B (04))
Program Officer
Serrano, Jose
Project Start
1994-05-01
Project End
2010-06-30
Budget Start
2007-07-01
Budget End
2010-06-30
Support Year
11
Fiscal Year
2007
Total Cost
$222,254
Indirect Cost
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Athippozhy, Antony; Huang, Liping; Wooton-Kee, Clavia Ruth et al. (2011) Differential gene expression in liver and small intestine from lactating rats compared to age-matched virgin controls detects increased mRNA of cholesterol biosynthetic genes. BMC Genomics 12:95
Wooton-Kee, Clavia Ruth; Coy, Donna J; Athippozhy, Antony T et al. (2010) Mechanisms for increased expression of cholesterol 7alpha-hydroxylase (Cyp7a1) in lactating rats. Hepatology 51:277-85
Wooton-Kee, Clavia Ruth; Cohen, David E; Vore, Mary (2008) Increased cholesterol 7alpha-hydroxylase expression and size of the bile acid pool in the lactating rat. Am J Physiol Gastrointest Liver Physiol 294:G1009-16
Wood, M; Ananthanarayanan, M; Jones, B et al. (2005) Hormonal regulation of hepatic organic anion transporting polypeptides. Mol Pharmacol 68:218-25
Cao, Jingsong; Wood, Marcie; Liu, Yong et al. (2004) Estradiol represses prolactin-induced expression of Na+/taurocholate cotransporting polypeptide in liver cells through estrogen receptor-alpha and signal transducers and activators of transcription 5a. Endocrinology 145:1739-49
Mottino, Aldo D; Hoffman, Tim; Dawson, Paul A et al. (2002) Increased expression of ileal apical sodium-dependent bile acid transporter in postpartum rats. Am J Physiol Gastrointest Liver Physiol 282:G41-50
Cao, J; Gowri, P M; Ganguly, T C et al. (2001) PRL, placental lactogen, and GH induce NA(+)/taurocholate-cotransporting polypeptide gene expression by activating signal transducer and activator of transcription-5 in liver cells. Endocrinology 142:4212-22
Cao, J; Huang, L; Liu, Y et al. (2001) Differential regulation of hepatic bile salt and organic anion transporters in pregnant and postpartum rats and the role of prolactin. Hepatology 33:140-7
Mottino, A D; Hoffman, T; Jennes, L et al. (2001) Expression of multidrug resistance-associated protein 2 in small intestine from pregnant and postpartum rats. Am J Physiol Gastrointest Liver Physiol 280:G1261-73
Ganguly, T C; O'Brien, M L; Karpen, S J et al. (1997) Regulation of the rat liver sodium-dependent bile acid cotransporter gene by prolactin. Mediation of transcriptional activation by Stat5. J Clin Invest 99:2906-14

Showing the most recent 10 out of 13 publications