Normal children and adults have sufficient bile acids to form micelles and thereby efficiently absorb dietary lipids. One group of individuals which has a lumenal bile acid concentration lower than that required to form micelles is the very small preterm infant. As a result of the lack of lumenal bile acids, lipid absorption and consequently growth is compromised in these rapidly growing infants. As the neonates mature, bile acid synthesis rates will eventually increase. The event(s) regulating the increase in bile acid synthesis rates in the neonate is(are) unknown. We hypothesize that the increase in bile acid synthesis rate in the neonate relates to an increase in the expression of mRNA for 7alpha- hydroxylase (CYP7A1), the major enzyme responsible for bile acid synthesis in humans, and from a change in the sterol balance across the liver. We also hypothesize that the induction of activity is regulable. The studies will be completed in the neonatal hamster due the similarities in sterol and bile acid metabolism between the human and hamster. To address these hypotheses, 3 specific aims are proposed. First, we will explore the mechanism of regulation of CYP7A1 protein levels; we have shown that protein levels and activities of Cyp7a1 increase as does the bile acid pool size in neonates. We initially will measure mRNA levels for Cyp7a1. If differences are detected, we will examine the mRNA levels and ligands of nuclear receptors known to affect CYP7A1 transcription. Second, we will identify the source(s) of cholesterol used for bile acid synthesis in the neonate. The percent conversion of newly synthesized cholesterol or lipoprotein-cholesterol to bile acids will be determined at different ages. The percent conversions will be correlated to Cyp7a1 activities and lipoprotein clearance rates. Third, we will test the hypothesis that the increase in CYP7A1 activity is not regulated ontogenically, but can be manipulated with exogenous factors. Based on studies reported previously and on our preliminary results, we will attempt to either delay or precociously express Cyp7a1 mRNA and protein by manipulating 1) the ligands for the nuclear receptors known to affect CYP7A1 transcription and 2) sterol balance. Additionally, these studies will examine any correlative relationships detected in previous aims so that we may be able to delineate the mechanisms responsible for changes in enzyme activity. Data obtained from the proposed studies may contribute towards new approaches to treat the very small premature infant and thereby have a beneficial impact upon their overall prognosis.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Grave, Gilman D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Cincinnati
Schools of Medicine
United States
Zip Code
Burke, Katie T; Horn, Paul S; Tso, Patrick et al. (2009) Hepatic bile acid metabolism in the neonatal hamster: expansion of the bile acid pool parallels increased Cyp7a1 expression levels. Am J Physiol Gastrointest Liver Physiol 297:G144-51
Woollett, Laura A (2008) Where does fetal and embryonic cholesterol originate and what does it do? Annu Rev Nutr 28:97-114
Jenkins, Katie T; Merkens, Louise S; Tubb, Matthew R et al. (2008) Enhanced placental cholesterol efflux by fetal HDL in Smith-Lemli-Opitz syndrome. Mol Genet Metab 94:240-7
Yao, Lihang; Horn, Paul S; Heubi, James E et al. (2007) The liver plays a key role in whole body sterol accretion of the neonatal Golden Syrian hamster. Biochim Biophys Acta 1771:550-7
Wang, Yanwen; Jones, Peter J H; Woollett, Laura A et al. (2006) Effects of chenodeoxycholic acid and deoxycholic acid on cholesterol absorption and metabolism in humans. Transl Res 148:37-45
Woollett, L A; Wang, Y; Buckley, D D et al. (2006) Micellar solubilisation of cholesterol is essential for absorption in humans. Gut 55:197-204
Yao, Lihang; Woollett, Laura A (2005) Adult sterol metabolism is not affected by a positive sterol balance in the neonatal Golden Syrian hamster. Am J Physiol Regul Integr Comp Physiol 288:R561-6