Induction of Bile Acid Synthesis in the Neonatal Liver

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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.