Ontogenic development-associated changes in the expression of genes involved in rat bile acid homeostasis

Susana Cuesta de Juan,Jose J.G. Marin,Rocio I.R. Macias,Valérie Wauthier,Maria J. Monte,Pedro Buc Calderon

doi:10.1194/jlr.m700034-jlr200

Abstract

Ontogenic changes in the rat bile acid (BA) pool, measured enzymatically and by GC-MS, and expression of enzymes (5alpha-reductase, 5beta-reductase, and cytochrome P450 enzymes Cyp7a1, Cyp8b1, Cyp27 and Cyp3a11), transporters [bile salt export pump, sodium taurocholate-cotransporting polypeptide, apical sodium-dependent bile acid transporter, and organic solute transporter alpha/beta (Ostalpha/Ostbeta)], and nuclear receptors [fetoprotein transcription factor (Ftf), farnesoid X receptor (Fxr), small heterodimer partner (Shp), and hepatic nuclear factor 4alpha (HNF-4alpha)], determined by quantitative PCR, were investigated. The absolute size of the BA pool increased progressively up to adulthood, whereas the complexity of its composition was high in fetuses, decreased after birth, increased again progressively up to adulthood, and decreased in aged animals. Allo-cholic acid only appeared early in development, in spite of low 5alpha-reductase expression. The relative size of the BA pool, corrected by liver weight, was maintained from 1 week after birth, except at weaning, when a transient peak accompanied by Shp downregulation and Cyp7a1 upregulation was observed. An imposed weaning delay of 1 week had no effect on the time course of the BA pool size but decreased the proportion of chenodeoxycholic and alpha-muricholic acids, whereas the proportion of cholic acid was increased, probably as a result of Cyp8b1 upregulation. In conclusion, changes in the expression of genes involved in BA homeostasis may play a role in physiological adaptations to digestive functions during the rat life span.

Highlights

Ontogenic changes in the rat bile acid (BA) pool, measured enzymatically and by GC-MS, and expression of enzymes (5a-reductase, 5b-reductase, and cytochrome P450 enzymes Cyp7a1, Cyp8b1, Cyp27 and Cyp3a11), transporters [bile salt export pump, sodium taurocholatecotransporting polypeptide, apical sodium-dependent bile acid transporter, and organic solute transporter a/b (Osta/ Ostb)], and nuclear receptors [fetoprotein transcription factor (Ftf), farnesoid X receptor (Fxr), small heterodimer partner (Shp), and hepatic nuclear factor 4a (HNF-4a)], determined by quantitative PCR, were investigated
The best known is their role in fat digestion and absorption. This is mainly performed by their detergent activity, which is closely related to their chemical structure, which varies among many different molecular species present in the BA pool
In light of the foregoing, the aim of this study was to investigate the relationship between changes in the BA pool size and composition during fetal life, postnatal development, youth, maturity, and senescence and modifications in the expression profiles of the enzymes, transporters, and nuclear receptors involved in the control of BA pool size and composition

Summary

Introduction

Ontogenic changes in the rat bile acid (BA) pool, measured enzymatically and by GC-MS, and expression of enzymes (5a-reductase, 5b-reductase, and cytochrome P450 enzymes Cyp7a1, Cyp8b1, Cyp and Cyp3a11), transporters [bile salt export pump, sodium taurocholatecotransporting polypeptide, apical sodium-dependent bile acid transporter, and organic solute transporter a/b (Osta/ Ostb)], and nuclear receptors [fetoprotein transcription factor (Ftf), farnesoid X receptor (Fxr), small heterodimer partner (Shp), and hepatic nuclear factor 4a (HNF-4a)], determined by quantitative PCR, were investigated. Changes in the expression of genes involved in BA homeostasis may play a role in physiological adaptations to digestive functions during the rat life span.—Cuesta de Juan, S., M. Proliferative processes occurring in the liver after partial hepatectomy or during hepatocarcinogenesis are accompanied by important changes in the composition of the BA pool [1,2,3]. Such changes are closely related to changes in the expression profiles of enzymes involved in BA metabolism [4, 5].

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