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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 taurocholate- cotransporting 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 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 pro- gressively up to adulthood, and decreased in aged ani- mals. Allo-cholic acid only appeared early in development, in spite of low 5a-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 up- regulation 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 a-muricholic acids, whereas the proportion of cholic acid was increased, probably as a result of Cyp8b1 up- regulation. 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.—Cuesta de Juan, S., M. J. Monte, R. I. R. Macias, V. Wauthier, P. B. Calderon, and J. J. G. Marin. Ontogenic development-associated changes in the expres- sion of genes involved in rat bile acid homeostasis. J. Lipid Res. 2007. 48: 1362-1370. Bile acids (BAs) are amphipathic steroids synthesized in the liver from cholesterol and are involved in important physiological functions. Among these, 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. The composition of the BA pool is not the same in all species, and in each species it probably changes during its life span. All BA variants share the presence of the steroid ring and the side chain, but they differ mainly in the degree of hydroxylation and the position of their hydroxyl groups. The total amount of BAs in the body and the composition of this pool are determined by the expres- sion and activity of enzymes involved in their synthesis and biotransformation in concerted action with plasma membrane transporters, which account for their retention in the enterohepatic circulation. BA metabolism by in- testinal bacteria and elimination by the kidney may also contribute to the final BA pool size and composition. Owing to the key role of the liver in BA homeostasis, it is easy to understand why phenotypic changes in this organ affect the BA pool. Thus, proliferative processes occurring in the liver after partial hepatectomy or during hepato- carcinogenesis are accompanied by important changes in the composition of the BA pool (1-3). Such changes are closely related to changes in the expression profiles of enzymes involved in BA metabolism (4, 5). Although on- togenic development also involves proliferation and differ- entiation, in addition to adaptive changes to modifications in the diet, little is known about the expression of enzymes

The physiological characterstics of allo-cholic acid (ACA), a typically fetal bile acid that reappears during liver regeneration and carcinogenesis were investigated. [(14)C] Tauro-ACA (TACA) uptake by Chinese hamster ovary cells expressing rat organic anion transporter polypeptide (Oatp)1 or sodium-taurocholate cotransporter polypeptide (Ntcp) was lower than that of [(14)C]taurocholic acid (TCA). Although TACA inhibited ATP-dependent TCA transport across plasma membrane vesicles from Sf9 cells expressing rat or mouse bile salt export pump (Bsep), no ATP-dependent TACA transport was found. In rats, TACA was secreted into bile with no major biotransformation and it had lower clearance and longer half-life than TCA. In mice, TACA bile output was lower (-50%) than that of TCA, whereas TACA induced 9-fold higher bile flow than TCA. Even though the intracellular levels were lower for TACA, translocation into the hepatocyte nucleus was higher for TACA than for TCA; however, rate of DNA synthesis, expression levels of alpha-fetoprotein, albumin, Ntcp, and Bsep, cell viability, and apoptosis in rat hepatocytes were similarly affected by both isomers. In conclusion, TACA partly shares hepatocellular uptake system(s) for TCA. Furthermore, in contrast to other "flat" bile acids, TACA is efficiently secreted into bile via transport system(s) other than Bsep and is highly choleretic, hence its appearance during certain situations may prevent accumulation of cholestatic precursors.