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1 Laboratory of Developmental and Molecular Hepatology, Department of Pediatrics, Mount Sinai School of Medical, New York, NY, USA
* To whom correspondence should be addressed. E-mail: meena.ananth{at}mssm.edu.
Nuclear receptors (NRs) play pivotal roles in the regulation of genes contributing
to hepatobiliary cholesterol and bile acid homeostasis. We have previously shown that
transporters involved in bile formation are developmentally regulated and are poorly
developed during the fetal stage but their expression reached gradual maturity during the
postnatal period. In order to define the molecular mechanisms underlying this regulation
and the role Class II NRs and associated members (LRH-1 and SHP) play, we have
analyzed the ontogeny of NR expression during liver development. Real time PCR
analysis of hepatic NR expression from fetal day 17 through adult revealed that steady
state mRNA levels for all NRs were very low during the embryonic period. However,
mRNA levels peaked close to that of adult rats (>6 weeks-old rats) by 4 weeks of age for
FXR, PXR, LXR
, PPAR, RAR, LRH-1, and SHP while RXR mRNA lagged
behind. FXR, PXR, LXR, RAR, and PPAR functional activity in liver nuclear
extracts assayed by gel shift (EMSA) analysis demonstrated that the activity attained
adult levels by four weeks of age exhibiting a strict correlation with mRNA levels.
Surprisingly, PPAR activity was delayed as seen by EMSA assay. Protein levels for
NRs also corresponded to the mRNA and functional activity except for RXR. RXR
protein levels were higher than message levels suggesting increased protein stability. We
conclude that expression of NRs during rat liver development is primarily regulated by
transcriptional mechanisms, which in turn control the regulation of bile acid and
cholesterol metabolic pathways.
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