Document Detail


Repression of hepatobiliary transporters and differential regulation of classic and alternative bile acid pathways in mice during pregnancy.
MedLine Citation:
PMID:  22903823     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
During pregnancy, proper hepatobiliary transport and bile acid synthesis protect the liver from cholestatic injury and regulate the maternal and fetal exposure to bile acids, drugs, and environmental chemicals. The objective of this study was to determine the temporal messenger RNA (mRNA) and protein profiles of uptake and efflux transporters as well as bile acid synthetic and conjugating enzymes in livers from virgin and pregnant mice on gestational days (GD) 7, 11, 14, and 17 and postnatal days (PND) 1, 15, and 30. Compared with virgins, the mRNAs of most transporters were reduced approximately 50% in pregnant dams between GD11 and 17. Western blot and immunofluorescence staining confirmed the downregulation of Mrp3, 6, Bsep, and Ntcp proteins. One day after parturition, the mRNAs of many uptake and efflux hepatobiliary transporters remained low in pregnant mice. By PND30, the mRNAs of all transporters returned to virgin levels. mRNAs of the bile acid synthetic enzymes in the classic pathway, Cyp7a1 and 8b1, increased in pregnant mice, whereas mRNA and protein expression of enzymes in the alternative pathway of bile acid synthesis (Cyp27a1 and 39a1) and conjugating enzymes (Bal and Baat) decreased. Profiles of transporter and bile acid metabolism genes likely result from coordinated downregulation of transcription factor mRNA (CAR, LXR, PXR, PPARα, FXR) in pregnant mice on GD14 and 17. In conclusion, pregnancy caused a global downregulation of most hepatic transporters, which began as early as GD7 for some genes and was maximal by GD14 and 17, and was inversely related to increasing concentrations of circulating 17β-estradiol and progesterone as pregnancy progressed.
Authors:
Lauren M Aleksunes; Ronnie L Yeager; Xia Wen; Julia Yue Cui; Curtis D Klaassen
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural     Date:  2012-08-17
Journal Detail:
Title:  Toxicological sciences : an official journal of the Society of Toxicology     Volume:  130     ISSN:  1096-0929     ISO Abbreviation:  Toxicol. Sci.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-16     Completed Date:  2013-05-29     Revised Date:  2013-12-05    
Medline Journal Info:
Nlm Unique ID:  9805461     Medline TA:  Toxicol Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  257-68     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Bile Acids and Salts / blood,  metabolism*
Biological Transport
Blotting, Western
Body Weight
Down-Regulation
Estradiol / blood
Female
Fluorescent Antibody Technique
Gene Expression Regulation, Enzymologic
Gestational Age
Lactation / genetics,  metabolism
Liver / metabolism*
Membrane Transport Proteins / genetics,  metabolism*
Mice
Mice, Inbred C57BL
Organ Size
Parturition / genetics,  metabolism
Pregnancy
Progesterone / blood
RNA, Messenger / metabolism
Real-Time Polymerase Chain Reaction
Transcription Factors / genetics,  metabolism
Transcription, Genetic
Grant Support
ID/Acronym/Agency:
DK080774/DK/NIDDK NIH HHS; DK081461/DK/NIDDK NIH HHS; ES007079/ES/NIEHS NIH HHS; ES009649/ES/NIEHS NIH HHS; ES019487/ES/NIEHS NIH HHS; ES020522/ES/NIEHS NIH HHS; P30ES005022/ES/NIEHS NIH HHS; R00 DK080774/DK/NIDDK NIH HHS; R01 ES020522/ES/NIEHS NIH HHS; RR021940/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Bile Acids and Salts; 0/Membrane Transport Proteins; 0/RNA, Messenger; 0/Transcription Factors; 4G7DS2Q64Y/Progesterone; 4TI98Z838E/Estradiol
Comments/Corrections

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