PMID- 12069850
OWN - NLM
STAT- MEDLINE
DCOM- 20020806
LR  - 20220331
IS  - 0006-3002 (Print)
IS  - 0006-3002 (Linking)
VI  - 1583
IP  - 1
DP  - 2002 Jun 13
TI  - On the mechanism of bile acid inhibition of rat sterol 12alpha-hydroxylase gene 
      (CYP8B1) transcription: roles of alpha-fetoprotein transcription factor and 
      hepatocyte nuclear factor 4alpha.
PG  - 63-73
AB  - The sterol 12alpha-hydroxylase (CYP8B1) is a key enzyme of the bile acid 
      biosynthetic pathway. It regulates the composition of bile acids in bile, i.e. 
      ratio between cholic acid (CA) and chenodeoxycholic acid (CDCA). In similarity 
      with cholesterol 7alpha-hydroxylase (CYP7A1), this enzyme is subjected to a 
      negative feedback regulation by bile acids. It has been recently reported that 
      bile acid-activated farnesoid X receptor (FXR) induces the small heterodimer 
      partner (SHP) that interacts with alpha-fetoprotein transcription factor (FTF) 
      and down-regulates CYP7A1 transcription. We studied whether the same mechanism 
      also regulated rat CYP8B1 gene transcription. Feeding rats with CDCA caused a 
      40-50% decrease of CYP8B1 and hepatocyte nuclear factor 4alpha (HNF4alpha) mRNA 
      expression levels. This was associated with an increase in FTF mRNA expression, 
      but SHP mRNA expression was not altered. Electrophoretic mobility shift assay 
      (EMSA) and transient transfection assay of promoter/reporter genes coupled to 
      mutagenesis analysis identified a putative bile acid response element (BARE) that 
      has an HNF4alpha binding site embedded in two overlapping FTF binding sites. 
      Mutation of the HNF4alpha binding site markedly reduced basal promoter activity 
      and its repression by bile acids. Cotransfection with FTF strongly repressed 
      CYP8B1 transcription. Interestingly, HNF4alpha could overcome the inhibitory 
      effects of FTF and bile acids. We conclude that FTF and HNF4alpha not only play 
      critical roles on CYP8B1 gene transcription, but also mediate bile acid feedback 
      inhibition. This study reveals a novel mechanism by which bile acids inhibit rat 
      CYP8B1 gene transcription by inducing FTF and inhibiting HNF4alpha expression.
FAU - Yang, Yizeng
AU  - Yang Y
AD  - Department of Biochemistry and Molecular Pathology, Northeastern Ohio 
      Universities College of Medicine, Rootstown 44272, USA.
FAU - Zhang, Ming
AU  - Zhang M
FAU - Eggertsen, Gosta
AU  - Eggertsen G
FAU - Chiang, John Y L
AU  - Chiang JY
LA  - eng
GR  - DK44442/DK/NIDDK NIH HHS/United States
GR  - GM31584/GM/NIGMS NIH HHS/United States
GR  - R01 DK058379/DK/NIDDK NIH HHS/United States
GR  - DK58379/DK/NIDDK NIH HHS/United States
GR  - R01 DK044442/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - Netherlands
TA  - Biochim Biophys Acta
JT  - Biochimica et biophysica acta
JID - 0217513
RN  - 0 (Bile Acids and Salts)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Hepatocyte Nuclear Factor 4)
RN  - 0 (Hnf4a protein, rat)
RN  - 0 (Phosphoproteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Transcription Factors)
RN  - 0 (alpha-Fetoproteins)
RN  - 9007-49-2 (DNA)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - EC 1.14.- (Steroid Hydroxylases)
RN  - EC 1.14.18.8 (Steroid 12-alpha-Hydroxylase)
SB  - IM
MH  - Animals
MH  - Base Sequence
MH  - Bile Acids and Salts/*pharmacology
MH  - Cattle
MH  - Cytochrome P-450 Enzyme System/*genetics
MH  - DNA
MH  - *DNA-Binding Proteins
MH  - Gene Expression Regulation, Enzymologic/*drug effects/physiology
MH  - Hepatocyte Nuclear Factor 4
MH  - Phosphoproteins/genetics/*physiology
MH  - Promoter Regions, Genetic
MH  - RNA, Messenger/genetics
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Steroid 12-alpha-Hydroxylase
MH  - Steroid Hydroxylases/*genetics
MH  - Transcription Factors/genetics/*physiology
MH  - Transcription, Genetic/*drug effects
MH  - alpha-Fetoproteins/genetics/*physiology
EDAT- 2002/06/19 10:00
MHDA- 2002/08/07 10:01
CRDT- 2002/06/19 10:00
PHST- 2002/06/19 10:00 [pubmed]
PHST- 2002/08/07 10:01 [medline]
PHST- 2002/06/19 10:00 [entrez]
AID - S1388198102001865 [pii]
AID - 10.1016/s1388-1981(02)00186-5 [doi]
PST - ppublish
SO  - Biochim Biophys Acta. 2002 Jun 13;1583(1):63-73. doi: 
      10.1016/s1388-1981(02)00186-5.