PMID- 15576845
OWN - NLM
STAT- MEDLINE
DCOM- 20050711
LR  - 20210217
IS  - 0022-2275 (Print)
IS  - 0022-2275 (Linking)
VI  - 46
IP  - 2
DP  - 2005 Feb
TI  - Disrupted coordinate regulation of farnesoid X receptor target genes in a patient 
      with cerebrotendinous xanthomatosis.
PG  - 287-96
AB  - Cerebrotendinous xanthomatosis (CTX), sterol 27-hydroxylase (CYP27A1) deficiency, 
      is associated with markedly reduced chenodeoxycholic acid (CDCA), the most 
      powerful activating ligand for farnesoid X receptor (FXR). We investigated the 
      effects of reduced CDCA on FXR target genes in humans. Liver specimens from an 
      untreated CTX patient and 10 control subjects were studied. In the patient, 
      hepatic CDCA concentration was markedly reduced but the bile alcohol level 
      exceeded CDCA levels in control subjects (73.5 vs. 37.8 +/- 6.2 nmol/g liver). 
      Cholesterol 7alpha-hydroxylase (CYP7A1) and Na+/taurocholate-cotransporting 
      polypeptide (NTCP) were upregulated 84- and 8-fold, respectively. However, small 
      heterodimer partner (SHP) and bile salt export pump were normally expressed. 
      Marked CYP7A1 induction with normal SHP expression was not explained by the 
      regulation of liver X receptor alpha (LXRalpha) or pregnane X receptor. However, 
      another nuclear receptor, hepatocyte nuclear factor 4alpha (HNF4alpha), was 
      induced 2.9-fold in CTX, which was associated with enhanced mRNA levels of 
      HNF4alpha target genes, CYP7A1, 7alpha-hydroxy-4-cholesten-3-one 
      12alpha-hydroxylase, CYP27A1, and NTCP. In conclusion, the coordinate regulation 
      of FXR target genes was lost in CTX. The mechanism of the disruption may be 
      explained by a normally stimulated FXR pathway attributable to markedly increased 
      bile alcohols with activation of HNF4alpha caused by reduced bile acids in CTX 
      liver.
FAU - Honda, Akira
AU  - Honda A
AD  - Ibaraki Prefectural Institute of Public Health, Mito, Ibaraki 310-0852, Japan. 
      akihonda-gi@umin.ac.jp
FAU - Salen, Gerald
AU  - Salen G
FAU - Matsuzaki, Yasushi
AU  - Matsuzaki Y
FAU - Batta, Ashok K
AU  - Batta AK
FAU - Xu, Guorong
AU  - Xu G
FAU - Hirayama, Takeshi
AU  - Hirayama T
FAU - Tint, G Stephen
AU  - Tint GS
FAU - Doy, Mikio
AU  - Doy M
FAU - Shefer, Sarah
AU  - Shefer S
LA  - eng
GR  - DK-26756/DK/NIDDK NIH HHS/United States
GR  - DK-56830/DK/NIDDK NIH HHS/United States
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20041201
PL  - United States
TA  - J Lipid Res
JT  - Journal of lipid research
JID - 0376606
RN  - 0 (ABCB11 protein, human)
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 11)
RN  - 0 (ATP-Binding Cassette Transporters)
RN  - 0 (Alcohols)
RN  - 0 (Bile Acids and Salts)
RN  - 0 (Cholestanols)
RN  - 0 (DNA Primers)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HNF4A protein, human)
RN  - 0 (Hepatocyte Nuclear Factor 4)
RN  - 0 (Liver X Receptors)
RN  - 0 (Membrane Transport Proteins)
RN  - 0 (NR1H3 protein, human)
RN  - 0 (Organic Anion Transporters, Sodium-Dependent)
RN  - 0 (Orphan Nuclear Receptors)
RN  - 0 (Phosphoproteins)
RN  - 0 (Pregnane X Receptor)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (Receptors, Steroid)
RN  - 0 (Symporters)
RN  - 0 (Transcription Factors)
RN  - 0 (nuclear receptor subfamily 0, group B, member 2)
RN  - 0C5V0MRU6P (farnesoid X-activated receptor)
RN  - 0GEI24LG0J (Chenodeoxycholic Acid)
RN  - 145420-23-1 (sodium-bile acid cotransporter)
RN  - EC 1.14.- (Steroid Hydroxylases)
RN  - EC 1.14.14.23 (Cholesterol 7-alpha-Hydroxylase)
RN  - EC 1.14.15.15 (CYP27A1 protein, human)
RN  - EC 1.14.15.15 (Cholestanetriol 26-Monooxygenase)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 11
MH  - ATP-Binding Cassette Transporters/biosynthesis
MH  - Adult
MH  - Alcohols/metabolism
MH  - Bile Acids and Salts/metabolism
MH  - Case-Control Studies
MH  - Chenodeoxycholic Acid/metabolism
MH  - Cholestanetriol 26-Monooxygenase
MH  - Cholestanols/metabolism
MH  - Cholesterol 7-alpha-Hydroxylase/biosynthesis
MH  - DNA Primers/metabolism
MH  - DNA-Binding Proteins/biosynthesis/*genetics/*metabolism
MH  - Female
MH  - Gene Expression Regulation
MH  - Hepatocyte Nuclear Factor 4
MH  - Humans
MH  - Liver/metabolism
MH  - Liver X Receptors
MH  - Male
MH  - Membrane Transport Proteins/biosynthesis
MH  - Middle Aged
MH  - Models, Biological
MH  - Organic Anion Transporters, Sodium-Dependent
MH  - Orphan Nuclear Receptors
MH  - Phosphoproteins/biosynthesis
MH  - Pregnane X Receptor
MH  - Protein Binding
MH  - RNA, Messenger/metabolism
MH  - Receptors, Cytoplasmic and Nuclear/biosynthesis
MH  - Receptors, Steroid/biosynthesis
MH  - Steroid Hydroxylases/biosynthesis
MH  - Symporters
MH  - Transcription Factors/biosynthesis/*genetics/*metabolism
MH  - Up-Regulation
MH  - Xanthomatosis, Cerebrotendinous/*genetics/*metabolism
EDAT- 2004/12/04 09:00
MHDA- 2005/07/12 09:00
CRDT- 2004/12/04 09:00
PHST- 2004/12/04 09:00 [pubmed]
PHST- 2005/07/12 09:00 [medline]
PHST- 2004/12/04 09:00 [entrez]
AID - S0022-2275(20)34062-1 [pii]
AID - 10.1194/jlr.M400256-JLR200 [doi]
PST - ppublish
SO  - J Lipid Res. 2005 Feb;46(2):287-96. doi: 10.1194/jlr.M400256-JLR200. Epub 2004 
      Dec 1.