title: Disrupted coordinate regulation of farnesoid X receptor target genes in a patient with cerebrotendinous xanthomatosis.
abstract: 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.
authors.affiliation: Ibaraki Prefectural Institute of Public Health, Mito, Ibaraki 310-0852, Japan. akihonda-gi@umin.ac.jp
authors.forename: Akira
authors.initials: A
authors.lastname: Honda
authors.forename: Gerald
authors.initials: G
authors.lastname: Salen
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsuzaki
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Batta
authors.forename: Guorong
authors.initials: G
authors.lastname: Xu
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hirayama
authors.forename: G Stephen
authors.initials: GS
authors.lastname: Tint
authors.forename: Mikio
authors.initials: M
authors.lastname: Doy
authors.forename: Sarah
authors.initials: S
authors.lastname: Shefer
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000328:Adult; D000438:Alcohols / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D016022:Case-Control Studies; D002635:Chenodeoxycholic Acid / Q000378:metabolism; D053493:Cholestanetriol 26-Monooxygenase; D002777:Cholestanols / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis; D017931:DNA Primers / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D026901:Membrane Transport Proteins / Q000096:biosynthesis; D008875:Middle Aged; D008954:Models, Biological; D029363:Organic Anion Transporters, Sodium-Dependent; D057093:Orphan Nuclear Receptors; D010750:Phosphoproteins / Q000096:biosynthesis; D000077297:Pregnane X Receptor; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis; D011987:Receptors, Steroid / Q000096:biosynthesis; D013250:Steroid Hydroxylases / Q000096:biosynthesis; D027981:Symporters; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation; D019294:Xanthomatosis, Cerebrotendinous / Q000235:genetics* / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D000438:Alcohols; D001647:Bile Acids and Salts; D002635:Chenodeoxycholic Acid; D053493:Cholestanetriol 26-Monooxygenase; D002777:Cholestanols; D002790:Cholesterol 7-alpha-Hydroxylase; D017931:DNA Primers; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; D000071518:Liver X Receptors; D026901:Membrane Transport Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D057093:Orphan Nuclear Receptors; D010750:Phosphoproteins; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013250:Steroid Hydroxylases; D027981:Symporters; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C093491:ABCB11 protein, human; C496592:HNF4A protein, human; C000605213:NR1H3 protein, human; C099713:nuclear receptor subfamily 0, group B, member 2; C071908:sodium-bile acid cotransporter; C506831:CYP27A1 protein, human