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.
Publication types
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Case Reports
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 11
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ATP-Binding Cassette Transporters / biosynthesis
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Adult
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Alcohols / metabolism
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Bile Acids and Salts / metabolism
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Case-Control Studies
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Chenodeoxycholic Acid / metabolism
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Cholestanetriol 26-Monooxygenase
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Cholestanols / metabolism
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Cholesterol 7-alpha-Hydroxylase / biosynthesis
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DNA Primers / metabolism
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism*
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Female
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Gene Expression Regulation
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Hepatocyte Nuclear Factor 4
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Humans
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Liver / metabolism
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Liver X Receptors
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Male
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Membrane Transport Proteins / biosynthesis
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Middle Aged
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Models, Biological
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Organic Anion Transporters, Sodium-Dependent
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Orphan Nuclear Receptors
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Phosphoproteins / biosynthesis
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Pregnane X Receptor
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Protein Binding
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RNA, Messenger / metabolism
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Receptors, Cytoplasmic and Nuclear / biosynthesis
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Receptors, Steroid / biosynthesis
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Steroid Hydroxylases / biosynthesis
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Symporters
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Transcription Factors / biosynthesis
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Transcription Factors / genetics*
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Transcription Factors / metabolism*
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Up-Regulation
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Xanthomatosis, Cerebrotendinous / genetics*
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Xanthomatosis, Cerebrotendinous / metabolism*
Substances
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ABCB11 protein, human
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ATP Binding Cassette Transporter, Subfamily B, Member 11
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ATP-Binding Cassette Transporters
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Alcohols
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Bile Acids and Salts
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Cholestanols
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DNA Primers
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DNA-Binding Proteins
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HNF4A protein, human
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Hepatocyte Nuclear Factor 4
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Liver X Receptors
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Membrane Transport Proteins
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NR1H3 protein, human
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Organic Anion Transporters, Sodium-Dependent
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Orphan Nuclear Receptors
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Phosphoproteins
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Pregnane X Receptor
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RNA, Messenger
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Receptors, Cytoplasmic and Nuclear
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Receptors, Steroid
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Symporters
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Transcription Factors
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nuclear receptor subfamily 0, group B, member 2
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farnesoid X-activated receptor
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Chenodeoxycholic Acid
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sodium-bile acid cotransporter
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Steroid Hydroxylases
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Cholesterol 7-alpha-Hydroxylase
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CYP27A1 protein, human
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Cholestanetriol 26-Monooxygenase