Submitted on July 6, 2004
Revised on November 16, 2004
Accepted on November 18, 2004
Disrupted coordinate regulation of farnesoid X receptor (FXR) target genes in a patient with cerebrotendinous xanthomatosis
Akira Honda, Gerald Salen, Yasushi Matsuzaki, Ashok K. Batta, Guorong Xu, Takeshi Hirayama, G. Stephen Tint, Mikio Doy, and Sarah Shefer
Ibaraki Prefectural Institute of Public Health, Mito, Ibaraki 310-0852
Corresponding Author: AkiraHonda{at}aol.com
Farnesoid X receptor (FXR) is a pivotal nuclear transcription factor that regulates bile acid biosynthesis and transport. Since cerebrotendinous xanthomatosis (CTX), CYP27A1 deficiency, is associated with markedly reduced chenodeoxycholic acid (CDCA) pool and CDCA is believed to be the most powerful activating ligand for FXR, we investigated the effects of reduced CDCA on FXR target genes in humans. Liver specimens from an untreated and a CDCA treated CTX patients and ten control humans were studied. Hepatic enzyme activities and concentrations of oxysterols, bile acids, and bile alcohols were measured by high-resolution GC-SIM. Hepatic mRNA levels were determined by real-time quantitative PCR assay. In the untreated CTX patient, hepatic CDCA concentration was markedly reduced but the bile alcohol level (73.5 nmol/g liver) exceeded CDCA levels in control subjects (37.8 6.2 nmol/g liver). CYP7A1 and Na+/taurocholate cotransporting polypeptide (NTCP) which are positively controlled by deactivated FXR were up-regulated 84- and 8-fold, respectively. However, small heterodimer partner (SHP) and bile salt export pump (BSEP) that are negatively controlled by deactivated FXR were normally expressed. To explore the mechanism of dissociating marked CYP7A1 induction from normal SHP expression, we evaluated the status of other nuclear receptors, liver X receptor 
(LXR) and pregnane X receptor (PXR), which may regulate CYP7A1 expression independent of SHP. However, activation of LXR or PXR pathway was not influenced by CYP27A1 deficiency. In contrast, another nuclear receptor, hepatocyte nuclear factor 4 (HNF4), was induced 2.9-fold in CTX, which was associated with enhanced mRNA levels of HNF4 target genes, CYP7A1, CYP8B1, 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 normally stimulated FXR pathway due to markedly increased bile alcohols with activation of HNF4 due to reduced bile acids in CTX liver.
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