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J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M400256-JLR200 on December 1, 2004

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Journal of Lipid Research, Vol. 46, 287-296, February 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Disrupted coordinate regulation of farnesoid X receptor target genes in a patient with cerebrotendinous xanthomatosis

Akira Honda1,*,{dagger}, Gerald Salen§,**, Yasushi Matsuzaki{dagger}, Ashok K. Batta§, Guorong Xu§,**, Takeshi Hirayama{dagger}, G. Stephen Tint§,**, Mikio Doy* and Sarah Shefer§

* Ibaraki Prefectural Institute of Public Health, Mito, Ibaraki 310-0852, Japan
{dagger} Division of Gastroenterology and Hepatology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
§ Gastrointestinal Division and Liver Center, Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07103
** Veterans Affairs Medical Center, East Orange, NJ 07018

1 To whom correspondence should be addressed. e-mail: akihonda-gi{at}umin.ac.jp

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 7{alpha}-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} (LXR{alpha}) or pregnane X receptor. However, another nuclear receptor, hepatocyte nuclear factor 4{alpha} (HNF4{alpha}), was induced 2.9-fold in CTX, which was associated with enhanced mRNA levels of HNF4{alpha} target genes, CYP7A1, 7{alpha}-hydroxy-4-cholesten-3-one 12{alpha}-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 HNF4{alpha} caused by reduced bile acids in CTX liver.

Abbreviations: BSEP, bile salt export pump; CA, cholic acid; CDCA, chenodeoxycholic acid; CTX, cerebrotendinous xanthomatosis; CYP3A, 5ß-cholestane-3{alpha},7{alpha},12{alpha}-triol 25-hydroxylase; CYP7A1, cholesterol 7{alpha}-hydroxylase; CYP7B1, oxysterol 7{alpha}-hydroxylase; CYP8B1, 7{alpha}-hydroxy-4-cholesten-3-one 12{alpha}-hydroxylase; CYP27A1, sterol 27-hydroxylase; DCA, deoxycholic acid; FTF, {alpha}-fetoprotein transcription factor; FXR, farnesoid X receptor; GC-SIM, gas chromatography-mass spectrometry with selected ion monitoring; HMGCR, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; HNF4{alpha}, hepatocyte nuclear factor 4{alpha}; JNK, c-Jun N-terminal kinase; LCA, lithocholic acid; LXR{alpha}, liver X receptor {alpha}; MDR1, multidrug-resistant protein 1; NTCP, Na+/taurocholate-cotransporting polypeptide; OATP2, organic anion transport protein 2; PGC-1{alpha}, peroxisome proliferator-activated receptor {gamma} coactivator 1{alpha}; PXR, pregnane X receptor; SHP, small heterodimer partner; SREBP1, sterol regulatory element binding protein 1; TMS, trimethylsilyl; UDCA, ursodeoxycholic acid

Supplementary key words bile acids • bile alcohols • sterol 27-hydroxylase • cholesterol 7{alpha}-hydroxylase • Na+/taurocholate-cotransporting polypeptide • bile salt export pump • hepatocyte nuclear factor 4{alpha} • small heterodimer partner • pregnane X receptor • liver X receptor {alpha}


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A. Honda, K. Yamashita, T. Hara, T. Ikegami, T. Miyazaki, M. Shirai, G. Xu, M. Numazawa, and Y. Matsuzaki
Highly sensitive quantification of key regulatory oxysterols in biological samples by LC-ESI-MS/MS
J. Lipid Res., February 1, 2009; 50(2): 350 - 357.
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