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

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 spe...

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Main Authors: Akira Honda, Gerald Salen, Yasushi Matsuzaki, Ashok K. Batta, Guorong Xu, Takeshi Hirayama, G. Stephen Tint, Mikio Doy, Sarah Shefer
Format: Article
Language:English
Published: Elsevier 2005-02-01
Series:Journal of Lipid Research
Subjects:
Online Access:http://www.sciencedirect.com/science/article/pii/S0022227520340621
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language English
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author Akira Honda
Gerald Salen
Yasushi Matsuzaki
Ashok K. Batta
Guorong Xu
Takeshi Hirayama
G. Stephen Tint
Mikio Doy
Sarah Shefer
spellingShingle Akira Honda
Gerald Salen
Yasushi Matsuzaki
Ashok K. Batta
Guorong Xu
Takeshi Hirayama
G. Stephen Tint
Mikio Doy
Sarah Shefer
Disrupted coordinate regulation of farnesoid X receptor target genes in a patient with cerebrotendinous xanthomatosis
Journal of Lipid Research
bile acids
bile alcohols
sterol 27-hydroxylase
cholesterol 7α-hydroxylase
Na+/taurocholate-cotransporting polypeptide
bile salt export pump
author_facet Akira Honda
Gerald Salen
Yasushi Matsuzaki
Ashok K. Batta
Guorong Xu
Takeshi Hirayama
G. Stephen Tint
Mikio Doy
Sarah Shefer
author_sort Akira Honda
title Disrupted coordinate regulation of farnesoid X receptor target genes in a patient with cerebrotendinous xanthomatosis
title_short Disrupted coordinate regulation of farnesoid X receptor target genes in a patient with cerebrotendinous xanthomatosis
title_full Disrupted coordinate regulation of farnesoid X receptor target genes in a patient with cerebrotendinous xanthomatosis
title_fullStr Disrupted coordinate regulation of farnesoid X receptor target genes in a patient with cerebrotendinous xanthomatosis
title_full_unstemmed Disrupted coordinate regulation of farnesoid X receptor target genes in a patient with cerebrotendinous xanthomatosis
title_sort disrupted coordinate regulation of farnesoid x receptor target genes in a patient with cerebrotendinous xanthomatosis
publisher Elsevier
series Journal of Lipid Research
issn 0022-2275
publishDate 2005-02-01
description 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 7α-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 α (LXRα) or pregnane X receptor. However, another nuclear receptor, hepatocyte nuclear factor 4α (HNF4α), was induced 2.9-fold in CTX, which was associated with enhanced mRNA levels of HNF4α target genes, CYP7A1, 7α-hydroxy-4-cholesten-3-one 12α-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 HNF4α caused by reduced bile acids in CTX liver.
topic bile acids
bile alcohols
sterol 27-hydroxylase
cholesterol 7α-hydroxylase
Na+/taurocholate-cotransporting polypeptide
bile salt export pump
url http://www.sciencedirect.com/science/article/pii/S0022227520340621
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AT yasushimatsuzaki disruptedcoordinateregulationoffarnesoidxreceptortargetgenesinapatientwithcerebrotendinousxanthomatosis
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spelling doaj-93d1bd6384294b5fade933663ec32d132021-04-27T04:46:34ZengElsevierJournal of Lipid Research0022-22752005-02-01462287296Disrupted coordinate regulation of farnesoid X receptor target genes in a patient with cerebrotendinous xanthomatosisAkira Honda0Gerald Salen1Yasushi Matsuzaki2Ashok K. Batta3Guorong Xu4Takeshi Hirayama5G. Stephen Tint6Mikio Doy7Sarah Shefer8Ibaraki Prefectural Institute of Public Health, Mito, Ibaraki 310-0852, Japan; 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 07018Ibaraki Prefectural Institute of Public Health, Mito, Ibaraki 310-0852, Japan; 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 07018Ibaraki Prefectural Institute of Public Health, Mito, Ibaraki 310-0852, Japan; 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 07018Ibaraki Prefectural Institute of Public Health, Mito, Ibaraki 310-0852, Japan; 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 07018Ibaraki Prefectural Institute of Public Health, Mito, Ibaraki 310-0852, Japan; 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 07018Ibaraki Prefectural Institute of Public Health, Mito, Ibaraki 310-0852, Japan; 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 07018Ibaraki Prefectural Institute of Public Health, Mito, Ibaraki 310-0852, Japan; 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 07018Ibaraki Prefectural Institute of Public Health, Mito, Ibaraki 310-0852, Japan; 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 07018Ibaraki Prefectural Institute of Public Health, Mito, Ibaraki 310-0852, Japan; 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 07018Cerebrotendinous 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 7α-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 α (LXRα) or pregnane X receptor. However, another nuclear receptor, hepatocyte nuclear factor 4α (HNF4α), was induced 2.9-fold in CTX, which was associated with enhanced mRNA levels of HNF4α target genes, CYP7A1, 7α-hydroxy-4-cholesten-3-one 12α-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 HNF4α caused by reduced bile acids in CTX liver.http://www.sciencedirect.com/science/article/pii/S0022227520340621bile acidsbile alcoholssterol 27-hydroxylasecholesterol 7α-hydroxylaseNa+/taurocholate-cotransporting polypeptidebile salt export pump