Disrupted coordinate regulation of farnesoid X receptor target genes in a patient with cerebrotendinous xanthomatosis Published, JLR Papers in Press, December 1, 2004. DOI 10.1194/jlr.M400256-JLR200

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.

[1]  Kazuhide Inoue,et al.  Identification of intermediates in the bile acid synthetic pathway as ligands for the farnesoid X receptor Published, JLR Papers in Press, May 16, 2004. DOI 10.1194/jlr.M400102-JLR200 , 2004, Journal of Lipid Research.

[2]  Sander M Houten,et al.  Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. , 2004, The Journal of clinical investigation.

[3]  Giovanni Galli,et al.  Coordinated Control of Cholesterol Catabolism to Bile Acids and of Gluconeogenesis via a Novel Mechanism of Transcription Regulation Linked to the Fasted-to-fed Cycle* , 2003, Journal of Biological Chemistry.

[4]  J. Chiang,et al.  Regulation of human sterol 27-hydroxylase gene (CYP27A1) by bile acids and hepatocyte nuclear factor 4α (HNF4α) , 2003 .

[5]  F. Gonzalez,et al.  Role of the hepatocyte nuclear factor 4α in control of the pregnane X receptor during fetal liver development , 2003, Hepatology.

[6]  S. Kliewer,et al.  Differential regulation of rat and human CYP7A1 by the nuclear oxysterol receptor liver X receptor-alpha. , 2003, Molecular endocrinology.

[7]  B. M. Forman,et al.  Identification of an endogenous ligand that activates pregnane X receptor-mediated sterol clearance , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[8]  S. Kliewer,et al.  Identification of bile acid precursors as endogenous ligands for the nuclear xenobiotic pregnane X receptor , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[9]  D. Russell,et al.  Cholic acid mediates negative feedback regulation of bile acid synthesis in mice. , 2002, The Journal of clinical investigation.

[10]  A. Walsh,et al.  Dietary Cholesterol Fails to Stimulate the Human Cholesterol 7α-Hydroxylase Gene (CYP7A1) in Transgenic Mice* 210 , 2002, The Journal of Biological Chemistry.

[11]  M. Karin,et al.  Redundant pathways for negative feedback regulation of bile acid production. , 2002, Developmental cell.

[12]  D. Russell,et al.  Loss of nuclear receptor SHP impairs but does not eliminate negative feedback regulation of bile acid synthesis. , 2002, Developmental cell.

[13]  J. Chiang,et al.  Transcriptional Regulation of the Human Sterol 12α-Hydroxylase Gene (CYP8B1) , 2001, The Journal of Biological Chemistry.

[14]  Y. Kasuya,et al.  Hydrolysis of conjugated steroids by the combined use of β-glucuronidase preparations from helix pomatia and ampullaria: determination of urinary cortisol and its metabolites , 2001, Steroids.

[15]  A. Honda,et al.  Side Chain Hydroxylations in Bile Acid Biosynthesis Catalyzed by CYP3A Are Markedly Up-regulated in Cyp27−/− Mice but Not in Cerebrotendinous Xanthomatosis* , 2001, The Journal of Biological Chemistry.

[16]  J. Chiang,et al.  Nuclear receptor-mediated repression of human cholesterol 7alpha-hydroxylase gene transcription by bile acids. , 2001, Journal of lipid research.

[17]  N. Mitro,et al.  The Negative Effects of Bile Acids and Tumor Necrosis Factor-α on the Transcription of Cholesterol 7α-Hydroxylase Gene (CYP7A1) Converge to Hepatic Nuclear Factor-4 , 2001, The Journal of Biological Chemistry.

[18]  N. Mitro,et al.  The negative effects of bile acids and tumor necrosis factor-alpha on the transcription of cholesterol 7alpha-hydroxylase gene (CYP7A1) converge to hepatic nuclear factor-4: a novel mechanism of feedback regulation of bile acid synthesis mediated by nuclear receptors. , 2001, The Journal of biological chemistry.

[19]  M. Makishima,et al.  Human Bile Salt Export Pump Promoter Is Transactivated by the Farnesoid X Receptor/Bile Acid Receptor* , 2001, The Journal of Biological Chemistry.

[20]  P. Dent,et al.  Down-regulation of Cholesterol 7α-Hydroxylase (CYP7A1) Gene Expression by Bile Acids in Primary Rat Hepatocytes Is Mediated by the c-Jun N-terminal Kinase Pathway* , 2001, The Journal of Biological Chemistry.

[21]  R. Evans,et al.  An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[22]  T. Willson,et al.  The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Jerrold M. Ward,et al.  Hepatocyte Nuclear Factor 4α (Nuclear Receptor 2A1) Is Essential for Maintenance of Hepatic Gene Expression and Lipid Homeostasis , 2001, Molecular and Cellular Biology.

[24]  A. Honda,et al.  Differences in hepatic levels of intermediates in bile acid biosynthesis between Cyp27(-/-) mice and CTX. , 2001, Journal of lipid research.

[25]  J. Carpten,et al.  Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees. , 2001, Journal of lipid research.

[26]  J. Chiang,et al.  Regulation of cholesterol 7α-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXRα) , 2001 .

[27]  D. Russell,et al.  Disruption of the Sterol 27-Hydroxylase Gene in Mice Results in Hepatomegaly and Hypertriglyceridemia , 2000, The Journal of Biological Chemistry.

[28]  I. Björkhem,et al.  Oxysterol 7α-Hydroxylase Activity by Cholesterol 7α-Hydroxylase (CYP7A)* , 2000, The Journal of Biological Chemistry.

[29]  I. Björkhem,et al.  24-hydroxycholesterol is a substrate for hepatic cholesterol 7alpha-hydroxylase (CYP7A). , 2000, Journal of lipid research.

[30]  Masahiro Tohkin,et al.  Targeted Disruption of the Nuclear Receptor FXR/BAR Impairs Bile Acid and Lipid Homeostasis , 2000, Cell.

[31]  L. Moore,et al.  A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. , 2000, Molecular cell.

[32]  T. A. Kerr,et al.  Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. , 2000, Molecular cell.

[33]  J. Chiang,et al.  Farnesoid X Receptor Responds to Bile Acids and Represses Cholesterol 7α-Hydroxylase Gene (CYP7A1) Transcription* , 2000, The Journal of Biological Chemistry.

[34]  J. Lehmann,et al.  Bile acids: natural ligands for an orphan nuclear receptor. , 1999, Science.

[35]  M. Makishima,et al.  Identification of a nuclear receptor for bile acids. , 1999, Science.

[36]  Jasmine Chen,et al.  Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. , 1999, Molecular cell.

[37]  S. Kliewer,et al.  Structural requirements of ligands for the oxysterol liver X receptors LXRalpha and LXRbeta. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[38]  N. Maeda,et al.  Markedly Reduced Bile Acid Synthesis but Maintained Levels of Cholesterol and Vitamin D Metabolites in Mice with Disrupted Sterol 27-Hydroxylase Gene* , 1998, The Journal of Biological Chemistry.

[39]  R. Hammer,et al.  Cholesterol and Bile Acid Metabolism Are Impaired in Mice Lacking the Nuclear Oxysterol Receptor LXRα , 1998, Cell.

[40]  I. Shimomura,et al.  Differential expression of exons 1a and 1c in mRNAs for sterol regulatory element binding protein-1 in human and mouse organs and cultured cells. , 1997, The Journal of clinical investigation.

[41]  D. Mangelsdorf,et al.  An oxysterol signalling pathway mediated by the nuclear receptor LXRα , 1996, Nature.

[42]  U. Diczfalusy,et al.  Determination of cholesterol oxidation products in human plasma by isotope dilution-mass spectrometry. , 1995, Analytical biochemistry.

[43]  Y. Seyama,et al.  Identification of new mutations in sterol 27-hydroxylase gene in Japanese patients with cerebrotendinous xanthomatosis (CTX). , 1994, Journal of lipid research.

[44]  V. Meiner,et al.  Frameshift and splice-junction mutations in the sterol 27-hydroxylase gene cause cerebrotendinous xanthomatosis in Jews or Moroccan origin. , 1993, The Journal of clinical investigation.

[45]  J. Sjövall,et al.  Synthesis of potential C27-intermediates in bile acid biosynthesis and their deuterium-labeled analogs , 1993, Steroids.

[46]  G. Everson,et al.  Bile Acid Metabolism and Its Role in Human Cholesterol Balance , 1992, Seminars in liver disease.

[47]  U. Francke,et al.  Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis. , 1991, The Journal of biological chemistry.

[48]  W. K. Wilson,et al.  Inhibitors of sterol synthesis. Chemical synthesis, structure, and biological activities of (25R)-3 beta,26-dihydroxy-5 alpha-cholest-8(14)-en-15-one, a metabolite of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one. , 1989, Journal of lipid research.

[49]  G. Tint,et al.  Increased plasma bile alcohol glucuronides in patients with cerebrotendinous xanthomatosis: effect of chenodeoxycholic acid. , 1987, Journal of lipid research.

[50]  G. Tint,et al.  Biosynthesis of bile acids in cerebrotendinous xanthomatosis. Relationship of bile acid pool sizes and synthesis rates to hydroxylations at C-12, C-25, and C-26. , 1985, The Journal of clinical investigation.

[51]  A. Batta,et al.  Effect of chenodeoxycholic acid on biliary and urinary bile acids and bile alcohols in cerebrotendinous xanthomatosis; monitoring by high performance liquid chromatography. , 1985, Journal of lipid research.

[52]  S. Shefer,et al.  Long-term treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid. , 1984, The New England journal of medicine.

[53]  T. Forte,et al.  Abnormal high density lipoproteins in cerebrotendinous xanthomatosis. , 1981, The Journal of clinical investigation.

[54]  M. Une,et al.  Occurrence of bile alcohol glucuronides in bile of patients with cerebrotendinous xanthomatosis. , 1980, Journal of lipid research.

[55]  G. Tint,et al.  Identification of pentahydroxy bile alcohols in cerebrotendinous xanthomatosis: characterization of 5beta-cholestane-3alpha, 7alpha, 12alpha, 24xi, 25-pentol and 5beta-cholestane-3alpha, 7alpha, 12alpha, 23xi, 25-pentol. , 1975, Journal of lipid research.

[56]  S. Shefer,et al.  Determination of hepatic cholesterol 7α-hydroxylase activity in man , 1974 .

[57]  Sasaki Takeshi,et al.  Stero-bile acids and bile sterols , 1964 .

[58]  T. Hoshita.  Stero-bile acids and bile sterols. 47. Syntheses of 3alpha,7alpha,12alpha,25,26- and 3alpha,7alpha,12alpha,24,25-pentahydroxycoprostanes. , 1962, Journal of biochemistry.

[59]  T. Hoshita.  Stero-bile acids and bile sterols , 1962 .

[60]  A. Honda,et al.  Increased bile acid concentration in liver tissue with cholesterol gallstone disease , 2005, Journal of Gastroenterology.

[61]  J. Chiang,et al.  Mechanism of rifampicin and pregnane X receptor inhibition of human cholesterol 7 alpha-hydroxylase gene transcription. , 2005, American journal of physiology. Gastrointestinal and liver physiology.

[62]  J. Chiang,et al.  Mechanism of Rifampicin and Pregnane X Receptor ( PXR ) inhibition of Human Cholesterol 7-Hydroxylase Gene ( CYP 7 A 1 ) Transcription , 2004 .

[63]  J. Chiang,et al.  HNF4 and COUP-TFII interact to modulate transcription of the cholesterol 7alpha-hydroxylase gene (CYP7A1). , 2000, Journal of lipid research.

[64]  Charles R.scriver.  The Metabolic basis of inherited disease , 1989 .

[65]  A. Batta,et al.  Biosynthesis of Bile Acids in Cerebrotendinous Xanthomatosis , 1985 .

[66]  G. Tint,et al.  Synthesis of 5/3-cholestane-3~,71x,12~,25-tetrol and 5P-choIestane-3a,7a,I 2a,24&25-pentol , 1976 .

[67]  G. Tint,et al.  Synthesis of 5beta-cholestane-3alpha, 7alpha, 12alpha, 25-tetrol and 5beta-cholestane-3alpha, 7alpha, 245, 25-pentol. , 1976, Journal of lipid research.