Metabolome analysis of abnormal bile acids as specific biomarkers in the inborn error of cholesterol biosynthesis (SLOS)

• Project/Area Number: 24550107
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Analytical chemistry
• Research Institution: Nihon University
• Principal Investigator: IIDA Takashi 日本大学, 文理学部, 教授 (60060125)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 生体分子 / 先天性コレステロール代謝異常症 / コレステロール異常代謝産物 / LC/ESI-MS/MS / スミス‐レムリ‐オピッツ症候群（SLOS） / 7-デヒドロコレステロール レダクターゼ欠損症 / SLOS疾患 / LC-MS/MS / 異常胆汁酸 / MassBank / SLOS症候群 / Mass Bank

Outline of Final Research Achievements

The synthesis of bile acids from cholesterol is a complex biochemical pathway involving at least 16 enzymes. Inborn errors of cholesterol biosynthesis in Smith-Lemli-Opitz Syndrome (SLOS: 7-dehydrocholesterol reductase deficiency, Dhcr7) result in excessive formation of abnormal intermediates of 4α- and 4β-hydroxy-7-dehydrocholesterols (as the unconjugated and conjugated forms) and/or their metabolites that accumulate in blood and are excreted in part in urine. In the past, these intermediates in cholesterol biosynthesis have been detected in neonatal blood or urine by screening with FAB-MS followed by detailed characterization using GC-MS. Both methods have proved difficult to automate, and currently most laboratories screen candidate samples using LC-MS/MS. Here, we describe a new, simple and sensitive analytical method for identification and chracterization of 4α- and 4β-dehydrocholesterols (as biomarkers for SLOS), using LC/ESI-MS/MS.

Research Products

• [Journal Article] Origin of myofiblasts in the fibrotic liver in mice (2014)
  • Author(s): K.Iwaisako, C.Jiang, M.Zhang, M.Cong, T.J.Moore-Morris, T.J.Park, X.Liu, J.Xu, P.Wang, Y-H.Paik, F.Meng, M.Asagiri, L.A.Murray, A.F.Hofmann, T.Iida, C.K.Glass, D.A.Brenner, T.Kisseleva
  • Journal Title: Proc. Natl. Acad. Sci. USA. Volume: 111 Issue: 32
  • DOI: 10.1073/pnas.1400062111
  • Peer Reviewed
• [Journal Article] Improved chemical synthesis, X-ray crystallographic analysis, and NMR characterization of (22R)-/(22S)-hydroxy epimers of bile acids (2014)
  • Author(s): K.Omura, A.Ohsaki, B.Zhou, M.Kushida, T.Mitsuma, A.Kobayashi, L.R.Hagey, A.F.Hofmann, T.Iida
  • Journal Title: Lipids Volume: 49 Pages: 1169-1180
  • Peer Reviewed
• [Journal Article] N-methyltaurine N-acyl amidated bile acids and deoxycholic acid in the bile of angelfish (Pomacanthidae): a novel bile acid profile in Perciform fish (2014)
  • Author(s): Okihara, R.S.Ｎ., Saito, T., Ogata, H., Ohsaki, A., Iida, T., Asahina, K., Mitamura, K., Ikegawa, S., Hofmann, A.E., Hagey, L.R.
  • Journal Title: Steroids Volume: 80 Pages: 15-23
  • DOI: 10.1016/j.steroids.2013.11.014
  • Peer Reviewed / Open Access
• [Journal Article] Tandem Mass Spectrometric Characterization of Bile Acid and Steroid Conjugates Based on Low-Energy Collision-Induced Dissociation. (2014)
  • Author(s): M.Maekawa, M.Shimada, T.Iida, J.Goto, N.Mano
  • Journal Title: Steroids Volume: 80 Pages: 80-91
  • DOI: 10.1016/j.steroids.2013.11.016
  • Peer Reviewed
• [Journal Article] Stereoselective Synthesis and NMR Characterization of C-24 Epimeric Pairs of 24-Alkyl Oxysterols (2013)
  • Author(s): S.Ogawa, H.Kawamoto, T.mitsuma, H.Fujimori, T.higashi, T.Iida
  • Journal Title: Lipids Volume: 48 Issue: 2 Pages: 197-207
  • DOI: 10.1007/s11745-012-3739-1
  • Peer Reviewed
• [Journal Article] LC/ESI-MS/MS Analysis of Urinary 3β-Sulfo-7β-N-acetylglucosaminyl-5-cholen-24-oic acid and its Amidates: New Biomarkers for the Detection of Niemann-Pick Type C Disease. (2013)
  • Author(s): M.Maekawa, Y.Misawa, A.Sotoura, H.Yamaguchi, M.Togawa, K.Ohno, H.Nittono, G.Kakiyama, T.Iida, A.F.Hofmann, J.Goto, M.Shimada, N.Mano
  • Journal Title: Steroids Volume: 78 Issue: 10 Pages: 967-972
  • DOI: 10.1016/j.steroids.2013.05.017
  • Peer Reviewed
• [Journal Article] An Efficient Synthesis of 4β-Hydroxy-7-dehydrocholesterol, Biomarkers for Patients with and Animal Models of the Smith-Lemli-Opitz Syndrome. (2013)
  • Author(s): H.Kawamoto, Y.Ohmori, M.Maekawa, M.Shimada, N.Mano, T.Iida
  • Journal Title: Chemistry and Physics of Lipids Volume: 73-78 Pages: 175-176
  • DOI: 10.1016/j.chemphyslip.2013.07.004
  • Peer Reviewed
• [Journal Article] Synthesis of 3-Sulfates of S-Acyl Glutathione Conjugated Bile Acids and their Biotransformation by a Rat Liver Cytosolic Fraction. (2012)
  • Author(s): K.Mitamura, N.Hori, S.Mino, T.Iida, A.F.Hofmann, S.Ikegawa
  • Journal Title: Chem. Phys. Lipids Volume: 165 Pages: 261-269
  • Peer Reviewed
• [Journal Article] Detection of Δ4-3-Oxo-steroid 5β-Reductase Deficiency by LC-ESI-MS/MS Measurement of Urinary Bile Acids. (2012)
  • Author(s): A.Muto, H.Takei, A.Unnno, T.Murai, T.Kurosawa, S.Ogawa, T.Iida, S.Ikegawa, J.Mori, A.Ohtake, T.Hoshitra, T.Muzuochi, A.,KImura, A.F.Hofmann, L.R.Hagey, H.Nittono
  • Journal Title: J. Chromagogr. B Volume: 900 Pages: 24-31
  • Peer Reviewed
• [Journal Article] Synthesis of Multiply Deuterated 3- and 21-Monmosulfates of Allo-Tetrahydrocorticosteroids as Internal Standards for Mass Spectrometry (2012)
  • Author(s): K.Mitamura, T.Mabuchi, K.Nagae, M.Nakajima, R.Matsumoto, S.Fujioka, K.Sato, R.Sato, T.Iida, S.Ogawa, A.F.Hofmann, S.Ikegawa
  • Journal Title: Steroids Volume: 77 Pages: 1423-1437
  • Peer Reviewed
• [Journal Article] A Novel Varanic Acid Epimer-(24R,25S)-3α,7α,12α,24-Tetrahydroxy-5β-cholestan-27-oic Acid-is a Major Biliary Bile Acid in Two Varanid Lizards and the Gila Monster (2012)
  • Author(s): L.R.Hagey, S.Ogawa, N.Kato, R.Satoh, M.Une, K.Mitamura, S.Ikegawa, A.F.Hofmann, T.Iida
  • Journal Title: Steroids Volume: 77 Pages: 1510-1521
  • Peer Reviewed
• [Journal Article] Stereoselective Synthesis and NMR Characterization of C-24 Epimeric Pairs of 24-Alkyl Oxysterols (2012)
  • Author(s): S.Ogawa, H.Kawamoto, T.Mitsuma, H.Fujimori, T.Higashi, T.Iida
  • Journal Title: Lipids Volume: 48 Pages: 197-207
  • Peer Reviewed
• [Presentation] Novel 2β-Hydroxylated bile acids from the gallbladder bile of arapaima (Arapaima gigas) (2014)
  • Author(s): Takashi Iida, et al.
  • Organizer: XXIII International Bile Acid Meeting (Falk Symposium 194)
  • Place of Presentation: Freiburg, Germany
  • Year and Date: 2014-10-08 – 2014-10-09
• [Presentation] Chemical synthesis of 11α-hydroxy-derivatives of lithocholic acid chenodeoxycholic acid as potential new natural bile acids (2014)
  • Author(s): Kaoru Omura, et al.
  • Organizer: XXIII International Bile Acid Meeting (Falk Symposium 194)
  • Place of Presentation: Freiburg, Germany
  • Year and Date: 2014-10-08 – 2014-10-09
• [Presentation] Efficient synthesis and anti-inflammatory properties of benzothiazole derivatives of bile acids (2014)
  • Author(s): Naoya Nakane, et al.
  • Organizer: XXIII International Bile Acid Meeting (Falk Symposium 194)
  • Place of Presentation: Freiburg, Germany
  • Year and Date: 2014-10-08 – 2014-10-09
• [Presentation] Solvent-free synthesis of bile acid derivatives having a thiazole group in the side-chain by the combined use of activated carbon/silica and microwave (2014)
  • Author(s): Ryou Sakiyama, et al.
  • Organizer: The 134th Annual Meeting of the Pharmaceutical Society of Japan
  • Place of Presentation: Kumamoto City General Gymnasium (Japan)
• [Presentation] Isolation and structural determination of a novel bile acid taurine conjugate from the bile of Pirarucu(Arapaima gigas) (2014)
  • Author(s): Tetsuya Saito, et al.
  • Organizer: The 134th Annual Meeting of the Pharmaceutical Society of Japan
  • Place of Presentation: Kumamoto City General Gymnasium (Japan)
• [Presentation] Chemical Synthesis of 7α,12α-Dihydroxy-cholest-4-en-3-one and its 12-Deoxy Analogue : Key Intermediates In the Biosynthesis of Bile Acids from Cholesterol (2012)
  • Author(s): Kaoru Omura
  • Organizer: Falk Symposium 184 XXII International Bile Acid Meeting
  • Place of Presentation: Wien (Austria)
• [Presentation] A novel, major epimaer of varanic acid from the bile of monitor lizards: Taurine-conjugated (24R,25S)-3α,7α,12α,24-tetrahydroxy-5β-cholestan-27-oic acid (2012)
  • Author(s): Narimi Kato
  • Organizer: Falk Symposium 184 XXII International Bile Acid Meeting
  • Place of Presentation: Wien (Austria)