Identification of NRDc, a novel key molecule for energy metabolism. Pathophysiological role of NRDc in Metabolic Syndrome

• Project/Area Number: 20390255
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kyoto University
• Principal Investigator: NISHI Eiichiro Kyoto University, 医学研究科, 准教授 (30362528)
• Co-Investigator(Kenkyū-buntansha): 堀内 久徳 京都大学, 医学研究科, 講師 (90291426)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000); Fiscal Year 2010: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2009: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2008: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: エネルギー代謝 / メタボリックシンドローム / メタロプロテアーゼ / 動脈硬化

Research Abstract

NRDc, a metalloendopeptidase of the M16 family, is a potent activator for ectodomain shedding of multiple membrane proteins. Homozygous mutant of NRDc-deficient mice (NRDc-/-) showed lean phenotype. Metabolic phenotypes of NRDc-/-are opposite to those in metabolic syndrome, suggesting that NRDc could be a novel therapeutic target for metabolic syndrome. Analysis of NRDc-/- adipose tissue and liver demonstrated that NRDc critically controls glucose and lipid homeostasis through the regulation of TNF-alpha shedding and the modulation of transcriptional co-activator, PGC-1alpha function.

Research Products

• [Journal Article] Continuous cell supply from the Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. (2011)
  • Author(s): Furuyama K, Kawaguchi Y, Akiyama H, Horiguchi M, Kodama S, Kuhara T, Hosokawa, S Elbahrawy A, Soeda T, Koizumi M, Masui T, Kawaguchi M, Takaori K, Doi R, Nishi E, Kakinoki R, Deng JM, Behringer RR, Nakamura T, Uemoto S.
  • Journal Title: Nat.Genet 43 Pages: 34-41
  • Peer Reviewed
• [Journal Article] Angulin/LSR defines cell corners for tricellular tight junction formation in epithelial cells. (2011)
  • Author(s): Masuda S, Oda Y, Sasaki H, Ikenouchi J, Higashi T, Akashi M, Nishi E, Furuse M.
  • Journal Title: J.Cell. Sci. 15 Pages: 548-555
  • Peer Reviewed
• [Journal Article] Angulin/LSR defines cell corners for tricellular tight junction formation in epithelial cells (2011)
  • Author(s): Masuda S, Oda Y, Sasaki H, Ikenouchi J, Higashi T, Akashi M, Nishi E, Furuse M.
  • Journal Title: J.Cell.Sci. Volume: 15 Pages: 548-555
  • Peer Reviewed
• [Journal Article] Continuous cell supply from the Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine (2011)
  • Author(s): Furuyama K, Kawaguchi Y, Akiyama H, Horiguchi M, Kodama S, Kuhara T, Hosokawa, S Elbahrawy A, Soeda T, Koizumi M, Masui T, Kawaguchi M, Takaori K, Doi R, Nishi E, Kakinoki R, Deng JM, Behringer RR, Nakamura T, Uemoto S
  • Journal Title: Nat.Genet. Volume: 43 Pages: 34-41
  • Peer Reviewed
• [Journal Article] Acute doxorubicin cardiotoxicity is associated with miR-146a-induced inhibition of the neuregulin-ErbB pathway. (2010)
  • Author(s): Horie T, Ono K, Nishi H, Nagao K, Kinoshita M, Watanabe S, Kuwabara Y, Nakashima Y, Takanabe-Mori R, Nishi E, Hasegawa K, Kita T, Kimura T.
  • Journal Title: Cardiovasc Res. 87 Pages: 656-664
  • Peer Reviewed
• [Journal Article] Acute doxorubicin cardiotoxicity is associated with milt-146a-induced inhibition of the neuregulin-ErbB pathway (2010)
  • Author(s): Horie T, Ono K, Nishi H, Nagao K, Kinoshita M, Watanabe S, Kuwabara Y, Nakashima Y, Takanabe-Mori R, Nishi E, Hasegawa K, Kita T, Kimura T.
  • Journal Title: Cardiovasc Res. Volume: 87 Pages: 656-664
  • Peer Reviewed
• [Journal Article] Nardilysin Regulates Axonal Maturation and Myelination in the Central and Peripheral Nervous System. (2009)
  • Author(s): Ohno M, Hiraoka Y, Matsuoka T, Tomimoto H, Takao K, Miyakawa T, Oshima N, Kiyonari H, Kimura T, Kita T, Nishi E.
  • Journal Title: Nat.Neurosci. 12 Pages: 1506-1513
  • Peer Reviewed
• [Journal Article] Clopidogrel Resistance in Japanese Patients Scheduled for Percutaneous Coronary Intervention. (2009)
  • Author(s): Hoshino K, Horiuchi H, Tada T, Tazaki J, Nishi E, Kawato M, Ikeda T, Yamamoto H, Akao M, Furukawa Y, Shizuta S, Toma M, Tamura T, Saito N, Doi T, Ozasa N, Jinnai T, Takahashi K, Watanabe H, Yoshikawa Y, Nishimoto N, Ouchi C, Morimoto T, Kita T, Kimura T.
  • Journal Title: Circ J. 73 Pages: 336-342
  • NAID: 110007042175
  • Peer Reviewed
• [Journal Article] Interleukin 18 stimulates release of soluble lectin-like oxidized LDL receptor-1 (sLOX-1). (2009)
  • Author(s): Mitsuoka H, Kume N, Hayashida K, Inui-Hayashiada A, Aramaki Y, Toyohara M, Jinnai T, Nishi E, Kita T.
  • Journal Title: Atherosclerosis. 202 Pages: 176-182
  • Peer Reviewed
• [Journal Article] Nardilysin Regulates Axonal Maturation and Myelination in the Central and Peripheral Nervous System (2009)
  • Author(s): Ohno M, Hiraoka Y, Matsuoka T, Tomimoto H, Takao K, Miyakawa T, Oshima N, Kiyonari H, Kimura T, Kita T, Nishi E
  • Journal Title: Nat.Neurosci. 12 Pages: 1506-1513
  • Peer Reviewed
• [Journal Article] Interleukin 18 stimulates release of soluble lectin-like oxidized LDL receptor-1 (sLOX-1) (2009)
  • Author(s): Mitsuoka H, Kume N, Hayashida K, Inui-Hayashiada A, Aramaki Y, Toyohara M, Jinnai T, Nishi E, Kita T.
  • Journal Title: Atherosclerosis 202 Pages: 176-182
  • Peer Reviewed
• [Journal Article] Clopidogrel resistance in Japanese patients scheduled for percutaneous coronary intervention (2009)
  • Author(s): Hoshino K, Horiuchi H, Tada T, Tazaki J, Nishi E, Kawato M, Ikeda T, Yamamoto H, Akao M, Furukawa Y, Shizuta S, Toma M, Tamura T, Saito N, Doi T, Ozasa N, Jinnai T, Takahashi K, Watanabe H, Yoshikawa Y, Nishimoto N, Ouchi C, Morimoto T, Kita T, Kimura T.
  • Journal Title: Circ J 73 Pages: 336-342
  • NAID: 110007042175
  • Peer Reviewed
• [Journal Article] Ectodomain shedding of TNF-alpha is enhanced by nardilysin via activation of ADAM proteases. (2008)
  • Author(s): Hiraoka Y, Yoshida K, Ohno M, Matsuoka T, Kita T, Nishi E.
  • Journal Title: Biochem. Biophs. Res.Commun. 370 Pages: 154-158
  • Peer Reviewed
• [Journal Article] Identification of adherens junction-associated GTPase activating proteins by the fluorescence localization-based expression cloning. (2008)
  • Author(s): Matsuda M, Kobayashi Y, Masuda S, Adachi M, Watanabe T, Yamashita JK, Nishi E, Tsukita S, Furuse M.
  • Journal Title: Exp Cell Res. 314 Pages: 939-949
  • NAID: 120001384679
  • Peer Reviewed
• [Journal Article] Identification of adherens junction-associated GTPase activating proteins by the fluorescence localization-based expression cloning. (2008)
  • Author(s): Matsuda M, Kobayashi Y, Masuda S, Adachi M, Watanabe T, Yamashita JK, Nishi E, Tsiukita S, Furuse M.
  • Journal Title: Exp Cell Res. 314 Pages: 939-949
  • NAID: 120001384679
  • Peer Reviewed
• [Journal Article] Ectodomain shedding of TNF-alpha is enhancecd by nardilysin via activation of ADAM proteases. (2008)
  • Author(s): Hiraoka Y, Yoshida K, Ohno M, Matsuoka T, Kita T, Nishi E
  • Journal Title: Biochem. Biophs. Res. Commun. 370 Pages: 154-158
  • Peer Reviewed
• [Journal Article] Biochemical characterization of the Rho GTPase-regulated actin assembly by diaphanous-related fomins, mDial and Daaml, in platelets. (2008)
  • Author(s): T. Higashi, T. Ikeda, R. Shirakawa, H. Kondo, M. Kawato, M. Horiguchi, T. Okuda, K. Okawa, S. Fukai, O. Niireki, T. Kita, H. Horiuchi*
  • Journal Title: J Biol Chem. 283 Pages: 8746-8755
  • Peer Reviewed
• [Journal Article] GTP-induced dense-granule secretion, in platelets is mediated by Ral GTPase-exocyst pathway. (2008)
  • Author(s): M. Kawato, R. Shirakawa, H. Kondo, T. Higashi, T. Ikeda, S. Fukai, O. Nuieki, T. Kita, H. Horiuchi*
  • Journal Title: J Biol Cheni. 283 Pages: 166-174
  • Peer Reviewed
• [Presentation] Nardilysin regulates axonal maturation and myelination through modulating ectodomain shedding of neuregulinl (2010)
  • Author(s): 西英一郎
  • Organizer: シンポジウム『Ectodomainshedding biology-細胞膜蛋白質の機能変換機構-』BMB2010
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-09
• [Presentation] The role of a metalloendopeptidase nardilysin in adaptive thermogenesis. (2010)
  • Author(s): Hiraoka Y, Matsuoka T, Ohno M, Kita T, Kimura T, Nishi E
  • Organizer: ポスター発表BMB2010
  • Place of Presentation: 神戸
• [Presentation] NRDc controls lipid and glucose metabolism through the modulation of PPARalpha activity. (2010)
  • Author(s): Matsuoka T, Hiraoka Y, Ohno M, Ohshima N, Kiyonari H, Kimura T, Kita T, Nishi E
  • Organizer: ポスター発表、BMB2010
  • Place of Presentation: 神戸
• [Presentation] シェディング活性化因子ナルディラジンの多発生硬化症における意義の解明 (2010)
  • Author(s): Ohno M, Hiraoka Y, Matsuoka T, Nishi K, Kimura T, Kita T, Nishi E
  • Organizer: ポスター発表BMB2010
  • Place of Presentation: 神戸
• [Presentation] A Metalloendopeptidase Nardilysin controls Lipid and Glucose metabolism through the modulation of Peroxisome Proliferator-activated Receptor alpha activity. (2010)
  • Author(s): Matsuoka T, Hiraoka Y, Ohno, M, Nishi, K, Kimura, T, Kita T, Nishi E
  • Organizer: American Heart Association Sessions
  • Place of Presentation: Chicago, Illinois
• [Presentation] ナルディライジンによるIL-6/Stat3シグナルを介した胃癌細胞の増殖制御 (2010)
  • Author(s): 神田啓太郎、米門秀行、妹尾浩、千葉勉、西英一郎
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪
• [Presentation] A metalloendopeptidase nardilysin is an essential regulator for glucose and lipid metabolism (2010)
  • Author(s): 松岡龍彦、平岡義範、大野美紀子、大島尚子、清成寛、木村剛、北徹、西英一郎
  • Organizer: 第47回日本臨床分子生物学会
  • Place of Presentation: 東京
• [Presentation] Nardilysin regulates axonal maturation and myelination in the central and peripheral nervous system (2010)
  • Author(s): 大野美紀子、平岡義範、松岡龍彦、木村剛、北徹、西英一郎
  • Organizer: 第47回日本臨床分子生物学会
  • Place of Presentation: 東京
• [Presentation] A Metalloendopeptidase Nardilysin is a Regulator of Blood Pressure and Heart Rate, Oral Presentation (2010)
  • Author(s): Ohno, M, Matsuoka T, HIraoka Y, Niizuma, S, Shioi, T, Kita T, Kimura, T, Nishi E
  • Organizer: The 74^<rd> Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Kyoto
• [Presentation] Nardilysin, a Novel Transcriptional Co-regulator of PPARalpha, Controls Glucose and Lipid Metabolism, Poster Presentation (2010)
  • Author(s): Matsuoka T, Ohno, M, HIraoka Y, Kita T, Kimura, T, Nishi E
  • Organizer: The 74^<rd> Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Kyoto
• [Presentation] A metalloendopeptidase nardilysin is an essential regulator for glucose and lipid metabolism (2010)
  • Author(s): 松岡龍彦、平岡義範、大野美紀子、大島尚子、清成寛、木村剛、北徹、西英一郎
  • Organizer: 第47回 日本臨床分子生物学会
  • Place of Presentation: 東京
• [Presentation] Nardilysin regulates axonal maturation and myelination in the central and peripheral nervous system (2010)
  • Author(s): 大野美紀子、平岡義範、松岡龍彦、木村剛、北徹、西英一郎
  • Organizer: 第47回 日本臨床分子生物学会
  • Place of Presentation: 東京
• [Presentation] Nardilysin regulates axonal maturation and myelination through modulating ectodomain shedding of neuregulin1 (2010)
  • Author(s): 西英一郎
  • Organizer: BMB2010
  • Place of Presentation: 神戸
• [Presentation] The role of a metalloendopeptidase nardilysin in adaptive thermogenesis (2010)
  • Author(s): Hiraoka Y, Matsuoka T, Ohno M, Kita T, Kimura T, Nishi E.
  • Organizer: BMB2010
  • Place of Presentation: 神戸
• [Presentation] NRDc controls lipid and glucose metabolism through the modulation of PPARalpha activity (2010)
  • Author(s): Matsuoka T, Hiraoka Y, Ohno M, Ohshima N, Kiyonari H, Kimura T, Kita T, Nishi E
  • Organizer: BMB2010
  • Place of Presentation: 神戸
• [Presentation] シェディング活性化因子ナルディライジンの多発性硬化症における意義の解明 (2010)
  • Author(s): Ohno M, Hiraoka Y, Matsuoka T, Nishi K, Kimura T, Kita T, Nishi E
  • Organizer: BMB2010
  • Place of Presentation: 神戸
• [Presentation] A Metalloendopeptidase Nardilysin controls Lipid and Glucose metabolism through the modulation of Peroxisome Proliferator-activated Receptor alpha activity (2010)
  • Author(s): Matsuoka, T, Hiraoka, Y, Ohno, M, Nishi, K, Kimura, T, Kita, T, Nishi, E
  • Organizer: American Heart Association Sessions 2010
  • Place of Presentation: Chicago, IL, USA
• [Presentation] A metalloendopeptidase nardilysin is a regulator of blood pressure and heart rate (2010)
  • Author(s): Ohno M, Matsuoka T, Hiraoka Y, Niizuma S, Shioi T, Kita T, Kimura T, Nish, E
  • Organizer: The 74th Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Kyoto
• [Presentation] Nardilysin, a novel transcriptional co-regulator of PPARalpha, controls glucose and lipid metabolism (2010)
  • Author(s): Hiraoka Y, Matsuoka T, Ohno M, Kita T, Kimura T, Nishi E
  • Organizer: The 74th Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Kyoto
• [Presentation] A metalloendopeptidase nardilysin is an essential regulator for glucose and lipid metabolism. Poster presentation (2009)
  • Author(s): Matsuoka T, Ohno, M, HIraoka Y, Kita T, Kimura, T, Nishi E
  • Organizer: The 82th Scientific Sessions of American Heart Association
  • Place of Presentation: Orland, Florida
• [Presentation] Nardilysin Regulates Axonal Maturation and Myelination in the Central Nervous System. Gordon Research Conference (2009)
  • Author(s): 西英一郎
  • Organizer: Matrix Metalloproteinases
  • Place of Presentation: Les Diablerets, Switzerland
• [Presentation] Nardilysin Regulates Axonal Maturation and Myelination in the Central and Peripheral Nervous System. Poster presentation, Gordon Research Conference (2009)
  • Author(s): Ohno, M, Matsuoka T, HIraoka Y, Kita T, Nishi E
  • Organizer: Matrix Metalloproteinases
  • Place of Presentation: Les Diablerets, Switzerland
• [Presentation] A metalloendopeptidase nardilysin is a critical regulator for 1ipid and glucose metabolism (2009)
  • Author(s): 西英一郎
  • Organizer: ボスター、第41回日本動脈硬化学会・学術集会
  • Place of Presentation: 下関
• [Presentation] Nardilysin, a Metalloendopeptidase, is a Novel Regulator of Blood Pressure and Heart Rate, Featured Research Session (2009)
  • Author(s): Ohno, M, Matsuoka T, HIraoka Y, Kita T, Nishi E
  • Organizer: The 73^<rd> Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Osaka
• [Presentation] Nardilysin Deficiency Causes Lean Phenotype with Hypotriglyceridemia and Hypoinsulinemia, Oral Presentation (2009)
  • Author(s): Matsuoka T, Ohno, M, HIraoka Y, Kita T, Nishi E
  • Organizer: The 73^<rd> Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Osaka
• [Presentation] Clopidogrel Resistance inJapanese Patients Scheduled for Percutaneous Coronary Intervention, Poster Session (2009)
  • Author(s): Tada, T, Horiuchi, H, Nagai, K, Tazaki, J, Nishi E, Touma, M, Tamura, T, Akao, M, Furukawa, Y, Kimura, T, Kita T
  • Organizer: The 73^<rd> Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Osaka
• [Presentation] A metalloendopeptidase nardilysin is a critical regulator for lipid and glucose metabolism (2009)
  • Author(s): 西英一郎
  • Organizer: 第41回 日本動脈硬化学会・学術集会
  • Place of Presentation: 下関
• [Presentation] Nardilysin regulates axonal maturation and myelination in the central nervous system (2009)
  • Author(s): 西英一郎
  • Organizer: Gordon Research Conference (Matrix Metalloproteinases)
  • Place of Presentation: Les Diablerets, Switzerland
• [Presentation] A metalloendopeptidase nardilysin is an essential regulator for glucose and lipid metabolism (2009)
  • Author(s): Matsuoka T, Ohno M, Hiraoka Y, Kita T, Kimura T, Nishi E
  • Organizer: The 32nd Annual Meeting of the Molecular Biology Society of Japan
  • Place of Presentation: Yokohama
• [Presentation] 細胞外ドメインシェディングの制御におけるナルディライジンの役割、シンポジウム『膜結合性プロテアーゼとその制御』 (2008)
  • Author(s): 西英一郎
  • Organizer: 第13回病態と治療におけるプロテアーゼとインヒビター学会
  • Place of Presentation: 大阪
• [Presentation] A metalloendopeptidase nardilysin, activator for ectodomain shedding, is an essential regulator forgrowthandenergymetabolism (2008)
  • Author(s): Hiraoka Y, Ohno, M, Matsuoka T, Kita T, Nishi E
  • Organizer: ミニシンポジウム「膜近傍におけるプロテオリシス」:Mini-symposium "ProteolysisinthePerimembrane Region"第60回日本細胞生物学会
  • Place of Presentation: 横浜
• [Presentation] 細胞外ドメインシェディングの制御におけるナルディライジンの役割 (2008)
  • Author(s): 西英一郎
  • Organizer: 第13回病態と治療におけるプロテアーゼとインヒビター学会
  • Place of Presentation: 大阪
• [Presentation] A metalloendopeptidase nardilysin, activator for ectodomain shedding, is an essential regulator for (2008)
  • Author(s): HIraoka, Y, Ohno, M, Matsuoka T, Kita, T, Nishi, E
  • Organizer: 第60回日本細胞生物学会
  • Place of Presentation: 横浜
• [Presentation] RalGAPの同定 (2008)
  • Author(s): 堀内久徳, 白川龍太郎, 深井周也, 北徹
  • Organizer: 第31回日本分子生物学会・第81回日本生化学会合同大会
  • Place of Presentation: 神戸市
• [Presentation] Molecular dissection of platelet dense granule secretion (2008)
  • Author(s): 堀内久徳
  • Organizer: 第3回UK-Japan Platelet Conference
  • Place of Presentation: シンガポール
• [Book] 神経軸索と髄鞘形成におけるシェディング活性化因子ナルディライジンの役割 (2010)
  • Author(s): 西英一郎
  • Publisher: BIO Clinica25(9)
• [Book] ナルディライジンによる細胞外ドメインシェディング制御機構と、その神経軸索・髄鞘形成における役割(特集:細胞外プロテオリシス研究の最前線、生化学) (2010)
  • Author(s): 西英一郎
• [Remarks]
  • URL: http://kyoto-u-cardio.jp/kisokenkyu/sentan-bunshi/
• [Remarks]
  • URL: http://kyoto-u-cardio.jp/kisokenkyu/sentan-bunshi/
• [Patent(Industrial Property Rights)] ナルディライジンの高感度免疫測定法 (2009)
  • Inventor(s): 西英一郎、平岡義範、松本恭一、國近誠
  • Industrial Property Rights Holder: 京都大学(50%)、三洋化成工業株式会社(50%)
  • Industrial Property Number: 2009-160792
  • Filing Date: 2009-07-07
• [Patent(Industrial Property Rights)] ナルディライジンの高感度免疫測定法 (2009)
  • Inventor(s): 西英一郎, 平岡義範, 他
  • Industrial Property Rights Holder: 京都大学, 他
  • Industrial Property Number: 2009-160792
  • Filing Date: 2009-07-07