The role of nardilysin in body temperature homeostasis

• Project/Area Number: 20200068
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research a proposed research project)
• Allocation Type: Single-year Grants
• Research Field: Environmental physiology (including Physical medicine and Nutritional physiology); Functional biochemistry
• Research Institution: Kyoto University
• Principal Investigator: HIRAOKA Yoshinori Kyoto University, 医学研究科, 助教 (60397552)
• Co-Investigator(Renkei-kenkyūsha): NISHI Eiichiro 京都大学, 医学研究科, 准教授 (30362528)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥33,800,000 (Direct Cost: ¥26,000,000、Indirect Cost: ¥7,800,000); Fiscal Year 2010: ¥11,050,000 (Direct Cost: ¥8,500,000、Indirect Cost: ¥2,550,000); Fiscal Year 2009: ¥11,050,000 (Direct Cost: ¥8,500,000、Indirect Cost: ¥2,550,000); Fiscal Year 2008: ¥11,700,000 (Direct Cost: ¥9,000,000、Indirect Cost: ¥2,700,000)
• Keywords: 体温恒常性 / 適応熱産生 / 褐色脂肪組織 / メタロプロテアーゼ

Research Abstract

Nardilysin (N-arginine dibasic convertase ; NRDc) is a metalloendopeptidase of M16 family. We have generated NRDc knockout mice (NRDc-/-) by gene targeting. NRDc-/- mice showed cold-intolerance when exposed to cold temperature (4℃). Brown adipose tissue (BAT) is specialized for adaptive thermogenesis in response to cold exposure, which occurs through the activity of uncoupling protein 1 (UCP1). UCP1, a mitochondrial inner-membrane protein, uncouples the mitochondrial proton gradient from ATP production, which results in heat generation. We have evaluated the expression of thermogenic genes including UCP1 in BAT of wild-type (NRDc+/+) and NRDc-/- mice. Quantitative RT-PCR (qRT-PCR) analysis revealed that UCP1 mRNA expression level of NRDc-/- BAT did not change after cold exposure, while that of NRDc+/+ BAT was markedly increased. We have also evaluated changes in tail blood flow after cold exposure by using laser doppler flowmetry. While tail blood flow of NRDc+/+ mice was dramatically reduced after cold exposure, that of NRDc-/- mice was not affected. These results indicate that NRDc-/- mice could not keep their body temperature after cold exposure because of (i) impaired adaptive thermogenesis and (ii) impaired vasoconstriction.

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
• [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
• [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
• [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
• [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
• [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
• [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] Ectodomain shedding of TNF-alpha is enhanced by nardilysin via activation of ADAM proteases.Biochem. (2008)
  • Author(s): Hiraoka Y, Yoshida K, Ohno M, Matsuoka T, Kita T, Nishi E.
  • Journal Title: Biophs.Res.Commun. 370 Pages: 154-158
• [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
• [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
• [Presentation] Nardilysin regulates axonal maturation and myelination through modulating ectodomain shedding of neuregulin1、シンポジウム『Ectodomain shedding biology-細胞膜蛋白質の機能変換機構-』 (2010)
  • Author(s): 西英一郎
  • Organizer: 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: 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 74rd 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 74rd Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Kyoto
• [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, 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 (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] 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] 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 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] Critical roles of nardilysin in energy balance and thermoregulation. (2009)
  • Author(s): Hiraoka Y, Matsuoka T, Ohno M, Kita T, Kimura T, Nishi E.
  • Organizer: ポスター発表第32回日本分子生物学会年回
  • Place of Presentation: 横浜
• [Presentation] Nardilysin regulates axonal maturation and myelination in the CNS and PNS. (2009)
  • Author(s): Ohno M, Hiraoka Y, Matsuoka T, Kimura T, Kita T, Nishi E.
  • Organizer: ポスター発表第32回日本分子生物学会年回
  • Place of Presentation: 横浜
• [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: ポスター発表第32回日本分子生物学会年回
  • Place of Presentation: 横浜
• [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: Poster presentation, 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. (2009)
  • Author(s): Nishi E.
  • Organizer: Gordon Research Conference(Matrix Metalloproteinases) 招待講演
  • Place of Presentation: Les Diablerets, Switzerland
• [Presentation] Nardilysin Regulates Axonal Maturation and Myelination in the Central and Peripheral Nervous System. (2009)
  • Author(s): Ohno M, Matsuoka T, Hiraoka Y, Kita T, Nishi E.
  • Organizer: Poster presentation, Gordon Research Conference(Matrix Metalloproteinases)
  • Place of Presentation: Les Diablerets, Switzerland
• [Presentation] A metalloendopeptidase nardilysin is a critical regulator for lipid and glucose metabolism, ポスター (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, 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] Critical roles of nardilysin in energy balance and thermoregulation. (2009)
  • Author(s): Hiraoka Y, Matsuoka T, Ohno M, Kita T, Kimura T, Nishi E
  • Organizer: The 32nd Annual Meeting of the Molecular Biology Society of Japan
  • Place of Presentation: Yokohama
• [Presentation] Nardilysin regulates axonal maturation and myelination in the US and PNS. (2009)
  • Author(s): Ohno M, Hiraoka Y, Matsuoka T, Kimura T, Kita T, Nishi E
  • Organizer: The 32nd Annual Meeting of the Molecular Biology Society of Japan
  • Place of Presentation: Yokohama
• [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] Nardilysin, a metalloendopeptidase, is a novel regulator of blood pressure and heart rate. (2009)
  • Author(s): Ohno M, Matsuoka T, Hiraoka Y, Kita T, Nishi E
  • Organizer: The 73rd Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Osaka
• [Presentation] Nardilysin deficiency causes lean phenotype with hypotriglyceridemia and hypoinsulinemia. (2009)
  • Author(s): Matsuoka T, Ohno M, Hiraoka Y, Kita T, Nishi E
  • Organizer: The 73rd Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Osaka
• [Presentation] A metalloendopeptidase nardilysin is an essential regulaor for inflammatory response. (2008)
  • Author(s): Hiraoka Y, Ohno M, Matsuoka T, Kita T, Nishi E.
  • Organizer: The 8th Awaji International Forum on Infection and Immunity
  • Place of Presentation: Hyogo
• [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: シンポジウム『膜結合性プロテアーゼとその制御』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 growth and energy metabolism, ミニシンポジウム「膜近傍におけるプロテオリシス」:Mini-symposium "Proteolysis in the Perimembrane Region" (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] 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 ミニシンポジウム「膜近傍におけるプロテオリシス」
  • Place of Presentation: 横浜
• [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 25(9) (2010)
  • Author(s): 西英一郎
  • Publisher: BIO Clinica
• [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 82(10) (2010)
  • Author(s): 西英一郎
  • Publisher: 生化学
• [Remarks] ホームページ等
  • URL: http://kyoto-u-cardio.jp/kisokenkyu/sentan-bunshi/
• [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