成人GH分泌不全症をモデルとした非アルコール性脂肪性肝炎の病態解明と治療法の開発

2010 Fiscal Year Final Research Report

• Project/Area Number: 20390262
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Endocrinology
• Research Institution: Kobe University
• Principal Investigator: CHIHARA Kazuo Kobe University, 医学研究科, 客員教授 (00107955)
• Project Period (FY): 2008 – 2010
• Keywords: 内分泌学

Research Abstract

Adult growth hormone deficiency (AGHD) is characterized by visceral obesity, abnormal lipid profile, and liver dysfunction. In this study, we clarified that in AGHD, the prevalence of NAFLD/NASH was substantially increased. We also demonstrated that GH exerts its effect mainly via IGF-I and IGF-I ameliorates mitochondrial dysfunction, oxidative stress, and abnormal activation of stellate cells, which leads to fibrosis in the liver. These results indicate that GH and IGF-I play an important role in liver and are closely related with the pathogenesis of NASH.

Research Products

• [Journal Article] Reactive oxygen species play an essential role in IGF-I signaling and IGF-I-induced myocyte hypertrophy in C2C12 myocytes. (2011)
  • Author(s): Handayaningsih AE, Iguchi G, Fukuoka H, Nishizawa H, Takahashi M, Yamamoto M, Herningtyas EH, Okimura Y, Kaji H, Chihara K, Seino S, Takahashi Y
  • Journal Title: Endocrinology
• [Journal Article] Branched-chain amino acids protect against dexamethasone-induced soleus muscle atrophy in rats. (2010)
  • Author(s): Yamamoto D, Maki T, Herningtyas EH, Ikeshita N, Shibahara H, Sugiyama Y, Nakanishi S, Iida K, Iguchi G, Takahashi Y, Kaji H, Chihara K, Okimura Y
  • Journal Title: Muscle Nerve. 41(6) Pages: 819-827
• [Journal Article] Dose-dependent changes in body composition during growth hormone (GH) treatment in Japanese patients with adult GH deficiency : a randomized, placebo-controlled trial. (2010)
  • Author(s): Chihara K, Fujieda K, Shimatsu A, Miki T, Tachibana K
  • Journal Title: Growth Horm IGF Res 20(3) Pages: 205-211
• [Journal Article] IGF-I stimulates reactive oxygen species (ROS) production and inhibits insulin-dependent glucose uptake via ROS in 3T3-L1 adipocytes. (2010)
  • Author(s): Fukuoka H, Iida K, Nishizawa H, Imanaka M, Takeno R, Iguchi G, Takahashi M, Okimura Y, Kaji H, Chihara K, Takahashi Y
  • Journal Title: Growth Horm IGF Res 20(3) Pages: 212-219
• [Journal Article] W194XProp1 and S156insTProp1, both of which have intact DNA-binding domain, show a different DNA-binding activity to the Prop1-binding element in human Pit-1 gene. (2010)
  • Author(s): Shibahara H, Ikeshita N, Sugiyama Y, Toda K, Yamamoto D, Herningtyas EH, Maki T, Kubota E, Iguchi G, Iida K, Takahashi Y, Kaji H, Chihara K, Okimura Y
  • Journal Title: Mol Cell Endocrinol 323(2) Pages: 167-171
• [Journal Article] Glucose-responsive insulinoma in a patient with postprandial hypoglycemia in the morning. (2010)
  • Author(s): Iida K, Ohara T, Hino Y, Nobuhara M, Ishida J, Chihara K
  • Journal Title: Intern Med 49(19) Pages: 2123-2127
• [Journal Article] Adult combined GH, prolactin, and TSH deficiency associated with circulating PIT-1 antibody in humans. (2010)
  • Author(s): Yamamoto M, Iguchi G, Takeno R, Okimura Y, Sano T, Takahashi M, Nishizawa H, Handayaningshi AE, Fukuoka H, Tobita M, Saitoh T, Tojo K, Mokubo A, Morinobu A, Iida K, Kaji H, Seino S, Chihara K, Takahashi Y
  • Journal Title: J Clin Invest 121(1) Pages: 113-119
• [Journal Article] A case of myxedema coma caused by isolated thyrotropin stimulating hormone deficiency and Hashimoto's thyroiditis. (2010)
  • Author(s): Iida K, Hino Y, Ohara T, Chihara K
  • Journal Title: Endocr J
• [Journal Article] 成長ホルモン分泌不全性低身長症における遺伝子組換え成長ホルモンの短期的および長期的治療効果-KIGSデータベースの解析- (2010)
  • Author(s): 田中敏章、藤枝憲二、清野佳紀、高野加壽江、千原和夫、入江實
  • Journal Title: 日本成長学会雑誌 16(2) Pages: P69-P75
• [Journal Article] 肝転移を伴った悪性インスリノーマの1例 (2010)
  • Author(s): 飯田啓二、高橋健太郎、千原和夫
  • Journal Title: 内科 106(1) Pages: 181-184
• [Journal Article] Difference between Japanese and Caucasian populations in the allelic frequency of growth hormone receptor polymorphisms. (2009)
  • Author(s): Iida K, Takahashi Y, Kaji H, Okimura Y, Nose O, Chihara K
  • Journal Title: J Pediatr Endocrinol Metab 22(1) Pages: 41-46
• [Journal Article] HypoCCS International Advisory Board (Chihara K). Changing patterns of the adult growth hormone deficiency diagnosis documented in a decade-long global surveillance database. (2009)
  • Author(s): Webb SM, Strasburger CJ, Mo D, Hartman ML, Melmed S, Jung H, Blum WF, Attanasio AF
  • Journal Title: J Clin Endocrinol Metab 94(2) Pages: 392-399
• [Journal Article] Very high doses of valsartan provide renoprotection independently of blood pressure in a type 2 diabetic nephropathy rat model. (2009)
  • Author(s): Tominaga N, Robert A, Izuhara Y, Ohtomo S, Dan T, Chihara K, Kurokawa K, Van Ypersele de Strihou C, Miyata T
  • Journal Title: Nephrology (Carlton) 14(6) Pages: 581-587
• [Journal Article] Role of Smad3, acting independently of transforming growth factor-beta, in the early induction of Wnt-beta-catenin signaling by parathyroid hormone in mouse osteoblastic cells. (2009)
  • Author(s): Inoue Y, Canaff L, Hendy GN, Hisa I, Sugimoto T, Chihara K, Kaji H
  • Journal Title: J Cell Biochem 108(1) Pages: 285-294
• [Journal Article] International HypoCCS Advisory Board (Chihara K) : Occurrence of impaired fasting glucose in GH-deficient adults receiving GH replacement compared with untreated subjects. (2009)
  • Author(s): Woodmansee WW, Hartman ML, Lamberts SW, Zagar AJ, Clemmons DR
  • Journal Title: Clin Endocrinol (Oxf) 72(1) Pages: 59-69
• [Journal Article] GHRP-2,a GHS-R agonist,directly acts on myocytes to attenuate the dexamethasone-induced expressions of muscle-specific ubiquitin ligases, Atrogin-1 and MuRF1. (2008)
  • Author(s): D Yamamoto, N Ikeshita, T Matsubara, H Tasaki, E Henny Herningtyas, K Toda, K Iida, Y Takahashi, H Kaji, K Chihara, Y Okimura
  • Journal Title: Life Sciences 82 Pages: 460-466
• [Journal Article] Low Serum IGF-I/GH Ratio Is Associated with Abnormal Glucose Tolerance in Acromegaly. (2008)
  • Author(s): H Fukuoka, Y Takahashi, K Iida, T Kudo, H Nishizawa, M Imanaka, R Takeno, G Iguchi, K Takahashi, Y Okimura, H Kaji, K Chihara
  • Journal Title: Hormone Research 69 Pages: 165-171
• [Journal Article] A novel growth hormone receptor gene deletion mutation in a patient with primary growth hormone insensitivity syndrome(Laron syndrome). (2008)
  • Author(s): H Yamamoto, H Kouhara, K Iida, K Chihara, S Kasayama
  • Journal Title: Growth Hormone & IGF Research 18 Pages: 136-142
• [Journal Article] Efficacy and safety of individualized growth hormone treatment in adult Japanese patients with growth hormone deficiency. (2008)
  • Author(s): K Chihara, Y Kato, A Shimatsu, T Tanaka, H Kohno
  • Journal Title: Growth Hormone & IGF Research 18 Pages: 394-403
• [Journal Article] Branched-chain amino acids and arginine suppress MaFbx/atrogin-1 mRNA expression via mTOR pathway in C2C12 cell line. (2008)
  • Author(s): E Henny Herningtyas, Y Okimura, A Evi Handayaningsih, D Yamamoto, T Maki, K Iida, Y Takahashi, H Kaji, K Chihara
  • Journal Title: Biochimica et Biophysica Acta 1780 Pages: 1115-1120
• [Journal Article] Identification and Analysis of Prophet of Pit-1-Binding Sites in Human Pit-1 Gene. (2008)
  • Author(s): N Ikeshita, M Kawagishi, H Shibahara, K Toda, T Yamashita, D Yamamoto, Y Sugiyama, G Iguchi, K Iida, Y Takahashi, H Kaji, K Chihara, Y Okimura
  • Journal Title: Endocrinology 149(11) Pages: 5491-5499
• [Journal Article] Relationship between endogenous parathyroid hormone and bone metabolism/geometry in female patients treated with glucocorticoid. (2008)
  • Author(s): H.Kaji, M.Yamauchi, K.Chihara, T.Sugimoto
  • Journal Title: Horm Metab Res 40(1) Pages: 60-65
• [Journal Article] Vitamin D status affects osteopenia in postmenopausal patients with primary hyperparathyroidism. (2008)
  • Author(s): Y.Inoue, H.Kaji, I.Hisa, T.Tobimatsu, J.Naito, M.F.Iu, T.Sugimoto, K.Chihara
  • Journal Title: Endocr J 55(1) Pages: 57-65
• [Journal Article] Chemerin enhances insulin signaling and potentiates insulin-stimulated glucose uptake in 3T3-L1 adipocytes. (2008)
  • Author(s): M.Takahashi, Y.Takahashi, K.Takahashi, F.N.Zolotaryov, K.S.Hong, R.Kitazawa, K.Iida, Y.Okimura, H.Kaji, S.Kitazawa, M.Kasuga, K.Chihara
  • Journal Title: FEBS Lett 582(5) Pages: 573-578
• [Journal Article] Glucocorticoid excess affects cortical bone geometry in premenopausal, but not postmenopausal, women. (2008)
  • Author(s): H.Kaji, M.Yamauchi, K.Chihara, T.Sugimoto
  • Journal Title: Calcif Tissue Int 82(3) Pages: 182-190
• [Journal Article] Safety and efficacy of growth hormone (GH) during extended treatment of adult Japanese patients with GH deficiency (GHD). (2008)
  • Author(s): K.Chihara, Y.Kato, H.Kohno, K.Takano, T.Tanaka, A.Teramoto, A.Shimatsu
  • Journal Title: Growth Horm IGF Res 18(4) 2008 Pages: 307-317
• [Journal Article] Hepatic failure and enhanced oxidative stress in mitochondrial diabetes. (2008)
  • Author(s): Y.Takahashi, K.Iida, R.Takeno, R.Kitazawa, S.Kitazawa, H.Kitamura, Y.Fujioka, H.Yamada, F.Kanda, S.Ohta, K.Nishimaki, M.Fujimoto, T.Kondo, G.Iguchi, K.Takahashi, H.Kaji, Y.Okimura, K.Chihara
  • Journal Title: Endocr J 55(3) Pages: 509-514
• [Journal Article] Statin Suppresses Apoptosis in Osteoblastic Cells : Role of Transforming Growth Factor-beta-Smad3 Pathway. (2008)
  • Author(s): H.Kaji, J.Naito, Y.Inoue, H.Sowa, T.Sugimoto, K.Chihara
  • Journal Title: Horm Metab Res 40(11) Pages: 746-751
• [Journal Article] Growth hormone stimulates mechano growth factor expression and activates myoblast transformation in C2C12 cells. (2008)
  • Author(s): M.Imanaka, K.Iida, A.Murawaki, H.Nishizawa, H.Fukuoka, R.Takeno, Y.Takahashi, Y.Okimura, H.Kaji, K.Chihara
  • Journal Title: Kobe J Med Sci 54(1) Pages: E46-E54
• [Journal Article] Fasting plasma glucose levels are related to bone mineral density in postmenopausal women with primary hyperparathyroidism. (2008)
  • Author(s): I.Hisa, H.Kaji, Y.Inoue, T.Sugimoto, K.Chihara
  • Journal Title: Int J Clin Exp Med 1(4) Pages: 319-326
• [Journal Article] 内分泌学 (2008)
  • Author(s): 千原和夫、高橋裕、飯田啓二、梶博史、加治秀介
  • Journal Title: 日本医事新報 4371 Pages: 15-21
• [Journal Article] 間脳下垂体領域の難病の現状とその対策 (2008)
  • Author(s): 置村康彦, 千原和夫
  • Journal Title: ホルモンと臨床 56(1) Pages: 3-8
• [Journal Article] 日本における成人GH分泌不全症の現状 (2008)
  • Author(s): 千原和夫
  • Journal Title: 内分泌・糖尿病科 26(4) Pages: 311-316
• [Journal Article] 成長ホルモン分泌不全症 (2008)
  • Author(s): 千原和夫
  • Journal Title: 総合臨床(増刊号) 57 Pages: 405-408
• [Presentation] 先端巨大症に対するオクトレオチドとカベルゴリン併用療法の検討 (2011)
  • Author(s): 隅田健太郎、井口元三、山本雅昭、Anastasia Evi Handayaningsih、西沢衡、高橋路子、置村康彦、加治秀介、千原和夫、清野進、高橋裕
  • Organizer: 第20回臨床内分泌代謝Update
  • Place of Presentation: 札幌(札幌コンベンションセンター)
  • Year and Date: 20110128-20110129
• [Presentation] 食後低血糖を繰り返したブドウ糖反応性インスリノーマの一例 (2011)
  • Author(s): 飯田啓二、日野泰久、大原毅、千原和夫
  • Organizer: 第20回臨床内分泌代謝Update
  • Place of Presentation: 札幌(札幌コンベンションセンター)
  • Year and Date: 20110128-20110129
• [Presentation] 粘液水腫性昏睡で発症した中枢性甲状腺機能低下症の一例 (2010)
  • Author(s): 飯田啓二、日野泰久、大原毅、千原和夫
  • Organizer: 第53回日本甲状腺学会
  • Place of Presentation: 長崎(奈が脇ブリックホール)
  • Year and Date: 20101111-20101113
• [Presentation] 視床下部下垂体機能異常を呈した1型糖尿病の1例 (2010)
  • Author(s): 飯田啓二、日野泰久、大原毅、千原和夫
  • Organizer: 第37回日本神経内分泌学会
  • Place of Presentation: 京都(京都大学医学部芝蘭会館)
  • Year and Date: 20101022-20101023
• [Presentation] Sirt1 negatively regulates IGF-I production by growth hormone in hepatocytes. (2010)
  • Author(s): M.Yamamoto, G.Iguchi, H.Fukuoka, M.Takahashi, H.Nishizawa, E.Handayaningsih, Y.Okimura, H.Kaji, K.Chihara, S.Seino, Y.Takahashi
  • Organizer: 5th International Congress of the GRS and the IGF Society
  • Place of Presentation: New York, NY, USA.(Sheraton New York Hotel & Towers)
  • Year and Date: 20101003-20101007
• [Presentation] Huge goiter identified in a patient with acromegaly and Hashimoto's thyroiditis. (2010)
  • Author(s): Iida K, Hino Y, Ohara T, Chihara K
  • Organizer: The 92nd Annual Meeting of the Endocrine Society(米国内分泌学会)
  • Place of Presentation: SanDiego, CA, USA.
  • Year and Date: 20100619-20101022
• [Presentation] うつ病、健忘症、甲状腺機能低下症を契機に見出されたクッシング病の1例 (2010)
  • Author(s): 荒井啓輔、飯田啓二、古東秀介、玉田拓也、長谷川詠子、日野泰久、大原毅、工藤工、千原和夫
  • Organizer: 第193回日本内科学会近畿地方会
  • Place of Presentation: 神戸(神戸国際会議場)
  • Year and Date: 2010-12-04
• [Presentation] 体重増加、浮腫、無月経で発症し、クッシング病との鑑別を要した1型糖尿病性ケトーシスの1例 (2010)
  • Author(s): 飯田啓二、日野泰久、大原毅、千原和夫
  • Organizer: 第11回日本内分泌学会近畿支部学術集会
  • Place of Presentation: 滋賀(ピアザ淡海)
  • Year and Date: 2010-10-30
• [Presentation] 2型糖尿病経過中にGraves病合併を認めた1例 (2010)
  • Author(s): 玉田拓也、飯田啓二、大原毅、井口智恵、多木拓子、長谷川詠子、日野泰久、千原和夫
  • Organizer: 第192回日本内科学会近畿地方会
  • Place of Presentation: 大阪(大阪国際交流センター)
  • Year and Date: 2010-09-11
• [Presentation] 繰り返す尿路結石を契機に診断されたプレクリニカルクッシング症候群の1例 (2010)
  • Author(s): 井口智恵、飯田啓二、玉田拓也、多木拓子、長谷川詠子、日野泰久、大原毅、千原和夫
  • Organizer: 第192回日本内科学会近畿地方会
  • Place of Presentation: 大阪(大阪国際交流センター)
  • Year and Date: 2010-09-11
• [Presentation] 著明な脂肪肝を合併した糖尿病ケトアシドーシスの1例 (2010)
  • Author(s): 大搗泰一郎、大原毅、白川裕、高橋佳子、高橋直人、飯田啓二、日野泰久、小池隆史、尹聖哲、千原和夫
  • Organizer: 第191回日本内科学会近畿地方会
  • Place of Presentation: 京都(京都大学医学部芝蘭会館)
  • Year and Date: 2010-06-12
• [Presentation] 低身長症の鑑別と治療 (2009)
  • Author(s): 千原和夫
  • Organizer: 第82回日本内分泌学会学術総会
  • Place of Presentation: 群馬県(群馬県民会館、前橋商工会議所)
  • Year and Date: 20090423-20090425
• [Presentation] 成人GH分泌不全症の治療 (2009)
  • Author(s): 島津章、千原和夫、大磯ユタカ、高野加寿恵
  • Organizer: 第82回日本内分泌学会学術総会
  • Place of Presentation: 群馬県(群馬県民会館、前橋商工会議所)
  • Year and Date: 20090423-20090425
• [Presentation] 成人GH分泌不全症の診断と治療のガイドライン (2009)
  • Author(s): 肥塚直美、島津章、千原和夫、大磯ユタカ、高野加寿恵
  • Organizer: 第82回日本内分泌学会学術総会
  • Place of Presentation: 群馬県(群馬県民会館、前橋商工会議所)
  • Year and Date: 20090423-20090425
• [Presentation] PIT1に対する自己抗体と関連した後天性GH, PRL, TSH欠損症3例の解析 (2009)
  • Author(s): 井口元三、高橋裕、竹野亮子、置村康彦、東條克能、杢保敦子、加治秀介、千原和夫
  • Organizer: 第82回日本内分泌学会学術総会
  • Place of Presentation: 群馬県(群馬県民会館、前橋商工会議所)
  • Year and Date: 20090423-20090425
• [Presentation] 健常成人における体格指数、ウエスト周囲径と血中IGF-1 SDスコア (2009)
  • Author(s): 島津章、千原和夫、肥塚直美、寺本明、田中敏章、巽圭太、立花克彦、勝又規行、横谷進、藤枝憲二、大磯ユタカ
  • Organizer: 第82回日本内分泌学会学術総会
  • Place of Presentation: 群馬県(群馬県民会館、前橋商工会議所)
  • Year and Date: 20090423-20090425
• [Presentation] IGF-IはNASHモデルマウスの耐糖能および肝線維化を改善する (2009)
  • Author(s): 西沢衡、飯田啓二、吉岡嗣朗、高橋健太郎、高橋路子、山本雅昭、村脇あゆみ、井口元三、置村康彦、加治秀介、清野進、千原和夫、高橋裕
  • Organizer: 第82回日本内分泌学会学術総会
  • Place of Presentation: 群馬県(群馬県民会館、前橋商工会議所)
  • Year and Date: 20090423-20090425
• [Presentation] JAHQ (Japan Adult Hypopituitarism Questionnaire)を用いたsubclinical hypothyroidism症例のQOLの検討 (2009)
  • Author(s): 田中正巳、島津章、千原和夫、石井均
  • Organizer: 第82回日本内分泌学会学術総会
  • Place of Presentation: 群馬県(群馬県民会館、前橋商工会議所)
  • Year and Date: 20090423-20090425
• [Presentation] Sirt1は肝細胞におけるGHによるIGF-I産生を抑制する (2009)
  • Author(s): 山本雅昭、福岡秀規、西沢衡、高橋路子、Handayaningsih Evi、千原和夫、清野進、高橋裕
  • Organizer: 第82回日本内分泌学会学術総会
  • Place of Presentation: 群馬県(群馬県民会館、前橋商工会議所)
  • Year and Date: 20090423-20090425
• [Presentation] Reactive oxygen species play an essential role in IGF-I signaling and its biological action (2009)
  • Author(s): Handayaningsih Evi、福岡秀規、西沢衡、高橋路子、山本雅昭、Herningtyas Henny、置村康彦、加治秀介、清野進、千原和夫、高橋裕
  • Organizer: 第82回日本内分泌学会学術総会
  • Place of Presentation: 群馬県(群馬県民会館、前橋商工会議所)
  • Year and Date: 20090423-20090425
• [Book] 内分泌代謝専門医ガイドブック (2009)
  • Author(s): 千原和夫
  • Publisher: 診断と治療社
• [Book] The Changing Face of Pituitary Disease (HypoCCS Series 10) (2008)
  • Author(s): Shimatsu,A., S.Tai, Y.Kato, H.Kohno, T.Tanaka, A.Teramoto, K.Chihara
  • Publisher: Bio Scientifica Ltd, Bristol
• [Book] 脳神経外科エキスパート間脳下垂体 (2008)
  • Author(s): 千原和夫
  • Publisher: 中外医学社
• [Book] アンチエイジング医学の基礎と臨床 第2版 (2008)
  • Author(s): 千原和夫
  • Publisher: メジカルビュー社
• [Remarks] ホームページ等