Novel diagnostic method of Non-alcoholic steatohepatitis used serum free choline score and ^<11>C-choline dynamic PET.

2009 Fiscal Year Final Research Report

• Project/Area Number: 20890185
• Research Category: Grant-in-Aid for Young Scientists (Start-up)
• Allocation Type: Single-year Grants
• Research Field: Gastroenterology
• Research Institution: Yokohama City University
• Principal Investigator: FUJITA Koji Yokohama City University, 附属病院, 助教 (30468160)
• Project Period (FY): 2008 – 2009
• Keywords: 非アルコール性脂肪肝炎 / 肝臓リン脂質代謝 / 遊離コリン / 診断

Research Abstract

1) The development of novel diagnostic method of Non-alcoholic steatohepatitis used serum free choline score.
We discovered to exist the abundant free choline (fCh) in serum in the NASH group than other liver disease and metabolic disorder. We established the method of HPLC system which is more convenient than the present LC-mass system.
2) The development of novel diagnostic method of earlier stage of Non-alcoholic steatohepatitis used ^<11>C-choline dynamic PET system.
We performed the pilot study used ^<11>C-choline dynamic PET system to measure liver phospholipid metabolism in 8 non fatty liver, 14 simple steatosis (SS), and 16 NASH. We certified NASH patients occurred the hypoactivity of liver phospholipid metabolism than other two pathogenesis.
3) Elucidation of the mechanisum of abundant free choline in NASH.
As a progress from SS to NASH, the hepatic expression of apoB100 mRNA and MTTP mRNA were impaired. And then, VLDL synthesis is impaired in NASH, in spite of the presence of abundant fCh in the serum, as a result of some obstacle in choline utilization.

Research Products

• [Journal Article] Dysfunctional VLDL synthesis and release is a key factor in non-alcoholic steato-hepatitis (NASH) pathogenesis. (2009)
  • Author(s): Fujita K, Nozaki Y, Wada K, Yoneda M, Fujimoto Y, Fujitake M, Endo H, Takahashi H, Inamori M, Kobayashi N, Kirikoshi H, Kubota K, Saito S, Nakajima A
  • Journal Title: Hepatplogy. (in press)
• [Journal Article] Association between angiotensin II type 1 receptor polymorphisms and the occurrence of nonalcoholic fatty liver disease. (2009)
  • Author(s): Yoneda M, Hotta K, Nozaki Y, Endo H, Uchiyama T, Mawatari H, Iida H, Kato S, Fujita K, Takahashi H, Kirikoshi H, Kobayashi N, Inamori M, Abe Y, Kubota K, Saito S, Maeyama S, Wada K, Nakajima A
  • Journal Title: Liver Int.
• [Journal Article] Serum Ferritin Is a Clinical Biomarker in Japanese Patients with Nonalcoholic Steatohepatitis (NASH) Independent of HFE Gene Mutation. (2009)
  • Author(s): Yoneda M, Nozaki Y, Endo H, Mawatari H, Iida H, Fujita K, Yoneda K, Takahashi H, Kirikoshi H, Inamori M, Kobayashi N, Kubota K, Saito S, Maeyama S, Hotta K, Nakajima A
  • Journal Title: Dig Dis Sci.
• [Journal Article] Effectiveness of antiplatelet drugs against experimental non-alcoholic fatty liver disease. (2008)
  • Author(s): Fujita K, Nozaki Y, Wada K, Yoneda M, Endo H, Takahashi H, Iwasaki T, Inamori M, Abe Y, Kobayashi N, Kirikoshi H, Kubota K, Saito S, Nagashima Y, Nakajima A
  • Journal Title: Gut. 57 Pages: 1583-91
• [Journal Article] Nitric Oxide Plays a Crucial Role in the Development/Progression of Nonalcoholic Steatohepatitis in the Choline-Deficient, l-Amino Acid-Defined Diet-Fed Rat Model. (2008)
  • Author(s): Fujita K, Nozaki Y, Yoneda M, Wada K, Takahashi H, Kirikoshi H, Inamori M, Saito S, Iwasaki T, Terauchi Y, Maeyama S, Nakajima A
  • Journal Title: Alcohol Clin Exp Res.
• [Journal Article] Gene expression profiling of non-alcoholic steatohepatitis using gene set enrichment analysis. (2008)
  • Author(s): Yoneda M, Endo H, Mawatari H, Nozaki Y, Fujita K, Akiyama T, Higurashi T, Uchiyama T, Yoneda K, Takahashi H, Kirikoshi H, Inamori M, Abe Y, Kubota K, Saito S, Kobayashi N, Yamaguchi N, Maeyama S, Yamamoto S, Tsutsumi S, Aburatani H, Wada K, Hotta K, NakajYoned
  • Journal Title: Hepatol Res. 38(12) Pages: 1204-12
• [Journal Article] Association between PPARGC1A polymorphisms and the occurrence of nonalcoholic fatty liver disease (NAFLD). (2008)
  • Author(s): Yoneda M, Hotta K, Nozaki Y, Endo H, Uchiyama T, Mawatari H, Iida H, Kato S, Hosono K, Fujita K, Yoneda K, Takahashi H, Kirikoshi H, Kobayashi N, Inamori M, Abe Y, Kubota K, Saito S, Maeyama S, Wada K, Nakajima A
  • Journal Title: BMC Gastroenterol. 8 Pages: 27
• [Journal Article] Transient erastography in patients with nonalcoholic fatty liver disease(NAFLD). (2007)
  • Author(s): Yoneda M, Yoneda M, Fujita K, Inamori M, Tamano M, Hiriishi H, Nakajima A
  • Journal Title: Gut. 56 Pages: 1330-1
• [Journal Article] High-sensitivity C-reactive protein is an independent clinical feature of nonalcoholic steatohepatitis (NASH) and also of the severity of fibrosis in NASH. (2007)
  • Author(s): Yoneda M, Mawatari H, Fujita K, Iida H, Yonemitsu K, Kato S, Takahashi H, Kirikoshi H, Inamori M, Nozaki Y, Abe Y, Kubota K, Saito S, Iwasaki T, Terauchi Y, Togo S, Maeyama S, Nakajima A
  • Journal Title: J Gastroenterol. 42(7) Pages: 573-82
• [Journal Article] Telmisartan, an angiotensin II type 1 receptor blocker, controls progress of nonalcoholic steatohepatitis in rats. (2006)
  • Author(s): Fujita K, Yoneda M, Wada K, Mawatari H, Takahashi H, Kirikoshi H, Inamori M, Nozaki Y, Maeyama S, Saito S, Iwasaki T, Terauchi Y, Nakajima A
  • Journal Title: Dig Dis Sci. 52(12) Pages: 3455-64
• [Presentation] NAFLD病態における肝ミクロソームTG輸送蛋白(MTTP)が果たす意義 (2009)
  • Author(s): 藤田浩司, 野崎雄一, 馬渡弘典, 米田正人, 桐越博之, 斉藤聡, 中島淳
  • Organizer: 第45回日本肝臓学会総会ワークショップ
  • Place of Presentation: 神戸
  • Year and Date: 2009-06-04
• [Presentation] NASH/NAFLD診断のためのLipoSEARCH^(R)システムを用いた簡易コリン測定法の開発 (2009)
  • Author(s): 中島淳, 斎藤聡, 桐越博之, 野崎雄一, 藤田浩司, 米田正人, 佐々木裕樹
  • Organizer: 第45回日本肝臓学会総会
  • Place of Presentation: 神戸
  • Year and Date: 2009-06-04
• [Presentation] Dysfunctional VLDL synthesis and release is a key factor in non-alcoholic steatohepatitis (NASH) progression (2009)
  • Author(s): Koji Fujita, Yuichi Nozaki, Masato Yoneda, Hiroyuki Kirikoshi, Satoru Saito, Atsushi Nakajima
  • Organizer: Digestive Disease Week 2009
  • Place of Presentation: Chicago, USA
  • Year and Date: 2009-06-02
• [Presentation] 肝ミクロソームTG輸送蛋白(MTTP)がNAFLD病態進展に与える影響 (2009)
  • Author(s): 藤田浩司, 野崎雄一, 米田正人, 留野渉, 加藤真吾, 内山崇, 渡辺誠太郎, 馬渡弘典, 飯田洋, 細野邦広, 遠藤宏樹, 高橋宏和, 阿部泰伸, 稲森正彦, 桐越博之, 小林規俊, 島村健, 窪田賢輔, 斉藤聡, 中島淳
  • Organizer: 第95回日本消化器病学会総会
  • Place of Presentation: 札幌
  • Year and Date: 2009-05-07
• [Presentation] Novel diagnostic approach for NASH using [11C] choline dynamic PET imaging. (2008)
  • Author(s): Koji Fujita, Yuichi Nozaki, Masato Yoneda, Hiroki Endo, Hirokazu Takahashi, Masahiko Inamori, Yasunobu Abe, Noritoshi Kobayashi, Hiroyuki Kirikoshi, Kensuke Kubota, Satoru Saito, Atsushi Nakajima
  • Organizer: 16th UEGW Oral presentation
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2008-10-21
• [Presentation] Novel diagnostic approach for NASH using [11C] choline dynamic PET imaging. (2008)
  • Author(s): Koji Fujita, Yuichi Nozaki, Masato Yoneda, Hiroki Endo, Hirokazu Takahashi, Masahiko Inamori, Yasunobu Abe, Noritoshi Kobayashi, Hiroyuki Kirikoshi, Kensuke Kubota, Satoru Saito, Atsushi Nakajima
  • Organizer: Digestive Disease Week 2008
  • Place of Presentation: San Diego, USA
  • Year and Date: 2008-05-20
• [Presentation] 坑血小板薬のNAFLD病態改善効果- NAFLD病態モデルラットを用いた検討- (2008)
  • Author(s): 藤田浩司, 野崎雄一, 米田正人, 馬渡弘典, 飯田洋, 遠藤宏樹, 秋山智之, 米田恭子, 高橋宏和, 後藤歩, 廣川智, 阿部泰伸, 稲森正彦, 桐越博之, 小林規俊, 窪田賢輔, 斉藤聡, 中島淳
  • Organizer: 日本消化器病学会総会
  • Year and Date: 2008-05-10
• [Presentation] Novel Therapeutic Approach for Nonalcoholic Fatty Liver Disease( NAFLD) using Antiplatelet Agents in an Animal Model. (2007)
  • Author(s): Koji Fujita, Yuichi Nozaki, Masato Yoneda, Masahiko Inamori, Hiroyuki Kirikoshi, Satoru Saito, Atsushi Nakajima
  • Organizer: AASLD
  • Year and Date: 20071100
• [Presentation] 血清コリン測定および11C-コリンPET-CTを用いたNASH, NAFLDの新しい診断法～肝脂質排出能に着目したNAFLD診断～. (2007)
  • Author(s): 藤田浩司, 野崎雄一, 米田正人, 中島淳
  • Organizer: 第4回酸化ストレスと肝研究会
  • Place of Presentation: 博多
  • Year and Date: 20071100
• [Presentation] 血清コリン測定および11C-コリンPET-CTを用いたNASH, NAFLDの新しい診断法～肝脂質排出能に着目したNAFLD診断～. (2007)
  • Author(s): 藤田浩司, 米田正人, 中島淳
  • Organizer: 日本消化器病学会総会
  • Year and Date: 20071000
• [Presentation] 非アルコール性脂肪性肝炎病態におけるNitric Oxideの役割～高脂肪高カロリー食投与肥満モデルマウスにおける検討～. (2006)
  • Author(s): 藤田浩司, 米田正人, 野崎雄一, 馬渡弘典, 秋本恵子, 飯田洋, 冨本彩子, 遠藤宏樹, 米満恭子, 秋山智之, 藤澤聡郎, 高橋宏和, 阿部泰伸, 稲森正彦, 桐越博之, 窪田賢輔, 斉藤聡, 中島淳
  • Organizer: 日本消化器病学会総会
  • Year and Date: 20061000
• [Presentation] Nonalcoholic Steatohepatitis~The role of Extrahepatic Nitric oxide ~ (2006)
  • Author(s): Koji Fujita, Masato Yoneda, Masahiko Inamori, Hiroyuki Kirikoshi, Tomoyuki Iwasaki, Yasuo Terauchi, Atsushi Nakajima
  • Organizer: アメリカDDW
  • Year and Date: 20060500
• [Book] NAFLD/NASHの診断. 「最新医学」第63巻9号 (2008)
  • Author(s): 野崎雄一, 藤田浩司, 米田正人, 前山史郎, 中島淳
  • Total Pages: 20-24
• [Book] 血清Choline測定によるNASHの新しい診断法.アルコールと医学生物学27巻 (2007)
  • Author(s): 藤田浩司, 野崎雄一, 米田正人, 稲森正彦, 桐越博之, 斉藤聡, 中島淳
  • Total Pages: 197-202
• [Book] 非アルコール性脂肪性肝炎(NASH)の病態進展におけるiNOS由来Nitric Oxideの役割. アルコールと医学生物学26巻 (2006)
  • Author(s): 藤田浩司, 米田正人, 野崎雄一, 稲森正彦, 桐越博之, 齋藤聡, 岩崎知之, 寺内康夫, 前山史朗, 和田孝一郎, 中島淳
  • Total Pages: 47-53
• [Book] 肝外性NOのNASH病態進展有力因子の検討. G. I. Research (0918-9408)14巻4号 (2006)
  • Author(s): 藤田浩司, 米田正人, 秋山智之, 池田多聞, 池田郁子, 藤澤聡郎, 藤澤信隆, 高橋宏和, 稲森正彦, 阿部泰伸, 桐越博之, 窪田賢輔, 斉藤聡, 中島淳
  • Total Pages: 416-417
• [Book] 肝脂質排出能に着目したNASH診断の検討～11C-Choline dynamic PETを用いて
  • Author(s): 藤田浩司, 野崎雄一, 米田正人, 中島淳
• [Patent(Industrial Property Rights)] 非アルコール性脂肪肝疾患の診断方法 (2008)
  • Inventor(s): 藤田浩司
  • Industrial Property Rights Holder: 藤田浩司
  • Industrial Property Number: 特願・2008-008933
  • Acquisition Date: 2008-07-18
• [Patent(Industrial Property Rights)] 非アルコール性脂肪肝障害の検査方法 (2008)
  • Inventor(s): 藤田浩司
  • Industrial Property Rights Holder: 藤田浩司
  • Industrial Property Number: 特願・2008-188560
  • Acquisition Date: 2008-07-22
• [Patent(Industrial Property Rights)] 脂肪肝炎の診断及び/又は治療における血清コリン値の有用性
  • Inventor(s): 藤田浩司
  • Industrial Property Rights Holder: 藤田浩司
  • Industrial Property Number: 特願・2006-299978
• [Patent(Industrial Property Rights)] 血液中一酸化窒素代謝物量測定による内臓脂肪量非侵襲的測定法
  • Inventor(s): 藤田浩司
  • Industrial Property Rights Holder: 藤田浩司
  • Industrial Property Number: 特願・2007-107257
• [Patent(Industrial Property Rights)] 11C-Choline PETを用いた非アルコール性脂肪性肝障害の診断・評価法の発明
  • Inventor(s): 藤田浩司
  • Industrial Property Rights Holder: 藤田浩司
  • Industrial Property Number: 特願・2007-42095
• [Patent(Industrial Property Rights)] 血中カイロミクロン及びVLDL測定による非アルコール性脂肪肝・脂肪肝炎の重症度判定・モニター法の発明
  • Inventor(s): 藤田浩司
  • Industrial Property Rights Holder: 藤田浩司
  • Industrial Property Number: 特願・2007-266431
• [Patent(Industrial Property Rights)] 脂肪性肝疾患の診断方法、診断装置、診断プログラム、診断薬及び脂肪性肝疾患用治療薬のスクリーニング方法
  • Inventor(s): 藤田浩司
  • Industrial Property Rights Holder: 藤田浩司
  • Industrial Property Number: PCT/JP・2007-067029