Analysis for the pathogenesis of development of NASH via ER stress by PNPLA3 gene mutant mice

• Project/Area Number: 15K09009
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kochi University
• Principal Investigator: Ogasawara Mitsunari 高知大学, 教育研究部医療学系臨床医学部門, 助教 (10605215)
• Co-Investigator(Kenkyū-buntansha): 小野 正文 高知大学, 教育研究部医療学系臨床医学部門, 准教授 (70304681) ; 西原 利治 高知大学, 教育研究部医療学系臨床医学部門, 教授 (60145125)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: NASH / PNPLA3 / 遺伝子多型 / PNPLA3 mutation / XBP-1 / 肝臓学

Outline of Final Research Achievements

Because XBP-1 was regulated by ATF6 and hyperglycemia, and expression of ATF6 was not different between wild type and Knockout mice, it was considered that regulation of XBP-1 gene was involved by PMPLA3 gene. In gene expression of lipid synthesis, expression of SREBP1c, ACC2, FASN, CPT1α, DGAT1, 2 were not different in between wild type and knockout mice, and saturated fatty acids/unsaturated fatty acids ratios were high both before and after ER stress. Therefore, we concluded that PNPLA3 may have roles for the changes of fatty acids composition. In addition, we have created PNPLA3 mutant transgenic mice (Tg: PNPLA3 KO mice with mutant PNPLA3 gene(I148M) which is liver specific regulated by albumin promoter.

Research Products

• [Journal Article] Are donors or recipients a more important predictive factor for the development of non-alcoholic fatty liver disease after liver transplantation? (2018)
  • Author(s): Ono Masafumi
  • Journal Title: Hepatology Research Volume: 48 Issue: 3
  • DOI: 10.1111/hepr.12975
  • Peer Reviewed / Open Access
• [Journal Article] Abnormal lipid/lipoprotein metabolism and high plasma testosterone levels in male but not female aromatase-knockout mice (2017)
  • Author(s): Amano A, Kondo Y, Noda Y, Ohta M, Kawanishi N, Machida S, Mitsuhashi K, Senmaru T, Fukui M, Takaoka O, Mori T, Kitawaki J, Ono M, Saibara T, Obayashi H, Ishigami A.
  • Journal Title: Arch Biochem Biophys Volume: - Pages: 47-58
  • DOI: 10.1016/j.abb.2017.03.007
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of glutathione for the treatment of nonalcoholic fatty liver disease: an open-label, single-arm, multicenter, pilot study (2017)
  • Author(s): Honda Y, Ono M, Nakajima A（他20名）
  • Journal Title: BMC Gastroenterology Volume: 17 Issue: 1 Pages: 96-96
  • DOI: 10.1186/s12876-017-0652-3
  • NAID: 120006936382
  • Peer Reviewed / Open Access
• [Journal Article] Use of Mac-2 binding protein as a biomarker for nonalcoholic fatty liver disease diagnosis. (2017)
  • Author(s): Kamada Y, Ono M, Hyogo H, Fujii H, Sumida Y, Yamada M, Mori K, Tanaka S, Maekawa T, Ebisutani Y, Yamamoto A, Takamatsu S, Yoneda M, Kawada N, Chayama K, Saibara T, Takehara T, Miyoshi E.; Japan Study Group of NAFLD (JSG-NAFLD)
  • Journal Title: Hepatol Commun. Volume: 1 Issue: 8 Pages: 780-791
  • DOI: 10.1002/hep4.1080
  • Peer Reviewed / Open Access
• [Journal Article] Differences in characteristics of glucose intolerance between patients with NAFLD and chronic hepatitis C as determined by CGMS (2017)
  • Author(s): Ochi T, Kawaguchi T, Nakahara T, Ono M, Noguchi S, Koshiyama Y, Munekage K, Murakami E, Hiramatsu A, Ogasawara M, Hirose A, Mizuta H, Masuda K, Okamoto N, Suganuma N, Chayama K, Yamaguchi M, Torimura T, Saibara T
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 10146-10146
  • DOI: 10.1038/s41598-017-09256-4
  • Peer Reviewed / Open Access
• [Journal Article] Prevalence of pruritus in patients with chronic liver disease: A multicenter study (2017)
  • Author(s): Oeda S, Ono M, Saibara T, Eguchi Y（他16名）
  • Journal Title: Hepatology Research Volume: 48 Issue: 3
  • DOI: 10.1111/hepr.12978
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of factors influencing glucose tolerance in Japanese patients with non-alcoholic fatty liver disease (2017)
  • Author(s): Ohmi Satoko、Ono Masafumi、Takata Hiroshi、Hirano Seiki、Funakoshi Shogo、Nishi Yuichi、Yoshimura Kumiko、Amano Eri、Terada Yoshio、Saibara Toshiji、Fujimoto Shimpei
  • Journal Title: Diabetology & Metabolic Syndrome Volume: 9 Issue: 1 Pages: 65-65
  • DOI: 10.1186/s13098-017-0264-7
  • Peer Reviewed
• [Journal Article] The transcription factor HOXB7 regulates ERK kinase activity and thereby stimulates the motility and invasiveness of pancreatic cancer cells. (2017)
  • Author(s): Tsuboi M，Taniuchi K，Shimizu T，Saito M、Saibara T
  • Journal Title: J Biol Chem Volume: 292 Issue: 43 Pages: 17681-17702
  • DOI: 10.1074/jbc.m116.772780
  • Peer Reviewed / Open Access
• [Journal Article] High fasting insulin concentrations may be a pivotal predictor for the severity of hepatic fibrosis beyond the glycemic status in non-alcoholic fatty liver disease patients before development of diabetes mellitus． (2016)
  • Author(s): Masuda K，Noguchi S，Ono M，Ochi T，Munekage K，Okamoto N，Suganuma N，Saibara T
  • Journal Title: Hepatol Res Volume: - Issue: 10 Pages: 983-990
  • DOI: 10.1111/hepr.12832
  • Peer Reviewed
• [Journal Article] Suppression of miR-7 biogenesis by NF90-NF45 controls cell proliferation in hepatocellular carcinoma. (2016)
  • Author(s): Higuchi T, Todaka H, Sugiyama Y, Ono M, Tamaki N, Hatano E, Takezaki Y, Hanazaki K, Miwa T, Chin See LS, Morisawa K, Tsuda M, Taniguchi T, Sakamoto S
  • Journal Title: J Biol Chem. Volume: 291 Pages: 21074-21084
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Magnetic Resonance Imaging More Accurately Classifies Steatosis and Fibrosis in Nonalcoholic Fatty Liver Disease Than Transient Elastography. (2016)
  • Author(s): Imajo K, Kessoku T, Honda Y, Tomeno W, Ogawa Y, Mawatari H, Fujita K, Yoneda M, Taguri M, Hyogo H, Sumida Y, Ono M, Eguchi Y, Inoue T,Yamanaka T, Wada K, Saito S, Nakajima A
  • Journal Title: Gastroenterology Volume: 150 Issue: 3 Pages: 626-37
  • DOI: 10.1053/j.gastro.2015.11.048
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PNPLA3 is involved in hepatic fatty acid and triglyceride metabolism through XBP1 and modulation of endoplasmic reticulum stress in mice. (2016)
  • Author(s): Ochi T, Munekage K, Ono M, Higuchi T, Tsuda M, Hayashi Y, Okamoto N, Toda K, Sakamoto S, Oben JA, Saibara T
  • Journal Title: Hepatol Res Volume: 印刷中 Issue: 6 Pages: 584-592
  • DOI: 10.1111/hepr.12587
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Are genetic variations the most important risk factors for development of hepatocellular carcinoma? (2016)
  • Author(s): Ono M，Saibara T
  • Journal Title: J Gastroenterol. Volume: 51 Issue: 4 Pages: 404-5
  • DOI: 10.1007/s00535-015-1130-8
  • Peer Reviewed / Open Access
• [Journal Article] Characterization of ovarian responses to equine chorionic gonadotropin of aromatase-deficient mice with or without 17-estradiol supplementation. (2016)
  • Author(s): Katsumi Toda, Yoshihiro Hayashi, Masafumi Ono, Toshiji Saibara
  • Journal Title: Endocrinology Volume: 157 Issue: 5 Pages: 2093-2103
  • DOI: 10.1210/en.2015-1701
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Hepatocellular carcinoma in Japanese patients with nonalcoholic fatty liver disease and alcoholic liver disease: multicenter survey. (2016)
  • Author(s): Tokushige K, Hyogo H, Nakajima T, Ono M, Kawaguchi T, Honda K, Eguchi Y, Nozaki Y, Kawanaka M, Tanaka S, Imajo K, Sumida Y, Kamada Y, Fujii H, Suzuki Y, Kogiso T, Karino Y, Munekage K, Kuromatsu R, Oeda S, Yanase M, Mori K, Ogawa Y, Seko Y, Takehara T, Itoh Y, Nakajima A, Kanemasa K, Saibara T
  • Journal Title: J Gastroenterol Volume: 印刷中 Issue: 6 Pages: 586-96
  • DOI: 10.1007/s00535-015-1129-1
  • Peer Reviewed / Open Access
• [Journal Article] 診断の進め方：専門医への紹介のポイント (2016)
  • Author(s): 小野正文，西原利治
  • Journal Title: 日本内科学会雑誌 Volume: 105 Pages: 47-55
  • Peer Reviewed
• [Journal Article] 脂肪肝を防ぐ食生活と治療を考える (2016)
  • Author(s): 西原利治
  • Journal Title: 日本内科学会雑誌 Volume: 105 Pages: 406-410
• [Journal Article] 非アルコール性脂肪肝炎を来す薬剤 (2016)
  • Author(s): 宮村充彦，横田淳子，西原利治
  • Journal Title: 薬学雑誌 Volume: 136 Pages: 579-582
  • NAID: 130005140771
• [Journal Article] A novel noninvasive diagnostic method for nonalcoholic steatohepatitis using two glycobiomarkers. (2015)
  • Author(s): Kamada Y, Ono M, Hyogo H, Fujii H, Sumida Y, Mori K, Tanaka S, Yamada M, Akita M, Mizutani K, Fujii H, Yamamoto A, Takamatsu S, Yoshida Y, Itoh Y, Kawada N, Chayama K, Saibara T, Takehara T, Miyoshi E
  • Journal Title: Hepatology. Volume: 62 Issue: 5 Pages: 1433-1443
  • DOI: 10.1002/hep.28002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Biphasic effect of alcohol intake on the development of fatty liver disease. (2015)
  • Author(s): Takahashi H, Ono M, Ono N, Eguchi T, Fujimoto K, Chayama K, Saibara T, Anzai K, Eguchi Y
  • Journal Title: J Gastroenterol Volume: 50 Issue: 11 Pages: 1114-23
  • DOI: 10.1007/s00535-015-1058-z
  • Peer Reviewed / Open Access
• [Journal Article] Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. (2015)
  • Author(s): Watanabe S, Hashimoto E, Ikejima K, Uto H, Ono M, Sumida Y, Seike M,
  • Journal Title: J Gastroenterol Volume: 50(4) Issue: 4 Pages: 364-377
  • DOI: 10.1007/s00535-015-1050-7
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. (2015)
  • Author(s): Watanabe S, Hashimoto E, Ikejima K, Uto H, Ono M, Sumida Y, Seike M, Takei Y, Takehara T, Tokushige K, Nakajima A, Yoneda M, Saibara T, Shiota G, Sakaida I, Nakamuta M, Mizuta T, Tsubouchi H, Sugano K, Shimosegawa T.
  • Journal Title: Hepatol Res. Volume: 45 Issue: 4 Pages: 363-377
  • DOI: 10.1111/hepr.12511
  • Peer Reviewed / Open Access
• [Journal Article] NASHはどれくらい存在するのか (2015)
  • Author(s): 越智経浩，小野正文，西原利治
  • Journal Title: Mebio Volume: 33 Pages: 4-9
• [Journal Article] NASH/NAFLDおよび肥満研究の最前線 (2015)
  • Author(s): 小野正文，西原利治
  • Journal Title: 分子消化器病 Volume: 12 Pages: 57-62
• [Journal Article] NAFLD、NASHの発症頻度はどれくらい？男女別および国内外の頻度について (2015)
  • Author(s): 小野正文，西原利治
  • Journal Title: Nutrition Care Volume: 8 Pages: 672-5
• [Journal Article] 肝臓における糖代謝の最新知見 (2015)
  • Author(s): 小野正文，越智経浩，西原利治
  • Journal Title: Diabetes Frontier Volume: 26 Pages: 287-96
• [Journal Article] 尿酸血症と非アルコール性脂肪性肝疾患（NAFLD・NASH） (2015)
  • Author(s): 西原利治
  • Journal Title: 尿酸と血糖 Volume: 1 Pages: 19-22
• [Journal Article] Is nonalcoholic fatty liver disease a systemic disease that promotes extrahepatic cancer development？． (2014)
  • Author(s): Ono M
  • Journal Title: Hepatology Reseach Volume: 45 Issue: 7 Pages: 711-713
  • DOI: 10.1111/hepr.12435
  • Peer Reviewed / Open Access
• [Presentation] Involvement of PNPLA3 function for hepatic lipids metabolism through XBP1 and modulation of endoplasmic reticulum stress in mice (2017)
  • Author(s): Nagano S，Ono M，Ochi T，Munekage K，Yano Y，Mizuta H，Ogasawara M，Hirose A，Nozalki Y，Okamoto N，Iwasaki S， Oben JA， Saibara T
  • Organizer: APDW 2017
  • Int'l Joint Research
• [Presentation] Characteristics of Japanese NAFLD/NASH (2017)
  • Author(s): Ono M
  • Organizer: The 103rd General Meeting of the Japanese Society of Gastroenterology The 6thInternational Forum
  • Int'l Joint Research / Invited
• [Presentation] POTASSIUM-COMPETITIVE ACID BLOCKER-BASED THIRD-LINE TRIPLE THERAPY IN HELICOBACTER PY-LORI ERADICATION AND STUDY OF THE DIVERSITY OF ANTIMICROBIAL SUSCEPTIBILITIES (2017)
  • Author(s): Yano Y，Mizuta H， Ono M，Saibara T.(他6名)
  • Organizer: uegweek2016
  • Int'l Joint Research
• [Presentation] :INVOLVEMENT OF AGE-RAGE SYSTEM FOR THE DEVEL-OPMENT OF HEPATIC FIBROSIS IN NASH (2017)
  • Author(s): Munekage K，Ono M，Ochi T，Saibara T.(他4名)
  • Organizer: uegweek2016
  • Int'l Joint Research
• [Presentation] EFFICACY OF GLUTATHIONE FOR THE TREATMENT OF NON-ALCOHOLIC FATTY LIVER DISEASE:AN OPEN-LABEL, MULTICENTER, PROSPECTIVE STUDY (2017)
  • Author(s): Kessoku T，Ono M，Eguchi Y，Nakajima A. (他13名)
  • Organizer: EASL
  • Int'l Joint Research
• [Presentation] 非Ｂ非Ｃ肝がんの発症・予後とアルブミンの関連：Random Forest分析． (2016)
  • Author(s): 川口巧，小野正文，鳥村拓司
  • Organizer: 第20回日本肝臓学会大会(JDDW)
  • Place of Presentation: 神戸コンベンションセンター（兵庫県神戸市）
  • Year and Date: 2016-11-03
• [Presentation] INVOLVEMENT OF AGE-RAGE SYSTEM FOR THE DEVEL-OPMENT OF HEPATIC FIBROSIS IN NASH． (2016)
  • Author(s): Munegage K，Ono M，Ochi T，Ogasawara M，Hirose A，Fujimura Y ，Iwasaki S，Saibara T
  • Organizer: uegweek2016（24th United European Gastroenterology Week）
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2016-10-15
  • Int'l Joint Research
• [Presentation] POTASSIUM-COMPETITIVE ACID BLOCKER-BASED THIRD-LINE TRIPLE THERAPY IN HELICOBACTER PY-LORI ERADICATION AND STUDY OF THE DIVERSITY OF ANTIMICROBIAL SUSCEPTIBILITIES． (2016)
  • Author(s): Yano Y，Mizuta H，Kira M，Matsumura Y，Kitagawa T，Hashiba M，Okamoto N，Takeuchi H，Ono M，Saibara T
  • Organizer: uegweek2016（24th United European Gastroenterology week)
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2016-10-15
  • Int'l Joint Research
• [Presentation] NASHの肝線維化進展におけるAGE-RAGE系の関与について． (2016)
  • Author(s): 宗景玄祐，小野正文，西原利治
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ幕張・東京ベイ幕張ホール（千葉県千葉市）県
  • Year and Date: 2016-05-19
• [Presentation] NAFLD患者の肝線維化進展抑制には早期からの高インスリン血症，血糖変動，DM発症抑制への対策が重要である (2016)
  • Author(s): 宗景玄祐，小野正文，西原利治
  • Organizer: 第102回日本消化器病学会総会．
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2016-04-21
• [Presentation] EFFICACY OF GLUTATHIONE FOR THE TREATMENT OF NON-ALCOHOLIC FATTY LIVER DISEASE:AN OPEN-LABEL,MULTICENTER,PROSPECTIVE STUDY． (2016)
  • Author(s): Kessoku T，Sumida Y，Imajo K，Honda Y，Ogawa Y，Yoneda M，Ono M，Egushi，Nakajima A
  • Organizer: EASL（51th Annual Meeting of The European Association For The Study of The Liver）
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2016-04-13
  • Int'l Joint Research
• [Presentation] PNPLA3 IS INVOLVED IN HEPATIC LIPIDS METABOLISM THROUGH XBP1 AND MODUALATION OF ENDOPLASMIC RETICULUM SYRESS IN MICE． (2016)
  • Author(s): Ono M，Ochi T，Munegage K，Ogasawara M，Hirose A，Nozaki-Fujimura Y，Okamoto N， Iwasaki S，Oben J，Saibara T
  • Organizer: EASL（51th Annual Meeting of The European Association For The Study of The Liv
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2016-04-13
  • Int'l Joint Research
• [Presentation] 高インスリン血症は糖尿病未発症NAFLD患者の肝線維化進展に重要な因子である (2015)
  • Author(s): 宗景玄祐，小野正文，西原利治
  • Organizer: 第41回日本肝臓学会西部会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-12-03
• [Presentation] A novel noninvasive diagnostic method for nonalcoholic steatohepatitis（NASH） using two glycobiomarkers． (2015)
  • Author(s): Kamada Y，Ono M，Hyogo H，Fujii H，Sumida Y，Mori K，Tanaka S，Yamada M，Akita M，Mizutani K，Fujii H，Yamamoto A，Takamatsu S，Yoshida Y，Itoh Y，Kawada N，Chayama K，Saibara T，Takehara T，Miyoshi E
  • Organizer: AASLD The Liver Meeting．
  • Place of Presentation: Sanfrancisco （USA）
  • Year and Date: 2015-11-13
  • Int'l Joint Research
• [Presentation] Risk factors for hepatocellular carcinoma recurrence in patients with nonalcoholic and alcoholic fatty liver disease：A Japanese multicenter survey． (2015)
  • Author(s): Kogiso T，Hashimoto E，Hyogo H，Nakajima T，Ono M，Kawaguchi T，Honda K，Eguchi Y，Nozaki Y，Kawanaka M，Imajo K，Sumida Y，Kamada Y，Fujii H，Suzuki Y，Tokushige K
  • Organizer: ASLD The Liver Meeting．
  • Place of Presentation: Sanfrancisco （USA）
  • Year and Date: 2015-11-13
  • Int'l Joint Research
• [Presentation] 糖尿病発症前NAFLD患者の肝線維化進展に寄与する因子の解析-男女別の比較検討より (2015)
  • Author(s): 久家直子，小野正文，増田弘誠，宗景玄祐，越智経浩，西原利治
  • Organizer: 第11回消化器病における性差医学・医療研究会
  • Place of Presentation: 旭川グランドホテル(北海道・旭川市)
  • Year and Date: 2015-07-25
• [Presentation] 脂肪肝発症に対する性差の影響について-多施設検診受診者の解析より- (2015)
  • Author(s): 黒川早紀，宗景玄祐，越智経浩，高橋宏和，兵庫秀幸，小野正文，江口有一郎，西原利治
  • Organizer: 第11回消化器病における性差医学・医療研究会
  • Place of Presentation: 旭川グランドホテル(北海道・旭川市)
  • Year and Date: 2015-07-25
• [Presentation] C型慢性肝炎患者とNAFLD患者の血糖日中変動に影響を及ぼす要因についての比較検討． (2015)
  • Author(s): 越智経浩，小野正文，西原利治
  • Organizer: 第101回日本消化器病学会総会
  • Place of Presentation: 仙台国際センター（宮城県・仙台市）
  • Year and Date: 2015-04-23
• [Presentation] PNPLA3遺伝子はER stressを介したapoptosisに関与する． (2015)
  • Author(s): 越智経浩，宗景玄祐，小野正文
  • Organizer: 第101回日本消化器病学会総会
  • Place of Presentation: 仙台国際センター（宮城県・仙台市）
  • Year and Date: 2015-04-23