PPAR-alpha mediated molecular mechanisms involved in spontaneous hepatocarcinogenesis among NASH mouse model

• Project/Area Number: 15K09010
• 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: SAIBARA Toshiji 高知大学, 教育研究部医療学系臨床医学部門, 教授 (60145125)
• Co-Investigator(Kenkyū-buntansha): 耕崎 拓大 高知大学, 教育研究部医療学系臨床医学部門, 講師 (00332833) ; 戸田 勝巳 高知大学, 教育研究部医療学系基礎医学部門, 准教授 (40197893) ; 水田 洋 高知大学, 教育研究部医療学系臨床医学部門, 助教 (70527605)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: PPAR-alpha / melanocortin receptor / insulin resistance / fatty liver / IL-6 / NASH / hepatocellular carcinoma / knockout mouse / Melanocortin receptor / 肝硬変 / 肝細胞癌 / ＭＣ４Ｒ / ノックアウトマウス

Outline of Final Research Achievements

Both MC4R KO mouse and MC4R-PPAR-alpha double KO mouse showed progressive impairment of insulin sensitivity and enhanced mRNA expression of genes involved in fatty acid synthesis, fatty acid beta and omega oxidation, inflammation, and scavenger receptors in addition to IL-6 mRNA. However, there was a significant difference in neoplastic nodule size and number among these two KO mice, i.e., averaged diameter and averaged number of tumor were significantly fewer in MC4R-PPAR-alpha double KO mouse than in MC4R KO mouse. This observation suggests that PPAR-alpha mediated mechanisms are involved in spontaneous hepatocarcinogenesis among NASH mouse models.

Research Products

• [Journal Article] Evaluation of postprandial hypoglycemia in patients with nonalcoholic fatty liver disease by oral glucose tolerance testing and continuous glucose monitoring (2018)
  • Author(s): Oki Y, Ono M, Hyogo H, Ochi T, Munekage K, Nozaki Y, Hirose A, Masuda K, Mizuta H, Okamoto N, Saibara T
  • Journal Title: Eur J Gastroenterol Hepatol Volume: - Issue: 7 Pages: 797-805
  • DOI: 10.1097/meg.0000000000001118
  • Peer Reviewed / Open Access
• [Journal Article] The novel cutoff points for the FIB4 index categorized by age increase the diagnostic accuracy in NAFLD: a multi-center study (2018)
  • Author(s): Ishiba H, Sumida Y, Tanaka S, Yoneda M, Hyogo H, Ono M, Fujii H, Eguchi Y, Suzuki Y, Yoneda M, Takahashi H, Nakahara T, Seko Y, Mori K, Kanemasa K, Shimada K, Imai S, Imajo K, Kawaguchi T, Nakajima A, Chayama K, Saibara T、 Shima T, Fujimoto K, Okanoue T, Itoh Y
  • Journal Title: J Gastroenterol Volume: - Issue: 11 Pages: 1216-1224
  • DOI: 10.1007/s00535-018-1474-y
  • Peer Reviewed
• [Journal Article] New scoring system combining the FIB-4 index and cytokeratin-18 fragments for predicting steatohepatitis and liver fibrosis in patients with nonalcoholic fatty liver disease (2018)
  • Author(s): Tada T, Kumada T, Toyoda H, Saibara T, Ono M, Kage M
  • Journal Title: Biomarkers Volume: 23 Issue: 4 Pages: 328-334
  • DOI: 10.1080/1354750x.2018.1425915
  • Peer Reviewed
• [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] 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] 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] 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] CCDC88A, a prognostic factor for human pancreatic cancers, promotes the motility and invasiveness of pancreatic cancer cells. (2016)
  • Author(s): Tanouchi A, Taniuchi K, Furihata M, Naganuma S, Dabanaka K, Kimura M, Watanabe R, Kohsaki T, Shimizu T, Saito M, Hanazaki K, Saibara T.
  • Journal Title: J Exp Clin Cancer Res. Volume: 35 Issue: 1 Pages: 190-190
  • DOI: 10.1186/s13046-016-0466-0
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Podocalyxin-like protein, linked to poor prognosis of pancreatic cancers, promotes cell invasion by binding to gelsolin. (2016)
  • Author(s): Taniuchi K, Furihata M, Naganuma S, Dabanaka K, Hanazaki K, Saibara T.
  • Journal Title: Cancer Sci. Volume: 107 Issue: 10 Pages: 1430-1442
  • DOI: 10.1111/cas.13018
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Vav3 is linked to poor prognosis of pancreatic cancers and promotes the motility and invasiveness of pancreatic cancer cells. (2016)
  • Author(s): Tsuboi M, Taniuchi K, Furihata M, Naganuma S, Kimura M, Watanabe R, Shimizu T, Saito M, Dabanaka K, Hanazaki K, Saibara T.
  • Journal Title: Pancreatology. Volume: 16 Issue: 5 Pages: 905-16
  • DOI: 10.1016/j.pan.2016.07.002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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] 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] A successful case of deceased donor liver transplantation for a patient with intrahepatic arterioportal fistula. (2015)
  • Author(s): Takagi K, Yagi T, Yoshida R, Shinoura S, Umeda Y, Nobuoka D, Watanabe N, Kuise T, Sui K, Hirose A, Tsuboi M, Ogasawara M, Iwasaki S, Saibara T, Fujiwara T.
  • Journal Title: Hepatol Res. Volume: - Issue: 13 Pages: 1409-1415
  • DOI: 10.1111/hepr.12701
  • Peer Reviewed / Open Access
• [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] Inhibition of Cyclic Adenosine Monophosphate (cAMP)-response Element-binding Protein (CREB)- binding Protein (CBP)/β-Catenin Reduces Liver Fibrosis in Mice. (2015)
  • Author(s): Osawa Y, Oboki K, Imamura J, Kojika E, Hayashi Y, Hishima T, Saibara T, Shibasaki F, Kohara M, Kimura K
  • Journal Title: EBioMedicine Volume: 2 Issue: 11 Pages: 1751-8
  • DOI: 10.1016/j.ebiom.2015.10.010
  • Peer Reviewed / Open Access
• [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
• [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，Jude A ObenT，Saibara T
  • Organizer: APDW 2017
  • Int'l Joint Research
• [Presentation] Vonoprazan-based third-line triple therapy in Helicobacter pyloli eradication and study of the diversity of antimicrobial susceptibilities (2017)
  • Author(s): Yano Y，Mizuta H，Ono M，Nagano S，Tsuda H，Kitagawa T，Hashiba M，Okamoto N，Kira M，Takeuchi H，Matsumura Y，Saibara T
  • Organizer: APDW 2017
  • Int'l Joint Research
• [Presentation] Functional roles of AGE-RAGE system for the development of hepatic fibrosis of NASH (2017)
  • Author(s): Ono M，Munekage K，Ochi T，Hirose A，Ogasawara M，Okamoto N，Saibara T
  • Organizer: AASLD THE LIVER MEETING 2017
  • Int'l Joint Research
• [Presentation] Efficient delivery of siRNA targeted CCDC88A mRNA topancreatic cancer tumor inhibits the invasiveness and metastasis (2017)
  • Author(s): Taniuchi K，Yawata T，Ueda T，Saibara T
  • Organizer: American Association for Cancer Research Annual Meeting 2017
  • Int'l Joint Research
• [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: 24th United European Gastroenterology Week
  • Place of Presentation: Vienna(Austria)
  • Year and Date: 2016-10-15
  • Int'l Joint Research
• [Presentation] A case of osteoclast-like giant cell tumor of the pancreas without epithelial differentiation． (2016)
  • Author(s): Kohsaki T，Oe K， Kigi A， Saibara T，Munekage M，Hanazaki K
  • Organizer: the 20th meeting of the International Association of Pancreatology(IAP)and the 6th meeting of the Asian Oceanic Pancreatic Association(AOPA)
  • Place of Presentation: Sendai(Japan)
  • Year and Date: 2016-08-04
  • 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: 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] 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