Elucidation of the pathogenesis of NASH and hepatocellular carcinoma induced by dietary fatty acid, and development of therapeutic strategies based on its pathogenesis

• Project/Area Number: 15K00874
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Eating habits
• Research Institution: Ehime University
• Principal Investigator: Teruki Miyake 愛媛大学, 医学部附属病院, 講師 (80573659)
• 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: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: NASH / hepatocellular carcinoma / High fat diet / NOX2 / trans fatty acid / トランス脂肪酸

Outline of Final Research Achievements

To elucidate the mechanism of nonalcoholic steatohepatitis and hepatocellular carcinoma (HCC) caused by excessive intake of fatty acid , we analyzed the mechanism of generation of oxidative stress in obese mice induced by three different types of high fat diet, 1) high trans fatty acid, 2) high oleic acid, or 3) high palmitic acid. A number of HCC was significantly increased in high trans fatty acid fed group compared with other two groups. Further, expression of a factor which related to lipid deposition was significantly higher in the high trans fatty acid diet fed mice. The over expression of the factor by excess trans acid facilitated the accumulation of inflammatory macrophage which express NOX2 and resulted in excessive oxidative stress. On the other hand, liver specific suppression of the factor related to lipid deposition in high trans fatty acid fed mice reduced the number of inflammatory macrophages and the expression of oxidative stress in the liver.

Research Products

• [Journal Article] Relationship between urine pH and abnormal glucose tolerance in a community-based study. (2018)
  • Author(s): Yoshida S, Miyake T, Yamamoto S, Furukawa S, Niiya T, Senba H, Kanzaki S, Yoshida O, Ishihara T, Koizumi M, Hirooka M, Kumagi T, Abe M, Kitai K, Matsuura B, Hiasa Y
  • Journal Title: Journal of Diabetes Investigation Volume: 印刷中 Issue: 4 Pages: 769-775
  • DOI: 10.1111/jdi.12777
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Differences in the risk of fatty liver for onset of impaired fasting glucose according to baseline plasma glucose levels (2017)
  • Author(s): Miyake T, Hirooka M, Yoshida O, Furukawa S, Kumagi T, Koizumi M, Yamamoto S, Kuroda T, Arimitsu E, Takeshita E, Abe M, Kitai K, Matsuura B, Hiasa Y
  • Journal Title: J Gastroenterol Volume: 52 Issue: 2 Pages: 237-244
  • DOI: 10.1007/s00535-016-1234-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Free testosterone concentration is inversely associated with markers of liver fibrosis in men with type 2 diabetes mellitus (2017)
  • Author(s): Miyauchi S, Miyake T, Miyazaki M, Eguchi T, Niiya T, Yamamoto S, Senba H, Furukawa S, Matsuura B, Hiasa Y
  • Journal Title: Endocrine Journal Volume: 64 Issue: 12 Pages: 1137-1142
  • DOI: 10.1507/endocrj.EJ17-0225
  • NAID: 130006287808
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Low alcohol consumption increases the risk of impaired glucose tolerance in patients with non-alcoholic fatty liver disease. (2016)
  • Author(s): Teruki Miyake
  • Journal Title: Journal of Gastroenterology Volume: 印刷中 Issue: 11 Pages: 1090-1100
  • DOI: 10.1007/s00535-016-1194-0
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 日本人2型糖尿病患者における血清Lipoprotein(a)濃度と糖尿病性腎症との関連について (2017)
  • Author(s): 仙波英徳，古川慎哉，三宅映己，山本晋，田中景子，松浦文三，日浅陽一，三宅吉博
  • Organizer: 第114回日本内科学会総会
• [Presentation] 非アルコール性脂肪性肝疾患の囲い込みにおける尿pH検査の有用性についての有用性について (2017)
  • Author(s): 三宅映己，仙波英徳，山本晋，吉田理，徳本良雄，廣岡昌史，古川慎哉，熊木天児，阿部雅則，小堀友恵，松浦文三，日浅陽一
  • Organizer: 第4回肝臓と糖尿病・代謝研究会
• [Presentation] Increase of serum chylomicron triglyceride concentration associated with intestinal overproduction of chylomicron triglyceride in nonobese, nondiabetic and normolipidemic NASH patients (2017)
  • Author(s): Hiroki Utsunomiya, Masakazu Hanayama, Yasunori Yamamoto, Eiji Takeshita, Yoshio Tokumoto, Teruki Miyake, Masashi Hirooka, Teru Kumagi, Bunzo Matsuura, Masanori Abe, Yoshio Ikeda, Yoichi Hiasa
  • Organizer: AASLD The Liver Meeting 2017
  • Int'l Joint Research
• [Presentation] 食事中脂肪酸分画がNAFLD発症に及ぼす影響 (2016)
  • Author(s): 三宅映己
  • Organizer: 第102回日本消化器病学会総会
  • Place of Presentation: 東京都新宿区西新宿2-2-1 京王プラザホテル
  • Year and Date: 2016-04-21
• [Presentation] 食事中脂肪酸分画がNAFLD発症に及ぼす影響 (2016)
  • Author(s): 三宅映己
  • 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] 飲酒量別にみた脂肪肝が耐糖能異常発症に及ぼす影響の検討 (2016)
  • Author(s): 三宅映己
  • Organizer: 第89回日本内分泌学会学術総会
  • Place of Presentation: 国立京都国際会館 京都府京都市
  • Year and Date: 2016-04-21