The study for the pathogenesis of NASH using three kinds of PNPLA3 gene-modified mice

• Project/Area Number: 16K19351
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Kochi University
• Principal Investigator: OCHI Tsunehiro 高知大学, 教育研究部医療学系基礎医学部門, 助教 (30617840)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2018: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: NASH / PNPLA3 / PNPLA3 mutation / XBP-1 / 肝臓学

Outline of Final Research Achievements

A sequence variation (I148M) in the patatin-like phospholipase domain-containing protein 3/adiponutrin(PNPLA3) gene and Endoplasmic reticulum (ER) stress have been reported to be important pathological characteristics in NAFLD/NASH. To clarify, therefore, the pathogenesis of NAFLD/NASH, we established three kinds of PNPLA3 gene-modified mice and investigated the phenotypes and involved factors under ER stress and other conditions. Our observations would indicate that PNPLA3 has an important role in hepatic fatty acid and triglyceride metabolism through XBP1 under ER stress. Moreover, human PNPLA3I148M knockin mice had a tendency to develop hepatic steatosis with high fat diet. Taken together, PNPLA3 and ER stress are important for the pathogenesis of NAFLD/NASH.

Academic Significance and Societal Importance of the Research Achievements

近年、メタボリックシンドロームとされる肥満、糖尿病、高血圧、脂質異常症は増加の一途であり、わが国でも社会問題となっている。それと並行して、メタボリックシンドロームを原因とした脂肪肝とそれに伴う慢性肝疾患（NAFLD/NASH）も増加してきている。
PNPLA3遺伝子多型およびERストレスが関与しているNAFLD/NASH発症メカニズムを解明することは、今まで推奨されてきた食事療法・運動療法などの治療に加えて、患者の病態に合わせたオーダーメイド治療や新たな創薬へ繋がることが期待され、学術的・社会的意義は高いものと思われる。

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] 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] 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] 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
• [Presentation] EVALUATION OF IMPAIRED FATTY ACID OXIDATION CAPACITY BY DYNAMIC LIVER SCINTIGRAPHY WITH 1231-BMIPP IS IMPORTANT IN THE DEVELOPMENT OF NONALCOHOLIC FATTY LIVER DISEASE IN NON-OBESE PATIENTS (2018)
  • Author(s): Yamamoto S, Ono M, Masuda K, Nagano S, Yano Y, Kitagawa T, Hashiba M, Ochi T, Munekage K, Hirose A, Mizuta H, Saibara T
  • Organizer: DDW2018
  • Int'l Joint Research
• [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] 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] 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: Austria Vienna（Austria Center Vienna）
  • Year and Date: 2016-10-15
• [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 Liver）
  • Place of Presentation: Spain Barcelona（Fira Barcelona Gran Via）
  • Year and Date: 2016-04-13
• [Book] 消化器疾患最新の治療2017-2018 (2017)
  • Author(s): 越智経浩／西原利治
  • Total Pages: 504
  • Publisher: 南江堂
• [Book] Mebio (2016)
  • Author(s): 越智経浩／小野正文／西原利治
  • Total Pages: 108
  • Publisher: メジカルレビュー社