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

2017 Fiscal Year Annual Research Report

• Project/Area Number: 15K09010
• Research Institution: Kochi University
• Principal Investigator: 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)
• 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
• Keywords: PPAR-alpha / melanocortin receptor / insulin resistance / fatty liver / IL-6 / NASH / hepatocellular carcinoma / knockout mouse

Outline of Annual Research Achievements

MC4R KO自然肝発癌モデルマウスは通常食の給餌下でも極めて強いインスリン抵抗性を示す。８週令に達すると空腹時血糖は正常であるが、野生型に比して高インスリン血症を示す。このような変化は20週令に至るまで持続した。しかし、16週令より尿糖が急激に増加し、体重の減少を認める個体が増加した。そこで、12週令よりインスリンを投与して尿糖を軽減したところ、その後の体重を維持することができた。他方、MC4RとPPAR-αのdouble KOマウスでは野生型に比してインスリン抵抗性が軽減されたが、20週令では野生型に比して耐糖能の低下がより顕著となり、多量の尿糖が続き体重の減少を生じてインスリン感受性は野生型と同等となった。そこで、MC4R KOと同様に12週令よりインスリンを投与して尿糖を軽減したところ、その後の体重を維持することができた。８週齢以降のMC4R KOマウスでは、既知の脂肪酸合成関連の遺伝子の発現が増強され、炎症関連遺伝子の発現も増強された。脂肪酸β酸化およびω酸化関連遺伝子群やスカベンジャー受容体の発現も継時的に増強された。自然経過では体重の減少とともに、その発現が低下したが、インスリンを併用して体重を維持することにより高発現を維持することができた。炎症性細胞浸潤に伴いIL-6の発現亢進が認められたが、これもβ細胞の枯渇に伴いその発現が抑制されたが、インスリンを併用して体重を維持することにより炎症細胞浸潤を維持することができ、IL-6の発現亢進を継続することが可能であった。このため48週齢の検討では、MC4R KOマウスにおける肝腫瘍発生数に比べてMC4RとPPAR-αのdouble KOマウスでは腫瘍数が有意に抑制できた。

Research Products

• [Journal Article] Prevalence of pruritus in patients with chronic liver disease: a multicenter study (2018)
  • Author(s): Oeda S, Takahashi H, Yoshida H, Ogawa Y, Imajo K, Yoneda M, Koshiyama Y, Ono M, Hyogo H, Kawaguchi T, Fujii H, Nishino K, Sumida Y, Tanaka S, Kawanaka M, Torimura T, Saibara T, Kawaguchi A, Nakajima A, Eguchi Y; Japan Study Group for NAFLD (JSG-NAFLD)
  • Journal Title: Hepatol Res Volume: 48 Pages: E252-E262
  • DOI: 10.1111/hepr.12978.
  • Peer Reviewed
• [Journal Article] Analysis of factors influencing glucose tolerance in Japanese patients with non-alcoholic fatty liver disease． (2018)
  • Author(s): Ohmi S，Ono M，Takata H，Hirano S，Funakoshi S， Nishi Y，Yoshimura K，Amano E，Terada Y，Saibara T，Fujimoto S
  • Journal Title: Diabetol Metab Syndr Volume: 9 Pages: 65
  • DOI: 10.1186/s13098-017-0264-7
  • Peer Reviewed
• [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: - Pages: -
  • DOI: 10.1097/MEG.0000000000001118.
  • Peer Reviewed
• [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: - Pages: -
  • 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 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: 622 Pages: 47-58
  • DOI: 10.1016/j.abb.2017.03.007.
  • Peer Reviewed
• [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 Nonalcoholic Fatty Liver Disease (JSG‐NAFLD)
  • Journal Title: Hepatol Commun Volume: 1 Pages: 780-791
  • DOI: 10.1002/hep4.1080
  • Peer Reviewed
• [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 (2017)
  • Author(s): Masuda K, Noguchi S, Ono M, Ochi T, Munekage K, Okamoto N, Suganuma N, Saibara T
  • Journal Title: Hepatol Res Volume: 47 Pages: 983-990
  • DOI: 10.1111/hepr.12832
  • Peer Reviewed
• [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: Sci Rep Volume: 7 Pages: 10146
  • DOI: 10.1038/s41598-017-09256-4
  • 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 Pages: 17681-17702
  • DOI: 10.1074/jbc.M116.772780
  • 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，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