Molecular pathological analysis of pathogenesis of non-alcoholic steatohepatitis: Propose of new treatment approach

• Project/Area Number: 18590324
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Human pathology
• Research Institution: University of Toyama
• Principal Investigator: TSUNEYAMA Koichi University of Toyama, Graduate School of Medical and Pharmaceutical Science, Associate Professor (10293341)
• Co-Investigator(Kenkyū-buntansha): TAKENO Yasuo University of Toyama, Graduate School of Medical and Pharmaceutical Science, Professor (60142022)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,960,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥360,000); Fiscal Year 2007: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2006: ¥2,400,000 (Direct Cost: ¥2,400,000)
• Keywords: NASH / animal model / oxidative stress / glycation / herval medicine / AGE / RAGE / ガレクチン3

Research Abstract

Metabolic syndrome is one of the most important disease conditions in all over the world. Severe and incurable diseases such as diabetes mellitus, arteriosclerosis and cerebro-vascular diseases were induced from lipid overdeposition in visceral fat. Recently, hepatic manifestation of metabolic syndrome was noted as non-alcoholic fatty liver diseases (NAFLD). Especially, non alcoholic steatohepatitis (NASH), which is severe phenotype of NAFLD is of a serious concern due to its increasing prevalence in the westernized world. Importantly, NASH may ultimately lead to the development of liver cirrhosis and hepatocellular carcinoma even in young generation. To make clarify the disease mechanism of NAFLD under the condition of obesity, we developed several unique animal models based on different disease condition. High-cholesterol fed rat and rabbit showed typical slender fibrosis as well as lipid overload in the liver, similar to human liver fibrosis. While Galectin-3 knock out mice, monosodium-glutamate treated mice and SHR/NDmcr-cp rats showed central obese, type 2 diabetes and marked fatty change with inflammation in predominant to male. We analyzed these animals showing NASH-like liver pathology as well as human liver specimens suffering NASH. In present study, we succeeded to clarify that lipid peroxidation, oxidative stress and glycation play important roles for disease progress of NASH. In addition, we made clarify the preventional roles of NASH using several traditional herval medicines. To find the effective products for metabolic syndrome including NASH is one of the most important contribution for primary care of peoples candidate of metabolic syndrome. We will continue to seek some effective natural products using our animal models.

Research Products

• [Journal Article] Cytoplasmic fine granular expression of 8-hydroxydeoxyguanosine reflects early mitochondrial oxidative NDA damage in nonalcoholic fatty liver disease. (2008)
  • Author(s): Nomoto K, et. al.
  • Journal Title: Appl Immunohistochem Mol Morphol. 16(1) Pages: 71-75
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Monosodium glutamate(MSG): a villain and promoter of liver inflamma tion and dysplasia. (2008)
  • Author(s): Nakanishi Y, et. al.
  • Journal Title: J Autoimmunity 30(1-2) Pages: 42-50
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] A possible rat model for non-alcoholic steatohepatitis: Histological findings in SHR/NDmcr-cp rats. (2008)
  • Author(s): Kato S, et. al.
  • Journal Title: Hepatol Res. 38(7) Pages: 743-744
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Effects of a Long-Term High-Fat Diet and Switching from a High-Fat to Low-Fat, Standard Diet on Hepatic Fat Accumulation in S-D Rats. (2008)
  • Author(s): Omagari K, et. al.
  • Journal Title: Dig Dis Sci. (In press)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Nonalcoholic steatohepatitis and hepatocellular carcinoma in galectin-3 knockout mice. (2008)
  • Author(s): Nakanishi Y, et. al.
  • Journal Title: Hepatol Res. (In press)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Evidence-based efficacy of Kampo formulas in a model of non alcoholic fatty liver. (2008)
  • Author(s): Fujimoto M, et. al.
  • Journal Title: Exp Biol Med(Maywood). 233(3) Pages: 328-337
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Cytoplasmic fine granular expression of 8-hydroxydeoxy guanosine reflects early mitochondrial oxidative DNA damage in nonalcoholic fatty liver disease (2008)
  • Author(s): Nomoto, K., Tsuneyama, K., Takahashi, H., Murai, Y., Takano, Y
  • Journal Title: Appl Immunohi stochem Mol Morphol 16(1) Pages: 71-5
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Nonalcoholic steatohepatitis and hepatocellular carcinoma in galectin-3 knockout mice (2008)
  • Author(s): Nakanishi, Y., Tsuneyama, K., Nomoto, K., Fujimoto, M., Salunga, TL., Nakajima, T., Miwa, S., Murai, Y., Hayashi, S., Kato, I., Hiraga, K., Hsu, DK., Liu, FT., Takano, Y
  • Journal Title: Hepatol Res (In press)
  • NAID: 10023920841
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Monosodium glutamate(MSG): a villain and promoter of liver inflammation and dysplasia (2008)
  • Author(s): Nakanishi, Y., Tsuneyama, K., Fujimoto, M., Salunga, TL., Nomoto, K., An, JL., Takano, Y., Iizuka, S., Nagata, M., Suzuki, W., Shimada, T., Aburada, M., Nakano, M., Selmi, C., Gershwin, ME
  • Journal Title: J Autoimmun 30(1-2) Pages: 42-50
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A possible rat model for non-alcoholic steatohepatitis: Histological findings in SHR/NDmcr-cp rats (2008)
  • Author(s): Kato, S., Omagari, K., Tsuneyama, K., Fukazawa, E., Tsukuda, H., Inohara, C., Kuroda, Y., Shiraishi, K., Mune, M
  • Journal Title: Hepatol Res 38(7) Pages: 743-4
  • NAID: 10021945559
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Effects of a Long-Term High-Fat Diet and Switching from a High-Fat to Low-Fat, Standard Diet on Hepatic Fat Accumulation in Sprague-Dawley Rats (2008)
  • Author(s): Omagari, K., Kato, S., Tsuneyama, K., Inohara, C., Kuroda, Y., Tsukuda, H., Fukazawa, E., Shiraishi, K., Mune, M
  • Journal Title: Dig Dis Sci
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Evidence-based efficacy of Kampo formulas in a model of non alcoholic fatty liver (2008)
  • Author(s): Fujimoto, M., Tsuneyama, K., Kainuma, M., Sekiya, N., Goto, H., Takano, Y., Terasawa, K., Selmi, C., Gershwin, ME., Shimada, Y
  • Journal Title: Exp Biol Med(Maywood) 233(3) Pages: 328-37
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] (MSG): a villain and promoter of liver inflammation and dysplasia (2008)
  • Author(s): Nakanishi Y
  • Journal Title: J. Autoimmun 30 Pages: 42-50
  • Peer Reviewed
• [Journal Article] A possible rat model for non-alcoholic steatohepatitis: Histological findings in SHR/NDmcr-cp rats (2008)
  • Author(s): Kato S
  • Journal Title: Hepatology research (In press)
  • Peer Reviewed
• [Journal Article] Nonalcoholic steatohepatitis and hepatocellular carcinoma in Galectin-3 knockout Mice (2008)
  • Author(s): Nakanishi Y.
  • Journal Title: Hepatology reserch (In press)
  • Peer Reviewed
• [Journal Article] Evidence-based efficacy of Kampo formulas in a model of non alcoholic fatty liver (2008)
  • Author(s): Fujimoto M
  • Journal Title: Exp Biol Med 233 Pages: 328-37
  • Peer Reviewed
• [Journal Article] Cytoplasmic fine granular expression of 8-hydroxydeoxyguanosine reflects early mitochondrial oxidative DNA damage in nonalcoholic fatty liver disease (2008)
  • Author(s): Nomoto K
  • Journal Title: Appl Immunohistochem Mol Morphol 16 Pages: 71-5
  • Peer Reviewed
• [Journal Article] Biliary enithelial cells and primary biliary cirrhosis: the role of liver-infiltrating mononuclear cells (2008)
  • Author(s): Shimoda S.
  • Journal Title: Hepatology 47 Pages: 958-65
  • Peer Reviewed
• [Journal Article] Impaired indoleamine 2,3-dioxygenase production contributes to the development of autoimmunity in primary biliary cirrhosis (2008)
  • Author(s): Oertelt-Prigione S
  • Journal Title: Autoimmunity 30 Pages: 42-50
  • Peer Reviewed
• [Journal Article] Oxidative stress-induced apoptosis of bile duct cells in primary biliary cirrhosis (2007)
  • Author(s): Salunga TL
  • Journal Title: J Autoimmun 29 Pages: 78-86
  • Peer Reviewed
• [Journal Article] Gene expression profiling in whole liver of bile duct ligated rats: VEGFA expression is up-regulated in hepatocytes adjacent to the portal tracts (2007)
  • Author(s): Tanaka A
  • Journal Title: J Gastroenterol Hepatol 22 Pages: 1993-2000
  • Peer Reviewed
• [Journal Article] Induction of primary biliary cirrhosis in guinea pigs following chemicalx enobiotic immunization (2007)
  • Author(s): Leung PS
  • Journal Title: J Immunol 179 Pages: 2651-7
  • Peer Reviewed
• [Journal Article] Knock down of gamma-glutamylcysteine synthetase in rat causes aceta minophen-induced hepatotoxicity (2007)
  • Author(s): Akai S.
  • Journal Title: J Biol Chem 282 Pages: 23996-4003
  • Peer Reviewed
• [Journal Article] Cytoplasmic fine granular expression of 8-Hydroxydeoxyguanosine reflects early mitochondrial oxidative DNA damage in non-alcoholic fatty liver disease (2007)
  • Author(s): Nomoto K
  • Journal Title: Applied Immunohistochemistry Molecular Morphology (in press)
• [Journal Article] Cholesterol-fed rabbit as a unique model of nonalcoholic, nonobese, non-insulin-resistant fatty liver disease with characteristic fibrosis. (2006)
  • Author(s): Kainuma M, et. al.
  • Journal Title: J Gastroenterol. 41(10) Pages: 971-980
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Disrupted galectin-3 causes non-alcoholic fatty liver disease in male mice. (2006)
  • Author(s): Nomoto K, et. al.
  • Journal Title: J Pathol. 210(4) Pages: 469-477
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Cholesterol-fed rabbit as a unique model of nonalcoholic, nonobese, non-insulin-resistant fatty liver disease with characteristic fibrosis (2006)
  • Author(s): Kainuma, M., Fujimoto, M., Sekiya, N., Tsuneyama, K., Cheng, C., Takano, Y., Terasawa, K., Shimada, Y
  • Journal Title: J Gastroenterol 41(10) Pages: 971-80
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Disrupted galectin-3 causes non-alcoholic fatty liver disease in male mice (2006)
  • Author(s): Nomoto, K., Tsuneyama, K., Abdel, Aziz, H0., Takahashi, H., Murai, Y., Cui, ZG., Fujimoto, M., Kato, I., Hiraga, K., Hsu, DK., Liu, FT., Takano, Y
  • Journal Title: J Pathol 210(4) Pages: 469-77
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cholesterol-fed rabbit as a unique model of nonalcoholic, nonobese, non-insulin resistant fatty liver disease with characteristic fibrosis. (2006)
  • Author(s): Kainuma M
  • Journal Title: J Gastroenterol 41(10) Pages: 971-980
• [Journal Article] Disrupted galectin-3 causes non-alcoholic fatty liver disease in male mice. (2006)
  • Author(s): Nomoto K
  • Journal Title: J Pathol 210(4) Pages: 469-477
• [Journal Article] RAGE control of diabetic nephropathy in a mouse model : effects of RAGE gene disruption and administration of low-molecular weight heparin. (2006)
  • Author(s): Myint KM
  • Journal Title: Diabetes 55(9) Pages: 2510-2522
• [Journal Article] Identification of mouse orthologue of endogenous secretory receptor for advanced glycation end-products : structure, function and expression. (2006)
  • Author(s): Harashima A
  • Journal Title: Biochem J. 396(1) Pages: 109-115
• [Presentation] Monosodium glutamate injection induces a new comprehensive model of lifestyle-related non alcoholic fatty liver disease with neoplastic nodules (2008)
  • Author(s): Nakanishi, Y., Tsuneyama, K., Fujimoto, M., Salunga, TL., Nomoto, K., An, JL., Gershwin, ME
  • Organizer: 43rd Annual Meeting of the European Association for the Study of the Liver(EASL)
  • Place of Presentation: Milan, Italy
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Evidence-Based Efficacy of Kampo Formulas on Liver Pathology in a Rabbit Model of Non Alcoholic Fatty Liver Disease (2007)
  • Author(s): Fujimoto M
  • Organizer: The 14th International Congress of Oriental Medi cine
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2007-12-10
• [Presentation] 非アルコール性脂肪性肝障害(NAFLD)の病態解析と漢方方剤の効果・新規モデル動物を用いた検討. (2007)
  • Author(s): 常山幸一
  • Organizer: 富山大学21世紀COEプログラムシンポジウム「東洋の知に立脚した個の医療の創生」
  • Place of Presentation: 富山
  • Year and Date: 2007-11-16
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] The Traditional Japanese Kampo Formula keishibukuryogan Ameliorates Steatosis, Reduces Oxidative Stress and Inflammation, and Ultimately Prevents Liver Fibrosis in a Rabbit Model of Non Alcoholic Steatohepatitis (2007)
  • Author(s): Fujimoto M
  • Organizer: The 58th Annual Meeting of The American Association for The Study of Liver Diseases
  • Place of Presentation: Boston, USA
  • Year and Date: 2007-11-07
• [Presentation] Impairment of the indoleamine 2,3-Dioxygenase pathway in primary biliary cirrhosis (2007)
  • Author(s): Oertelt-Prigione S
  • Organizer: The 58th Annual Meeting of The American Association for The Study of Liver Diseases
  • Place of Presentation: Boston, USA
  • Year and Date: 2007-11-05
• [Presentation] Induction of primary biliary cirrhosis in guinea pigs using chemical xenobiotic immunization: implications for tolerance and the etiology of hum an PBC (2007)
  • Author(s): Leung PS
  • Organizer: The 58th Annual Meeting of The American Association for The Study of Liver Diseases
  • Place of Presentation: Boston, USA
  • Year and Date: 2007-11-05
• [Presentation] Strategy of future food science and food business. (2007)
  • Author(s): Tsuneyama K.
  • Organizer: 21st COE seminar "Integrate of New lnsights between Western and Eastern Medicines"
  • Place of Presentation: Davis, USA
  • Year and Date: 2007-08-27
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] メタボリックシンドロームモデル動物に出現する非アルコール性脂肪性肝障害(NAFLD)の病理学的特徴 (2007)
  • Author(s): 常山幸一
  • Organizer: 第3回TSOD(肥満・糖尿病)マウス研究会情報交換会
  • Place of Presentation: 東京
  • Year and Date: 2007-08-10
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] メタボリツクシンドロームモデル動物に出現する非アルコール性脂肪性肝障害(NAFLD)の病理学的特徴 (2007)
  • Author(s): 常山 幸一
  • Organizer: 第3回TSOD(肥満・糖尿病)マウス研究会情報交換会
  • Place of Presentation: 東京
  • Year and Date: 2007-08-10
• [Presentation] 病理医からみたメタボリックシンドローム (2007)
  • Author(s): 常山幸一
  • Organizer: 富山大学公開講座、「知っ得?納得!メタボリックシンドローム」
  • Place of Presentation: 富山
  • Year and Date: 2007-08-04
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] The Traditional Japanese Kampo Formula keishibukuryogan Ameliorates Steatosis, Reduces Oxidative Stress and Inflammation, and Ultimately Prevents Liver Fibrosis in a Rabbit Model of Non Alcoholic Steatohepatitis. (2007)
  • Author(s): Fujimoto M, et. al.
  • Organizer: The 58th Annual Meeting of The American Association for The Study of Liver Diseases
  • Place of Presentation: Boston, USA
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Evidence-Based Efficacy of Kampo Formulas on Liver Pathology in a Rabbit Model of Non Alcoholic Fatty Liver Disease. (2007)
  • Author(s): Fujimoto M, et. al.
  • Organizer: The 14th International Congress of Oriental Medicine
  • Place of Presentation: Taipei, Taiwan
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Japanese Herbal Medicines in the Prevention of Hepatic Fibrosis in NAFLD (2007)
  • Author(s): Fujimoto M, et. al.
  • Organizer: The United States and Canadian Academy of Pathology, annual meeting 2007
  • Place of Presentation: San Diego, USA
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] The Traditional Japanese Kampo Formula keishibukuryogan Ameliorates Steatosis, Reduces Oxidative Stress and Inflammation and Ultimately Prevents Liver Fibrosis in a Rabbit Model of Non Alcoholic Steatohepatitis (2007)
  • Author(s): Fujimoto, M., Tsuneyama, K., Kainuma, M., Sekiya, N., Goto, H., Takano, Y., Terasawa, K., Selmi, C., Gershwin, ME., Shimada, Y
  • Organizer: The 58th Annual Meeting of The American Association for The Study of Liver Diseases
  • Place of Presentation: Boston, USA
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Disrupted galectin-3 causes nonalcoholic fatty liver disease in mice. (2006)
  • Author(s): Tsuneyama K, et. al.
  • Organizer: 20th IUBMB International Congress of Biochemistry and Molecular Biology and 11th FAOBMB Congress
  • Place of Presentation: Kyoto
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] 非アルコール性脂肪性肝障害モデルの病態解析と漢方方剤の効果-コレステロール負荷ウサギを用いた検討- (2006)
  • Author(s): 常山幸一
  • Organizer: 北里大学21世紀COEプログラム・富山大学21世紀COEプログラム「天然資源からの抗感染症薬と病態制御へのアプローチ-東洋の知と生命科学の融合-」
  • Place of Presentation: 東京
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Disrupted galectin-3 causes nonalcoholic fatty liver disease in mice (2006)
  • Author(s): Tsuneyama, K., Nomoto, K., Kato, I., Hiraga, K., Takano, Y
  • Organizer: 20th IUBMB International Congress of Biochemistry and Molecular Biology and 11th FAOBMB Congress
  • Place of Presentation: Kyoto
  • Description: 「研究成果報告書概要(欧文)」より
• [Remarks] 「研究成果報告書概要(和文)」より
  • URL: http://www.med.u-toyama.ac.jp/dpathol/index.html