過栄養状態における肝臓機能の破綻と生活習慣病の研究

2010 年度 研究成果報告書

• 研究課題/領域番号: 18109008
• 研究種目: 基盤研究(S)
• 配分区分: 補助金
• 研究分野: 消化器内科学
• 研究機関: 金沢大学
• 研究代表者: 金子 周一 金沢大学, 医学系, 教授 (60185923)
• 研究分担者: 中沼 安二 金沢大学, 医学系, 教授 (10115256)
• 連携研究者: 本多 政夫 金沢大学, 保健学系, 教授 (00272980) ; 篁 俊成 金沢大学, 医学系, 准教授 (00324111)
• 研究期間 (年度): 2006 – 2010
• キーワード: ゲノム / 発現制御 / 肝臓 / 栄養 / 生活習慣病 / 糖尿病

研究概要

肝臓は、糖・タンパク・脂質の代謝や薬物および異物の解毒を専門とする巨大な臓器である。大量の物質を血液から取り込んで代謝し、全身の臓器に代謝物を供給する。21世紀の最大の課題である動脈硬化、糖尿病、癌、炎症といった栄養状態が関与する症候群に、肝臓の機能破綻が大きく関与している可能性を示した。本研究は、過栄養状態における肝臓の変化を明らかにすることによって新たな肝臓病の疾病概念を確立するとともに、肝臓機能の破綻によって生じる肝代謝異常の診断および治療法開発の基盤となるべき研究を行った。

研究成果

• [雑誌論文] A liver-derived secretory protein, selenoprotein P, causes insulin resistance. (2010)
  • 著者名/発表者名: H Misu, T Takamura, H Takayama, H Hayashi, N Matsuzawa-Nagata, S Kurita, K Ishikura, H Ando, Y Takeshita, T Ota, M Sakurai, T Yamashita, E Mizukoshi, T Yamashita, M Honda, K Miyamoto, T Kubota, N Kubota, T Kadowaki, HJ Kim, IK Lee, Y Minokoshi, Y Saito, K Takahashi, Y Yamada, N Takakura, S Kaneko.
  • 雑誌名: Cell Metab 12(5) ページ: 483-495
  • 査読あり
• [雑誌論文] Differential interferon signaling in liver lobule and portal area cells under treatment for chronic hepatitis (2010)
  • 著者名/発表者名: M Honda, M Nakamura, M Tateno, A Sakai, T Shimakami, T Shirasaki, T Yamashita, K Arai, T Yamashita, Y Sakai, S Kaneko.
  • 雑誌名: C.J Hepatol 53(5) ページ: 817-826
  • 査読あり
• [雑誌論文] Hokuriku Liver Study Group. Differential gene expression profiling in blood from patients with digestive system cancers. (2010)
  • 著者名/発表者名: M Honda, Y Sakai, T Yamashita, T Yamashita, A Sakai, E Mizukoshi, Y Nakamoto, I Tatsumi, Y Miyazaki, H Tanno, S Kaneko
  • 雑誌名: Biochem Biophys Res Commun 400(1) ページ: 7-15
  • 査読あり
• [雑誌論文] Hepatocellular Carcinoma : Signal Intensity at Gadoxetic Acid-enhanced MR Imaging-Correlation with Molecular Transporters and Histopathologic Features. (2010)
  • 著者名/発表者名: A Kitao, Y Zen, O Matsui, T Gabata, S Kobayashi, W Koda, K Kozaka, N Yoneda, T Yamashita, S Kaneko, Y Nakanuma.
  • 雑誌名: Radiology 256(3) ページ: 817-826
  • 査読あり
• [雑誌論文] Antitumor Effect after Radiofrequency Ablation of Murine Hepatoma Is Augmented by an Active Variant of CC Chemokine Ligand 3/Macrophage Inflammatory Protein-1α. (2010)
  • 著者名/発表者名: S Kaneko
  • 雑誌名: Cancer Res 70(16) ページ: 6556-6565
  • 査読あり
• [雑誌論文] Hokuriku Liver Study Group. Hepatic ISG expression is associated with genetic variation in IL28B and the outcome of IFN therapy for chronic hepatitis C. (2010)
  • 著者名/発表者名: M Honda, A Sakai, T Yamashita, Y Nakamoto, E Mizukoshi, Y Sakai, T Yamashita, M Nakamura, T Shirasaki, K Horimoto, Y Tanaka, K Tokunaga, M Mizokami, S Kaneko
  • 雑誌名: Gastroenterology 139(2) ページ: 499-509
  • 査読あり
• [雑誌論文] Oncostatin m renders epithelial cell adhesion molecule-positive liver cancer stem cells sensitive to 5-Fluorouracil by inducing hepatocytic differentiation. (2010)
  • 著者名/発表者名: T Yamashita, M Honda, K Nio, Y Nakamoto, T Yamashita, H Takamura, T Tani, Y Zen, S Kaneko.
  • 雑誌名: Cancer Res 70(11) ページ: 4687-4697
  • 査読あり
• [雑誌論文] Enhancement of tumor-specific T cell responses by transcatheter arterial embolization with dendritic cell infusion for hepatocellular carcinoma. (2010)
  • 著者名/発表者名: S Kaneko
  • 雑誌名: Int J Cancer 126(9) ページ: 2164-2174
  • 査読あり
• [雑誌論文] Comprehensive gene expression analysis of 5'-end of mRNA identified novel intronic transcripts associated with hepatocellular carcinoma. (2010)
  • 著者名/発表者名: Y Hodo, SI Hashimoto, M Honda, T Yamashita, Y Suzuki, S Sugano, S Kaneko, K Matsushima.
  • 雑誌名: Genomics 95(4) ページ: 217-223
  • 査読あり
• [雑誌論文] CD14+monocytes are vulnerable and functionally impaired under ER stress in patients with type 2 diabetes. (2010)
  • 著者名/発表者名: T Komura, Y Sakai, M Honda, T Takamura, K Matsushima, S Kaneko.
  • 雑誌名: Diabetes 59(3) ページ: 634-643
  • 査読あり
• [雑誌論文] Altered hepatic gene expression profiles associated with myocardial ischemia. (2010)
  • 著者名/発表者名: H Ootsuji, M Honda, S Kaneko, S Usui, M Okajima, H Okada, Y Sakai, T Takamura, K Horimoto, M Takamura.
  • 雑誌名: Circ Cardiovasc Genet 3(1) ページ: 68-77
  • 査読あり
• [雑誌論文] The histological course of nonalcoholic fatty liver disease in Japanese patients : Tight glycemic control, rather than weight reduction, ameliorates liver fibrosis. (2010)
  • 著者名/発表者名: E Hamaguchi, T Takamura, M Sakurai, E Mizukoshi, Y Zen, Y Takeshita, S Kurita, K Arai, T Yamashita, M Sasaki, Y Nakanuma, S Kaneko.
  • 雑誌名: Diabetes Care 33(2) ページ: 284-286
  • 査読あり
• [雑誌論文] J-shaped relationship between waist circumference and subsequent risk for Type 2 diabetes : an 8-year follow-up of relatively lean Japanese individuals. (2009)
  • 著者名/発表者名: M Sakurai, K Miura, T Takamura, M Ishizaki, Y Morikawa, K Nakamura, K Yoshita, T Kido, Y Naruse, S Kaneko, H Nakagawa.
  • 雑誌名: Diabet Med 26(8) ページ: 753-759
  • 査読あり
• [雑誌論文] Palmitate Induces Insulin Resistance in H4IIEC3 Hepatocytes through Reactive Oxygen Species Produced by Mitochondria. (2009)
  • 著者名/発表者名: S Nakamura, T Takamura, N Matsuzawa-Nagata, H Takayama, H Misu, H Noda, S Nabemoto, S Kurita, T Ota, H Ando, K Miyamoto, S Kaneko.
  • 雑誌名: J Biol Chem 284(22) ページ: 14809-14818
  • 査読あり
• [雑誌論文] The hepatic circadian clock is preserved in a lipid-induced mouse model of non-alcoholic steatohepatitis. (2009)
  • 著者名/発表者名: H Ando, T Takamura, N Matsuzawa-Nagata, KR Shima, S Nakamura, M Kumazaki, S Kurita, H Misu, N Togawa, T Fukushima, A Fujimura, S Kaneko.
  • 雑誌名: Biochem Biophys Res Commun 380(3) ページ: 684-688
  • 査読あり
• [雑誌論文] Middle-aged Japanese women are resistant to obesity-related metabolic abnormalities. (2009)
  • 著者名/発表者名: M Sakurai, T Takamura, K Miura, S Kaneko, H Nakagawa.
  • 雑誌名: Metabolism 58(4) ページ: 456-459
  • 査読あり
• [雑誌論文] Differential microRNA expression between hepatitis B and hepatitis C leading disease progression to hepatocellular carcinoma. (2009)
  • 著者名/発表者名: S Ura, M Honda, T Yamashita, T Ueda, H Takatori, R Nishino, H Sunakozaka, Y Sakai, K Horimoto, S Kaneko.
  • 雑誌名: Hepatology 49(4) ページ: 1098-1112
  • 査読あり
• [雑誌論文] EpCAM-Positive Hepatocellular Carcinoma Cells Are Tumor-Initiating Cells With Stem/Progenitor Cell Features. (2009)
  • 著者名/発表者名: T Yamashita, J Ji, A Budhu, M Forgues, W Yang, HY Wang, H Jia, Q Ye, LX Qin, E Wauthier, LM Reid, H Minato, M Honda, S Kaneko, ZY Tang, XW Wang.
  • 雑誌名: Gastroenterology 136(3) ページ: 1012-1024
  • 査読あり
• [雑誌論文] Clock gene expression in peripheral leucocytes of patients with type 2 diabetes. (2009)
  • 著者名/発表者名: H Ando, T Takamura, N Matsuzawa-Nagata, KR Shima, T Eto, H Misu, M Shiramoto, T Tsuru, S Irie, A Fujimura, S Kaneko.
  • 雑誌名: Diabetologia 52(2) ページ: 329-335
  • 査読あり
• [雑誌論文] Activation of lipogenic pathway correlates with cell proliferation and poor prognosis in hepatocellular carcinoma. (2009)
  • 著者名/発表者名: T Yamashita, M Honda, H Takatori, R Nishino, H Minato, H Takamura, T Ohta, S Kaneko.
  • 雑誌名: J Hepatology 50(1) ページ: 100-110
  • 査読あり
• [雑誌論文] Common transcriptional signature of tumor-infiltrating mononuclear inflammatory cells and peripheral blood mononuclear cells in hepatocellular carcinoma patients. (2008)
  • 著者名/発表者名: Y Sakai, M Honda, H Fujinaga, I Tatsumi, E Mizukoshi, Y Nakamoto, S Kaneko.
  • 雑誌名: Cancer Res 68(24) ページ: 10267-10279
  • 査読あり
• [雑誌論文] Obesity upregulates genes involved in oxidative phosphorylation in livers of diabetic patients. (2008)
  • 著者名/発表者名: T Takamura, H Misu, N Matsuzawa-Nagata, M Sakurai, T Ota, A Shimizu, S Kurita, Y Takeshita, H Ando, M Honda, S Kaneko.
  • 雑誌名: Obesity (Silver Spring) 16(12) ページ: 2601-2609
  • 査読あり
• [雑誌論文] Comparative analysis of proteome and transcriptome in human hepatocellular carcinoma using 2D-DIGE and SAGE. (2008)
  • 著者名/発表者名: H Minagawa, T Yamashita, M Honda, Y Tabuse, K Kamijo, A Tsugita, S Kaneko.
  • 雑誌名: Protein J 27(7-8) ページ: 409-419
  • 査読あり
• [雑誌論文] SAGE application in the study of diabetes. (2008)
  • 著者名/発表者名: T Takamura, H Misu, T Yamashita, S Kaneko.
  • 雑誌名: Curr Pharm Biotechnol 9(5) ページ: 392-399
  • 査読あり
• [雑誌論文] Optimal amount of monocyte chemoattractant protein-1 enhances antitumor effects of suiside gene therapy against hepatocelluar carcinoma by M1 macrophage activation. (2008)
  • 著者名/発表者名: T Tsuchiyama, Y Nakamoto, Y Sakai, N Mukaida, S Kaneko.
  • 雑誌名: Cancer Sci 99(10) ページ: 2075-2082
  • 査読あり
• [雑誌論文] Increased oxidative stress precedes the onset of high-fat diet-induced insulin resistance and obesity. (2008)
  • 著者名/発表者名: N Matsuzawa-Nagata, T Takamura, H Ando, S Nakamura, S Kurita, H Misu, T Ota, M Yokoyama, M Honda, K Miyamoto, S Kaneko.
  • 雑誌名: Metabolism 57(8) ページ: 1071-1077
  • 査読あり
• [雑誌論文] Tranilast, an antifibrogenic agent, ameliorates a dietary rat model of nonalcoholic steatohepatitis. (2008)
  • 著者名/発表者名: M Uno, S Kurita, H Misu, H Ando, T Ota, N Matsuzawa-Nagata, Y Kita, S Nabemoto, H Akahori, Y Zen, Y Nakanuma, S Kaneko, T Takamura.
  • 雑誌名: Hepatology 48(1) ページ: 109-118
  • 査読あり
• [雑誌論文] Olmesartan ameliorates a dietary rat model of non-alcoholic steatohepatitis through its pleiotropic effects. (2008)
  • 著者名/発表者名: S Kurita, T Takamura, T Ota, N Matsuzawa-Nagata, Y Kita, M Uno, S Nabemoto, K Ishikura, H Misu, H Ando, Y Zen, Y Nakanuma, S Kaneko.
  • 雑誌名: Eur J Pharmacol 588(2-3) ページ: 316-324
  • 査読あり
• [雑誌論文] Protein expression profile characteristic to hepatocellular carcinoma revealed by 2D-DIGE with supervised learning. (2008)
  • 著者名/発表者名: R Teramoto, H Minagawa, M Honda, K Miyazaki, Y Tabuse, K Kamijo, T Ueda, S Kaneko.
  • 雑誌名: Biochim Biophys Acta 1784(5) ページ: 764-772
  • 査読あり
• [雑誌論文] BMI may be better than waist circumference for defining metabolic syndrome in Japanese women. (2008)
  • 著者名/発表者名: M Sakurai, T Takamura, K Miura, S Kaneko, H Nakagawa.
  • 雑誌名: Diabetes Care 31(3) ページ: 12
  • 査読あり
• [雑誌論文] Comparative proteomic and transcriptomic profiling of the human hepatocellular carcinoma. (2008)
  • 著者名/発表者名: H Minagawa, M Honda, K Miyazaki, Y Tabuse, R Teramoto, T Yamashita, R Nishino, H Takatori, T Ueda, K Kamijo, S Kaneko.
  • 雑誌名: Biochem Biophys Res Commun 366(1) ページ: 186-192
  • 査読あり
• [雑誌論文] Cross talk of tumor necrosis factor-alpha and the renin-angiotensin system in tumor necrosis factor-alpha-induced plasminogen activator inhibitor-1 production from hepatocytes. (2008)
  • 著者名/発表者名: Y Takeshita, T Takamura, H Ando, E Hamaguchi, A Takazakura, N Matsuzawa-Nagata, S Kaneko.
  • 雑誌名: Eur J Pharmacol 579(1-3) ページ: 426-432
  • 査読あり
• [雑誌論文] Impact of diabetes mellitus on prognosis of patients infected with hepatitis C virus. (2007)
  • 著者名/発表者名: Y Kita, E Mizukoshi, T Takamura, M Sakurai, Y Takata, K Arai, T Yamashita, Y Nakamoto, S Kaneko.
  • 雑誌名: Metabolism 56(12) ページ: 1682-1288
  • 査読あり
• [雑誌論文] Regulation of adiponectin receptor expression in human liver and a hepatocyte cell line. (2007)
  • 著者名/発表者名: A Shimizu, T Takamura, N Matsuzawa, S Nakamura, S Nabemoto, Y Takeshita, H Misu, S Kurita, M Sakurai, M Yokoyama, Y Zen, M Sasaki, Y Nakanuma, S Kaneko.
  • 雑誌名: Metabolism 56(11) ページ: 1478-1485
  • 査読あり
• [雑誌論文] Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet. (2007)
  • 著者名/発表者名: N Matsuzawa, T Takamura, S Kurita, H Misu, T Ota, H Ando, M Yokoyama, M Honda, Y Zen, Y Nakanuma, K Miyamoto, S Kaneko.
  • 雑誌名: Hepatology 46(5) ページ: 1392-1403
  • 査読あり
• [雑誌論文] Gene expression profiles in peripheral blood mononuclear cells reflect the pathophysiology of type 2 diabetes. (2007)
  • 著者名/発表者名: T Takamura, M Honda, Y Sakai, H Ando, A Shimizu, T Ota, M Sakurai, H Misu, S Kurita, N Matsuzawa-Nagata, M Uchikata, S Nakamura, R Matoba, M Tanino, K Matsubara, S Kaneko.
  • 雑誌名: Biochem Biophys Res Commun 361(2) ページ: 379-384
  • 査読あり
• [雑誌論文] Possible role of alpha-cell insulin resistance in exaggerated glucagon responses to arginine in type 2 diabetes. (2007)
  • 著者名/発表者名: N Tsuchiyama, T Takamura, H Ando, M Sakurai, A Shimizu, K Kato, S Kurita, S Kaneko.
  • 雑誌名: Diabetes Care 30(10) ページ: 2583-2587
  • 査読あり
• [雑誌論文] Liver steatosis, but not fibrosis, is associated with insulin resistance in nonalcoholic fatty liver disease. (2007)
  • 著者名/発表者名: M Sakurai, T Takamura, T Ota, H Ando, H Akahori, K Kaji, M Sasaki, Y Nakanuma, K Miura, S Kaneko.
  • 雑誌名: J Gastroenterol 42(4) ページ: 312-317
  • 査読あり
• [雑誌論文] Selective estrogen receptor modulator raloxifene-associated aggravation of nonalcoholic steatohepatitis. (2007)
  • 著者名/発表者名: T Takamura, A Shimizu, H Ando, S Kaneko.
  • 雑誌名: Intern Med 46(9) ページ: 579-581
  • 査読あり
• [雑誌論文] Pioglitazone in nonalcoholic steatohepatitis. (2007)
  • 著者名/発表者名: T Ota, T Takamura, S Kaneko.
  • 雑誌名: N Engl J Med 356(10) ページ: 1068
  • 査読あり
• [雑誌論文] Induction of reactive oxygen species from isolated rat glomeruli by protein kinase C activation and TNF-α stimulation, and effects of a phosphodiesterase inhibitor. (2007)
  • 著者名/発表者名: N Koike, T Takamura, S Kaneko.
  • 雑誌名: Life Sci 80(18) ページ: 1721-1278
  • 査読あり
• [雑誌論文] Association of the C825T polymorphism of the G-protein β3 subunit gene with hypertension, obesity, hyperlipidemia, insulin resistance, diabetes, diabetic complications, and diabetic therapies among Japanese. (2007)
  • 著者名/発表者名: T Hayakawa, T Takamura, T Abe, SKaneko.
  • 雑誌名: Metabolism 56(1) ページ: 44-48
  • 査読あり
• [雑誌論文] Comment on : Nathan DM, Buse JB, Davidson MB et al. (2006) Management of hyperglycaemia in type 2 diabetes : a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. (2007)
  • 著者名/発表者名: Takamura, A Shimizu, H Ando, S Kaneko.
  • 雑誌名: Diabetologia 50(1) ページ: 229-330
  • 査読あり
• [雑誌論文] Genes involved in oxidative phosphorylation are coordinately upregulated with fasting hyperglycaemia in livers of patients with type 2 diabetes. (2007)
  • 著者名/発表者名: H Misu, T Takamura, N Matsuzawa, A Shimizu, T Ota, M Sakurai, H Ando, K Arai, T Yamashita, M Honda, T Yamashita, S Kaneko.
  • 雑誌名: Diabetologia 50(2) ページ: 268-277
  • 査読あり
• [雑誌論文] Insulin resistance accelerates a dietary rat model of nonalcoholic steatohepatitis. (2007)
  • 著者名/発表者名: T Ota, T Takamura, S Kurita, N Matsuzawa, Y Kita, M Uno, H Akahori, H Misu, M Sakurai, Y Zen, Y Nakanuma, S Kaneko.
  • 雑誌名: Gastroenterology 132(1) ページ: 282-293
  • 査読あり
• [雑誌論文] Factors associated with improvement of fasting plasma glucose level by mealtime dosing of a rapid-acting insulin analog in type 2 diabetes. (2007)
  • 著者名/発表者名: T Takamura, M Sakurai, M Nakamura, A Shimizu, T Ota, H Misu, Y Takeshita, N Tsuchiyama, S Kurita, H Ando, S Kaneko.
  • 雑誌名: Diabetes Res Clin Pract 75(3) ページ: 278-284
  • 査読あり
• [雑誌論文] Clinical challenges and images in GI.Yersiniaenterocolitica mesenteric adenitis and terminal ileitis. (2006)
  • 著者名/発表者名: S Kaneko
  • 雑誌名: Gastroenterology 131(5) ページ: 1379,1659
  • 査読あり
• [雑誌論文] Erythrocyte sorbitol level as a predictor of the efficacy of epalrestat treatment for diabetic peripheral polyneuropathy. (2006)
  • 著者名/発表者名: H Ando, T Takamura, Y Nagai, S Kaneko.
  • 雑誌名: J Diabetes Complications 20(6) ページ: 367-370
  • 査読あり
• [雑誌論文] Different signaling pathways in the livers of patients with chronic hepatitis B or chronic hepatitis C. (2006)
  • 著者名/発表者名: M Honda, T Yamashita, T Ueda, H T, R Nishino, S Kaneko.
  • 雑誌名: Hepatology 44(5) ページ: 1122-1138
  • 査読あり
• [雑誌論文] Tumor necrosis factor-alpha-induced production of plasminogen activator inhibitor 1 and its regulation by pioglitazone and cerivastatin in a nonmalignant human hepatocyte cell line. (2006)
  • 著者名/発表者名: Y Takeshita, T Takamura, E Hamaguchi, A Shimizu, T Ota, M Sakurai, S Kaneko.
  • 雑誌名: Metabolism 55(11) ページ: 1464-1472
  • 査読あり
• [雑誌論文] Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis. (2006)
  • 著者名/発表者名: S Kaneko
  • 雑誌名: P Natl Acad Sci USA 103(38) ページ: 14098-14103
  • 査読あり
• [雑誌論文] Pancreatic exocrine and endocrine events occur concomitantly but independently during the course of fulminant type 1 diabetes. (2006)
  • 著者名/発表者名: T Kahara, T Takamura, M Sakurai, H Misu, R Usuda, T Hayakawa, Y Nishimura, Y Bando, T Nagaoka, Y Nagai, S Kaneko.
  • 雑誌名: Diabetes Res Clin Pract 71(3) ページ: 241-246
  • 査読あり
• [備考] ホームページ等
  • URL: http://m-kanazawa.jp/
• [産業財産権] 脂肪組織由来間質細胞群を含む肝炎治療剤 (2010)
  • 発明者名: 東元真実、金子周一、酒井佳夫
  • 権利者名: 金沢大学
  • 産業財産権番号: 特許,特願2010-203796
  • 出願年月日: 2010-09-11
• [産業財産権] 遺伝子発現プロファイルによる消化器癌、胃癌、大腸癌及び膵臓癌の検出 (2009)
  • 発明者名: 金子周一、本多政夫、酒井佳夫、山下太郎
  • 権利者名: 金沢大学
  • 産業財産権番号: 特許,特願2009-193702
  • 出願年月日: 2009-08-24
• [産業財産権] 生理的状態分析方法、生理的状態分析システム、及びコンピュータシステムに生理的状態を分析するための処理を実行させるコンピュータープログラム (2008)
  • 発明者名: 松原謙一、下田正文、的場亮、谷野元彦、中村誠二、岡山利次、田村卓郎、金子周一、篁俊成、河合昴三
  • 権利者名: (株) DNAチップ研究所、ビッツ(株)
  • 産業財産権番号: 特許,特願2008-311346
  • 出願年月日: 2008-12-05