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| 1.
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論文
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安藤, 仁 ; Ando, Hitoshi
概要:
生体の様々な行動や生理機能には，約24時間を1周期とする概日リズム (circadian rhythm) が認められる．この概日リズムは時計遺伝子群からなる細胞内体内時計によって発振されていることが，1980年代にショウジョウバエの研究によ
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り明らかされた．この発見に対しては，2017年に米国の3氏にノーベル生理学・医学賞が授与されたことは記憶に新しい．1990年代には，哺乳類においても時計遺伝子群が同定され，ショウジョウバエと同様に，細胞内体内時計は時計遺伝子群の転写・翻訳フィードバックループにより構築されていることが明らかになった．哺乳類の体内時計は視床下部の視交叉上核に存在することは以前より知られていたが，時計遺伝子群の発見により，細胞内体内時計はほぼすべての細胞に存在することも判明した．視交叉上核の細胞内体内時計は，光刺激により時刻がセットされ，中枢時計として視交叉上核以外の細胞の体内時計 (末梢時計) の時刻を調節している一方，個々の臓器の生理機能のリズムは，直接的にはその臓器の末梢時計によって制御されている．我々は，末梢時計の障害がいわゆる生活習慣病の発症と密接に関連することを見出し，その病態の解明と治療法の開発を進めているので，本稿ではその一部を紹介する．
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| 2.
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安藤, 仁 ; Ando, Hitoshi
概要:
取得学位：博士(医学)，学位授与番号：医博甲第1445号，学位授与年月日：平成12年12月31日,学位授与年：2000
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| 3.
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Misu, Hirofumi ; Takamura, Toshinari ; Takayama, Hiroaki ; Hayashi, Hiroto ; Matsuzawa-Nagata, Naoto ; Kurita, Seiichiro ; Ishikura, Kazuhide ; Ando, Hitoshi ; Takeshita, Yumie ; Ota, Tsuguhito ; Sakurai, Masaru ; Yamashita, Tatsuya ; Mizukoshi, Eishiro ; Yamashita, Taro ; Honda, Masao ; Miyamoto, Kenichi ; Kubota, Tetsuya ; Kubota, Naoto ; Kadowaki, Takashi ; Kim, Han-Jong ; Lee, In-kyu ; Minokoshi, Yasuhiko ; Saito, Yoshiro ; Takahashi, Kazuhiko ; Yamada, Yoshihiro ; Takakura, Nobuyuki ; Kaneko, Shuichi
概要:
金沢大学医薬保健研究域医学系<br />The liver may regulate glucose homeostasis by modulating the sensitivity/resistance of peripheral ti
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ssues to insulin, by way of the production of secretory proteins, termed hepatokines. Here, we demonstrate that selenoprotein P (SeP), a liver-derived secretory protein, causes insulin resistance. Using serial analysis of gene expression (SAGE) and DNA chip methods, we found that hepatic SeP mRNA levels correlated with insulin resistance in humans. Administration of purified SeP impaired insulin signaling and dysregulated glucose metabolism in both hepatocytes and myocytes. Conversely, both genetic deletion and RNA interference-mediated knockdown of SeP improved systemic insulin sensitivity and glucose tolerance in mice. The metabolic actions of SeP were mediated, at least partly, by inactivation of adenosine monophosphate-activated protein kinase (AMPK). In summary, these results demonstrate a role of SeP in the regulation of glucose metabolism and insulin sensitivity and suggest that SeP may be a therapeutic target for type 2 diabetes. © 2010 Elsevier Inc.
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| 4.
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Nakamura, Seiji ; Takamura, Toshinari ; Matsuzawa-Nagata, Naoto ; Takayama, Hiroaki ; Misu, Hirofumi ; Noda, Hiroyo ; Nabemoto, Satoko ; Kurita, Seiichiro ; Ota, Tsuguhito ; Ando, Hitoshi ; Miyamoto, Kenichi ; Kaneko, Shuichi
概要:
Visceral adiposity in obesity causes excessive free fatty acid (FFA) flux into the liver via the portal vein and may cau
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se fatty liver disease and hepatic insulin resistance. However, because animal models of insulin resistance induced by lipid infusion or a high fat diet are complex and may be accompanied by alterations not restricted to the liver, it is difficult to determine the contribution of FFAs to hepatic insulin resistance. Therefore, we treated H4IIEC3 cells, a rat hepatocyte cell line, with a monounsaturated fatty acid (oleate) and a saturated fatty acid (palmitate) to investigate the direct and initial effects of FFAs on hepatocytes. We show that palmitate, but not oleate, inhibited insulin-stimulated tyrosine phosphorylation of insulin receptor substrate 2 and serine phosphorylation of Akt, through c-Jun NH2-terminal kinase (JNK) activation. Among the well established stimuli for JNK activation, reactive oxygen species (ROS) played a causal role in palmitate-induced JNK activation. In addition, etomoxir, an inhibitor of carnitine palmitoyltransferase-1, which is the rate-limiting enzyme in mitochondrial fatty acid β-oxidation, as well as inhibitors of the mitochondrial respiratory chain complex (thenoyltrifluoroacetone and carbonyl cyanide m-chlorophenylhydrazone) decreased palmitate-induced ROS production. Together, our findings in hepatocytes indicate that palmitate inhibited insulin signal transduction through JNK activation and that accelerated β-oxidation of palmitate caused excess electron flux in the mitochondrial respiratory chain, resulting in increased ROS generation. Thus, mitochondria-derived ROS induced by palmitate may be major contributors to JNK activation and cellular insulin resistance. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.
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| 5.
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論文
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Kurita, Seiichiro ; Ando, Hitoshi ; Kaneko, Shuichi ; Takamura, Toshinari
概要:
金沢大学医薬保健研究域医学系
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| 6.
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Uno, Masafumi ; Kurita, Seiichiro ; Misu, Hirofumi ; Ando, Hitoshi ; Ota, Tsuguhito ; Matsuzawa-Nagata, Naoto ; Kita, Yuki ; Nabemoto, Satoko ; Akahori, Hiroshi ; Zen, Yoh ; Nakanuma, Yasuni ; Kaneko, Shuichi ; Takamura, Toshinari
概要:
金沢大学医薬保健研究域医学系<br />Nonalcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease and
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is one of the most common liver diseases in the developed world. The histological findings of NASH are characterized by hepatic steatosis, inflammation, and fibrosis. However, an optimal treatment for NASH has not been established. Tranilast, N-(3′,4′-dimedioxycinnamoyl)- anthranilic acid, is an antifibrogenic agent that inhibits the action of transforming growth factor beta (TGF-β). This drug is used clinically for fibrogenesis-associated skin disorders including hypertrophic scars and scleroderma. TGF-β plays a central role in the development of hepatic fibrosis, and tranilast may thus ameliorate the pathogenesis of NASH. We investigated the effects of tranilast using an established dietary animal model of NASH, obese diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats and nondiabetic control Long-Evans Tokushima Otsuka (LETO) rats fed a methionine-deficient and choline-deficient diet. Treatment with 2% tranilast (420 mg/kg/day) for 8 weeks prevented the development of hepatic fibrosis and the activation of stellate cells, and down-regulated the expression of genes for TGF-β and TGF-β-target molecules, including α1 procollagen and plasminogen activator-1. In addition, tranilast attenuated hepatic inflammation and Kupffer cell recruitment, and down-regulated the expression of tumor necrosis factor alpha. Unexpectedly, tranilast ameliorated hepatic steatosis and up-regulated the expression of genes involved in beta-oxidation, such as peroxisome proliferator-activated receptor α and carnitine O-palmitoyltransferase-1. Most of these effects were observed in LETO rats and OLETF rats, which suggest that the action of tranilast is mediated through the insulin resistance-independent pathway. Conclusion: Our findings suggest that targeting TGF-β with tranilast represents a new mode of therapy for NASH. Copyright © 2008 by the American Association for the Study of Liver Diseases.
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| 7.
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Ando, Hitoshi ; Takamura, Toshinari ; Matsuzawa-Nagata, Naoto ; Shima, Kosuke R. ; Nakamura, Seiji ; Kumazaki, Masafumi ; Kurita, Seiichiro ; Misu, Hirofumi ; Togawa, Naoyuki ; Fukushima, Tatsunobu ; Fujimura, Akio ; Kaneko, Shuichi
概要:
金沢大学医薬保健研究域医学系<br />Recent studies have correlated metabolic diseases, such as metabolic syndrome and non-alcoholic fatt
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y liver disease, with the circadian clock. However, whether such metabolic changes per se affect the circadian clock remains controversial. To address this, we investigated the daily mRNA expression profiles of clock genes in the liver of a dietary mouse model of non-alcoholic steatohepatitis (NASH) using a custom-made, high-precision DNA chip. C57BL/6J mice fed an atherogenic diet for 5 weeks developed hypercholesterolemia, oxidative stress, and NASH. DNA chip analyses revealed that the atherogenic diet had a great influence on the mRNA expression of a wide range of genes linked to mitochondrial energy production, redox regulation, and carbohydrate and lipid metabolism. However, the rhythmic mRNA expression of the clock genes in the liver remained intact. Most of the circadianly expressed genes also showed 24-h rhythmicity. These findings suggest that the biological clock is protected against such a metabolic derangement as NASH. © 2009 Elsevier Inc. All rights reserved.
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| 8.
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論文
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Takamura, Toshinari ; Shimizu, Akiko ; Komura, Takuya ; Ando, Hitoshi ; Zen, Yoh ; Minato, Hiroshi ; Matsushita, Eiki ; Kaneko, Shuichi
概要:
金沢大学大学院医学系研究科環境社会医学<br />A 53-year-old postmenopausal woman, who had a family history of cryptogenic liver cirrhosis, wa
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s diagnosed with osteoporosis, and started on the selective estrogen receptor modulator (SERM) raloxifene 60 mg/day orally. She developed marked liver dysfunction. Her body mass index (BNU) was 26.5. Her blood chemistry indicated AST 342 IU/L, ALT 356 IU/L, and hyaluronic acid 255 ng/mL. An oral glucose tolerance test showed impaired glucose tolerance with marked insulin resistance. Histologically, we diagnosed this case as having pre-cirrhotic nonalcoholic steatohepatitis (NASH). This is the first histologically confirmed case of NASH that was aggravated by raloxifene. © 2007 The Japanese Society of Internal Medicine.
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| 9.
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論文
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Takamura, Toshinari ; Shimizu, Akiko ; Ando, Hitoshi ; Kaneko, Shuichi
概要:
金沢大学大学院医学系研究科環境社会医学
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| 10.
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論文
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Sakurai, Masaru ; Takamura, Toshinari ; Ota, Tsuguhito ; Ando, Hitoshi ; Akahori, Hiroshi ; Kaji, Kyosuke ; Sasaki, Motoko ; Nakanuma, Yasuni ; Miura, Katsuyuki ; Kaneko, Shuichi
概要:
金子, 周一<br />金沢大学大学院医学系研究科環境社会医学<br />Background: To address the hypothesis that liver steatosis causes systemic insulin
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resistance, we sought to determine the liver histological feature that most strongly contributes to insulin resistance in patients with nonalcoholic fatty liver disease (NAFLD). Methods: Liver biopsy specimens were obtained from 131 patients with clinically suspected NAFLD. The stage, grade of nonalcoholic steatohepatitis (NASH), and level of steatosis were scored and analyzed in relation to the homeostasis model assessment of insulin resistance (HOMA-IR) and the metabolic clearance rate (MCR), measured using the glucose clamp method. Results: In the univariate analysis, the degree of hepatic steatosis (r = 0.458, P < 0.001), stage (r = 0.360, P < 0.001), and grade (r = 0.349, P < 0.01) of NASH were significantly correlated with the HOMA-IR. Multiple regression analysis adjusting for age, sex, body mass index, and each histological score showed that steatosis was significantly and independently associated with HOMA-IR (coefficient = 1.42, P < 0.001), but not with the stage (coefficient = 0.33, P = 0.307) or grade (coefficient = 0.67, P = 0.134) of NASH. Similar independent relationships were observed between steatosis and MCR, but the relationship was weaker (coefficient = -0.98, P = 0.076). Conclusions: Steatosis of the liver, but not the stage or the grade of NASH, is associated with insulin resistance in patients with NAFLD. © Springer-Verlag Tokyo 2007.
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