Research

Doctoral course in the Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences
Nature ascertains a pivotal role for every biological system like clockwork and is unlikely to maintain systems that are detrimental for survival. Any pathway and molecule that causes illness must also have a meaningful role. Overnutrition disrupts inter-organ networks to keep energy homeostasis governed by the liver. Our group has identified key pathways and molecules (hepatokine world) through comprehensive gene expression analyses of tissue and cell samples from humans and model animals. Through functional analyses of these diagnostic/therapeutic targets, we aim to create medical systems for preclinical diagnosis and preemptive/tailor-made medicine.

Research projects

  1. Molecular pathology and clinical research in diabetes/obesity and its complications
  2. Cross-talks among glucose-, protein-, and lipid-metabolism pathways to keep energy homeostasis
  3. Hepatokines (liver-derived hormones) and inter-organ networks
  4. Histological course and molecular pathology of non-alcoholic fatty liver disease (NAFLD)

Figure
Pathology of type 2 diabetes caused by a liver-derived hormone hepatokine
The liver plays a role as an endocrine organ to produce functional hepatokines and thereby mediates fatty liver-associated systemic pathology. We discovered a liver-derived hormone selenoprotein P that causes multi-signal resistances via reductive stress leading to pathology of type 2 diabetes such as insulin resistance, angiogenesis resistance, exercise resistance, and insulin secretory failure.

近年、全身の臓器がエネルギー代謝とホルモン産生を担うことが明らかになるにつれ、内分泌学の概念と領域はますます拡大しています。

内分泌・代謝内科学教室は、下垂体、甲状腺、副腎はじめとする古典的内分泌臓器に関連した内分泌疾患、および膵・消化管ホルモンが複雑に絡む糖尿病の臨床、研究、そしてそれらを通じた教育を担当しています。

古くて新しいこの領域に関心をお持ちの学生、研修医、基礎研究者のみなさん、ぜひお問い合わせください。

  1. 私たちは糖尿病・肥満症の病態を形成する代謝経路を研究しています。これまで、Toxic lipidｓが肝臓に炎症とインスリン抵抗性をもたらす機序（J Biol Chem 2009, Hepatology 2007, Diabetologia 2014）、タンパク質分解系と糖・脂質代謝経路のクロストーク（Diabetes 2013, J Diabetes Invest 2018）を解明してきました。これらの知見に基づいて、生活習慣病に対する早期診断と先制・最適医療実現のための新しい診断・治療技術創出を目指します
  2. ヒト肝臓遺伝子発現情報から糖尿病病態形成の鍵となる肝臓由来生理活性分子ヘパトカインを複数同定しました。ヘパトカインの新規作用とそれを担う受容体とメカニズム解明を通じて、2型糖尿病の新病態を明らかにする基礎研究が進行中です。糖尿病・肥満症患者の肝臓から分泌されるセレノプロテインP（Cell Metab 2010）およびLECT2（Diabetes 2014）を同定し、肝臓由来生理活性分子「ヘパトカイン」と総称しました。セレノプロテインPが2型糖尿病や老化で観察される、インスリン抵抗性(Cell Metab 2010)、血管新生抵抗性（Diabetologia 2014）、運動抵抗性（Nat Med 2017）をはじめとする多様なシグナル抵抗性を形成することを見出しました。これらの知見は、肝臓もまた内分泌臓器であり、ヘパトカイン異常分泌を介して、糖尿病、肥満症、老化関連疾患の病態形成に深く関わっていることを示唆し、多くの研究領域に影響を与えています。
  3. 糖尿病・肥満症の病態解析、糖尿病薬のエビデンス構築に向けたユニークな臨床研究を進めています。竹下有美枝助教は、スイス・ジュネーブのWHO本部に出向し、国際保健医療を学んできました。今後の新展開が期待されます。
  4. 2016年4月より金沢・千葉・長崎大学の3大学共同先進予防医学研究科がスタートしました。公衆衛生学教室と連携して、能登地区で前向き追跡コホート研究進めています。詳細な栄養実態調査、脂肪肝、骨密度、体組成、インスリン抵抗性、微量元素、ヘパトカインレベルなど、通常の検診では測定しないユニークな項目を評価し、健康状態との関連を検討しています。将来的には疾病の発症に関わるゲノム背景と環境因子のクロストークを担う因子を絞り込むことで、生活習慣病に対する先制医療に資する新規診断・治療法の開発を目指します。

    先進予防医学研究で解明を目指す日本人の生活習慣病病態
    金沢大学先進予防医学研究科では、石川県志賀町と「生涯一貫型・全住民参加型健康づくり」の推進協定調印を交わし、平成25年度より新規前向き追跡コホート研究を開始しました。通常の検診では測定しないユニークな項目を評価し、栄養摂取や疾病との関連を検討しています。今後、能登地区の病院コホートと統合データベースを構築し、前向きに疾病発症を追跡する予定です。将来的には、次世代シーケンサーを用いて遺伝子多型、末梢血発現遺伝子、エピゲノム修飾、エキソソーム中のマイクロRNA、腸内細菌叢を解析し、疾病の発症に関わる体質的背景と環境因子のクロストークを担う因子を絞り込みたく思います。

Key publications

  1. Misu H, Takayama H, Saito Y, Mita Y, Kikuchi A, Ishii KA, Chikamoto K, Kanamori T, Tajima N, Lan F, Takeshita Y, Honda M, Tanaka M, Kato S, Matsuyama N, Yoshioka Y, Iwayama K, Tokuyama K, Akazawa N, Maeda S, Takekoshi K, Matsugo S, Noguchi N, Kaneko S, Takamura T*. Deficiency of the hepatokine selenoprotein P increases responsiveness to exercise in mice through upregulation of reactive oxygen species and AMP-activated protein kinase in muscle. Nat Med 23:508-516, 2017
  2. Mita Y, Nakayama K, Inari S, Nishito Y, Yoshioka Y, Sakai N, Sotani K, Nagamura T, Kuzuhara Y, Inagaki K, Iwasaki M, Misu H, Ikegawa M, Takamura T, Noguchi N, Saito Y. Selenoprotein P-neutralizing antibodies improve insulin secretion and glucose sensitivity in type 2 diabetes mouse models. Nat Commun 8:1658, 2017
  3. Misu H, Takamura T* (co-first author), Takayama H, Hayashi H, Matsuzawa-Nagata N, Kurita S, Ishikura K, Ando H, Takeshita Y, Ota T, Sakurai M, Yamashita T, Mizukoshi E, Yamashita T, Honda M, Miyamoto K, Kubota T, Kubota N, Kadowaki T, Kim HJ, Lee IK, Minokoshi Y, Saito Y, Takahashi K, Yamada Y, Takakura N, Kaneko S. A liver-derived secretory protein, selenoprotein P, causes insulin resistance. Cell Metab 12:483-95, 2010
  4. Ishikura K, Misu H, Kumazaki M, Takayama H, Matsuzawa-Nagata N, Tajima N, Chikamoto K, Lan F, Ando H, Ota T, Sakurai M, Takeshita Y, Kato K, Fujimura A, Miyamoto K, Saito Y, Kameo S, Okamoto Y, Takuwa Y, Takahashi K, Kidoya H, Takakura N, Kaneko S, Takamura T*. Selenoprotein P as a diabetes-associated hepatokine that impairs angiogenesis by inducing VEGF resistance in vascular endothelial cells. Diabetologia 57:1968-76, 2014
  5. Oo SM, Misu H, Saito Y, Tanaka M, Kato S, Kita Y, Takayama H, Takeshita Y, Kanamori T, Nagano T, Nakagen M, Urabe T, Matsuyama N, Kaneko S, Takamura T*. Serum selenoprotein P, but not selenium, predicts future hyperglycemia in a general Japanese population. Sci Rep 2018 Nov 13;8(1)
  6. Tajima-Shirasaki N, Ishii KA, Takayama H, Shirasaki T, Iwama H, Chikamoto K, Saito Y, Iwasaki Y, Teraguchi A, Lan F, Kikuchi A, Takeshita Y, Murao K, Matsugo S, Kaneko S, Misu H, Takamura T*. Eicosapentaenoic acid down-regulates expression of the selenoprotein P gene by inhibiting SREBP-1c protein independently of the AMP-activated protein kinase pathway in H4IIEC3 hepatocytes. J Biol Chem 292:10791-10800, 2017
  7. Takayama H, Misu H, Iwama H, Chikamoto K, Saito Y, Murao K, Teraguchi A, Lan F, Kikuchi A, Saito R, Tajima N, Shirasaki T, Matsugo S, Miyamoto K, Kaneko S, Takamura T*. Metformin suppresses expression of the selenoprotein P gene via an AMP-activated kinase (AMPK)/FoxO3a pathway in H4IIEC3 hepatocytes. J Biol Chem 289:335-45, 2014
  8. Tanaka M, Saito Y, Misu H, Kato S, Kita Y, Takeshita Y, Kanamori T, Nagano T, Nakagen M, Urabe T, Takamura T, Kaneko S, Takahashi K, Matsuyama N. Development of a Sol Particle Homogeneous Immunoassay for Measuring Full-Length Selenoprotein P in Human Serum. J Clin Lab Anal 30:114-22, 2016
  9. Sugiyama M, Kikuchi A, Misu H, Igawa H, Ashihara M, Kushima Y, Honda K, Suzuki Y, Kawabe Y, Kaneko S, Takamura T. Inhibin βE (INHBE) is a possible insulin resistance-associated hepatokine identified by comprehensive gene expression analysis in human liver biopsy samples. PLOS ONE 13:e0194798, 2018
  10. Misu H, Ishikura K, Kurita S, Takeshita Y, Ota T, Saito Y, Takahashi K, Kaneko S, Takamura T*. Inverse correlation between serum levels of selenoprotein P and adiponectin in patients with type 2 diabetes. PLOS ONE 7:e34952, 2012
  11. Iwakami S, Misu H, Takeda T, Sugimori M, Matsugo S, Kaneko S, Takamura T*. Concentration-dependent dual effects of hydrogen peroxide on insulin signal transduction in H4IIEC hepatocytes. PLoS ONE 6:e27401, 2011
  12. Hellwege JN, Palmer ND, Ziegler JT, Langefeld CD, Lorenzo C, Norris JM, Takamura T, Bowden DW. Genetic variants in selenoprotein P plasma 1 gene (SEPP1) are associated with fasting insulin and first phase insulin response in Hispanics. Gene 534:33-9, 2014
  13. Lan F, Misu H, Chikamoto K, Takayama H, Kikuchi A, Mohri K, Takata N, Hayashi H, Matsuzawa-Nagata N, Takeshita Y, Noda H, Matsumoto Y, Ota T, Nagano T, Nakagen M, Miyamoto KI, Takatsuki K, Seo T, Iwayama K, Tokuyama K, Matsugo S, Tang H, Saito Y, Yamagoe S, Kaneko S, Takamura T*. LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance. Diabetes 63:1649-64, 2014
  14. Kato K, Takamura T* (co-first author), Takeshita Y, Ryu Y, Misu H, Ota T, Tokuyama K, Nagasaka S, Matsuhisa M, Matsui O, Kaneko S. Ectopic fat accumulation and distant organ-specific insulin resistance in Japanese people with nonalcoholic fatty liver disease. PLOS ONE 9:e92170, 2014
  15. Takeshita Y, Takamura T* (co-first author), Honda M, Kita Y, Zen Y, Kato K, Misu H, Ota T, Nakamura M, Yamada K, Sunagozaka H, Arai K, Yamashita T, Mizukoshi E, Kaneko S. The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial. Diabetologia 57:878-90, 2014
  16. Otoda T, Takamura T* (co-first author), Misu H, Ota T, Murata S, Hayashi H, Takayama H, Kikuchi A, Kanamori T, Shima KR, Lan F, Takeda T, Kurita S, Ishikura K, Kita Y, Iwayama K, Kato KI, Uno M, Takeshita Y, Yamamoto M, Tokuyama K, Iseki S, Tanaka K, Kaneko S. Proteasome Dysfunction Mediates Obesity-Induced Endoplasmic Reticulum Stress and Insulin Resistance in the Liver. Diabetes 62:811-24, 2013
  17. Takamura T*, Misu H, Matsuzawa-Nagata N, Sakurai M, Ota T, Shimizu A, Kurita S, Takeshita Y, Ando H, Honda M, Kaneko S. Obesity upregulates genes involved in oxidative phosphorylation in livers of diabetic patients. Obesity (Silver Spring). 16:2601-9, 2008
  18. Nakamura S, Takamura T*, Matsuzawa-Nagata N, Takayama H, Misu H, Noda H, Nabemoto S, Kurita S, Ota T, Ando H, Miyamoto K, Kaneko S. Palmitate Induces Insulin Resistance in H4IIEC3 Hepatocytes through Reactive Oxygen Species Produced by Mitochondria. J Biol Chem 284:14809-14818, 2009
  19. Matsuzawa N, Takamura T*, Kurita S, Misu H, Ota T, Ando H, Yokoyama M, Honda M, Zen Y, Nakanuma Y, Miyamoto K, Kaneko S. Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet. Hepatology 46:1392-1403, 2007
  20. Misu H, Takamura T*, Matsuzawa N, Shimizu A, Ota T, Sakurai M, Ando H, Arai K, Yamashita T, Honda M, Yamashita T, Kaneko S. Genes involved in oxidative phosphorylation are coordinately upregulated with fasting hyperglycaemia in livers of patients with type 2 diabetes. Diabetologia 50:268-277, 2007
  21. Takamura T, Sakurai M, Ota T, Ando H, Honda M, Kaneko S. Genes for systemic vascular complications are differentially expressed in the livers of type 2 diabetic patients. Diabetologia 47:638-647, 2004