異所性脂肪の心臓血管病発症における病態生理学的意義の解明

• 研究課題/領域番号: 23591314
• 研究種目: 基盤研究(C)
• 配分区分: 基金
• 応募区分: 一般
• 研究分野: 代謝学
• 研究機関: 徳島大学
• 研究代表者: 島袋 充生 徳島大学, ヘルスバイオサイエンス研究部, 特任教授 (60271144)
• 研究分担者: 益崎 裕章 琉球大学, 医学(系)研究科(研究院), 教授 (00291899) ; 苅谷 研一 琉球大学, 医学(系)研究科(研究院), 教授 (40263371)
• 研究期間 (年度): 2011 – 2013
• 研究課題ステータス: 完了 (2013年度)
• 配分額: 5,200千円 (直接経費: 4,000千円、間接経費: 1,200千円); 2013年度: 1,430千円 (直接経費: 1,100千円、間接経費: 330千円); 2012年度: 1,690千円 (直接経費: 1,300千円、間接経費: 390千円); 2011年度: 2,080千円 (直接経費: 1,600千円、間接経費: 480千円)
• キーワード: 遊離脂肪酸 / 内臓肥満症 / 異所性脂肪 / 糖尿病 / インスリン抵抗性

研究概要

(1)腹部脂肪、肝臓、骨格筋、心臓周囲脂肪および筋量を非侵襲的に測定し、異所性脂肪分布様式を検証した。玄米食介入で減量および血管内皮機能改善効果を確認した。 (2)飽和脂肪酸処理されたヒト臍帯静脈血管内皮細胞(HUVEC)でプロテオーム ・トランスクリプトーム解析をおこない、発現変動の顕著な産物Xを同定した。分子X siRNAを過剰発現したHUVECでは、飽和脂肪酸による細胞死が、カスパーゼ3,7切断を阻害することで抑制された。 (3)心臓手術症例で、心臓脂肪発現シグナルと全身および心臓脂肪分布との関係を検証した。心臓バイパス手術症例は、心臓周囲脂肪量が増加して炎症性シグナルが増加していた。

研究成果

• [雑誌論文] Effects of Brown Rice Diet on Visceral Obesity and Endothelial Function: The BRAVO Study (2014)
  • 著者名/発表者名: Shimabukuro M, et al
  • 雑誌名: British J Nutr 巻: 111 ページ: 310-20
  • DOI: 10.1017/s0007114513002432
  • 査読あり
• [雑誌論文] Azilsartan, an angiotensin II type 1 receptor blocker, restores endothelial function by reducing vascular inflammation and by increasing the phosphorylation ratio Ser(1177)/Thr(497) of endothelial nitric oxide synthase in diabetic mice. (2014)
  • 著者名/発表者名: Matsumoto S, Shimabukuro M, Fukuda D, Soeki T, Yamakawa K, Masuzaki H, Sata M.
  • 雑誌名: Cardiovasc Diabetology 巻: 13 ページ: 30-30
  • DOI: 10.1186/1475-2840-13-30
  • 査読あり / オープンアクセスとしている / 謝辞記載あり
• [雑誌論文] Association of lower limb muscle mass and energy expenditure with visceral fat mass in healthy men. (2014)
  • 著者名/発表者名: Yagi S, Kadota M, Aihara K, Nishikawa K, Hara T, Ise T, Ueda Y, Iwase T, Akaike M, Shimabukuro M, Katoh S, Sata M.
  • 雑誌名: Diabetol Metab Syndr. 巻: 6 ページ: 27-27
  • DOI: 10.1186/1758-5996-6-27
  • 査読あり / オープンアクセスとしている / 謝辞記載あり
• [雑誌論文] Association of borderline ankle-brachial index with mortality and the incidence of peripheral artery disease in diabetic patients (2014)
  • 著者名/発表者名: Natsuaki C, Inoguchi T, Maeda Y, Yamada T, Sasaki S, Sonoda N, Shimabukuro M, Nawata H, Takayanagi R.
  • 雑誌名: Atherosclerosis 巻: 234 ページ: 360-365
  • DOI: 10.1016/j.atherosclerosis.2014.03.018
  • 査読あり
• [雑誌論文] Pentraxin 3 is a local inflammatory marker in atrial fibrillation. (2014)
  • 著者名/発表者名: Soeki T, Bando S, Uematsu E, Matsuura T, Niki T, Ise T, Kusunose K, Hotchi J, Ueda Y, Tomita N, Yamaguchi K, Yagi S, Fukuda D, Taketani Y, Iwase T, Yamada H, Wakatsuki T, Shimabukuro M, Sata M.
  • 雑誌名: Heart Vessels. 巻: - ページ: 27-27
  • DOI: 10.1007/s00380-013-0400-8
  • 査読あり / オープンアクセスとしている
• [雑誌論文] Miglitol, α-glycosidase inhibitor, reduces visceral fat accumulation and cardiovascular risk factors in subjects with the metabolic syndrome : A randomized comparable study (2013)
  • 著者名/発表者名: Shimabukuro M, et al
  • 雑誌名: Int J Cardiol. 巻: 167 ページ: 2108-2113
  • DOI: 10.1016/j.ijcard.2012.05.109
  • 査読あり
• [雑誌論文] Exendin-4, a glucagon-like peptide-1 receptor agonist, attenuates neointimal hyperplasia after vascular injury. (2013)
  • 著者名/発表者名: Y. Hirata, H. Kurobe, C. Nishio, K. Tanaka, D. Fukuda, E. Uematsu, S. Nishimoto, T. Soeki, N. Harada, H. Sakaue, T. Kitagawa, M. Shimabukuro, N. Nakaya, M. Sata
  • 雑誌名: Eur J Pharmacol. 巻: 699 ページ: 106-111
  • DOI: 10.1016/j.ejphar.2012.11.057
  • 査読あり / 謝辞記載あり
• [雑誌論文] Beneficial effect of a synthetic prostacyclin agonist, 0NO-1301, in rat autoimmune myocarditis model (2013)
  • 著者名/発表者名: Y. Hirata, H. Kurobe, E. Uematsu, S. Yagi, T. Soeki, H. Yamada, D. Fukuda, M. Shimabukuro, M. Nakayama, K. Matsumoto, Y. Sakai, T. Kitagawa, M. Sata
  • 雑誌名: Eur J Pharmacol. 巻: 699 ページ: 81-87
  • DOI: 10.1016/j.ejphar.2012.11.045
  • 査読あり / 謝辞記載あり
• [雑誌論文] Lipid deposition in various sites of skeletal muscle and liver shows correlation with visceral fat accumulation in male patients with metabolic syndrome (2013)
  • 著者名/発表者名: Taira S, et al
  • 雑誌名: Intern. Med. 巻: 52 号: 14 ページ: 1561-1571
  • DOI: 10.2169/internalmedicine.52.0521
  • NAID: 130003365715
  • 査読あり
• [雑誌論文] 13. Perivascular adipose tissue-secreted angiopoietin-like protein 2 (Angptl2) accelerates neointimal hyperplasia after endovascular injury. (2013)
  • 著者名/発表者名: Tian Z, Miyata K, Tazume H, Sakauguchi H, Kadomatsu T, Horio E, Takahashi O, Komohara Y, Araki K, Hirata Y, Tabata M, Takanashi S, Takeya M, Hao H, Shimabukuro M, Sata M, Kawasuji M, Oike Y.
  • 雑誌名: Journal of Molecular and Cellular Cardiology 巻: 57 ページ: 1-12
  • DOI: 10.1016/j.yjmcc.2013.01.004
  • 査読あり
• [雑誌論文] Defects of vascular nitric oxide bioavailability in subjects with impaired glucose tolerance : A potential link to insulin resistance (2013)
  • 著者名/発表者名: Michio Shimabukuro
  • 雑誌名: Int J Cardiol. 巻: in press ページ: 298-300
  • DOI: 10.1016/j.ijcard.2012.09.194
  • 査読あり
• [雑誌論文] Epicardial adipose tissue volume and adipocytokine imbalance are strongly linked to human coronary atherosclerosis. (2013)
  • 著者名/発表者名: M. Shimabukuro, Y. Hirata, M. Tabata, M. Dagvasumberel, H. Sato, H. Kurobe, D. Fukuda, T. Soeki, T. Kitagawa, S. Takanashi, M. Sata
  • 雑誌名: Arterioscler Thromb Vasc Biol. 巻: 33 ページ: 1077-1084
  • DOI: 10.1161/atvbaha.112.300829
  • 査読あり / 謝辞記載あり
• [雑誌論文] Ghrelin protects the heart against ischemia-induced arrhythmias bypreserving connexin-43 protein. (2013)
  • 著者名/発表者名: Soeki T, Niki T, Uematsu E, Bando S, Matsuura T, Kusunose K, Ise T, Ueda Y, Tomita N, Yamaguchi K, Koshiba K, Yagi S, Fukuda D, Taketani Y, Iwase T, Yamada H, Wakatsuki T, Akaike M, Shimabukuro M, Kishimoto I, Kangawa K, Sata M
  • 雑誌名: Heart Vessels. 巻: 28 ページ: 795-801
  • DOI: 10.1007/s00380-013-0333-2
  • 査読あり / 謝辞記載あり
• [雑誌論文] Protective effects of selective mineralocorticoid receptor antagonist against aortic aneurysm progression in a novel murine model (2013)
  • 著者名/発表者名: Kurobe H, Hirata Y, Matsuoka Y, Sugasawa N, Higashida M, Nakayama T, Maxfield MW, Yoshida Y, Shimabukuro M, Kitagawa T, Sata M.
  • 雑誌名: J Surg Res. 巻: 185 ページ: 455-462
  • DOI: 10.1016/j.jss.2013.05.002
  • 査読あり
• [雑誌論文] Role of macrophage-derived hypoxia-inducible factor (HIF)-1α as a mediator of vascular remodeling (2013)
  • 著者名/発表者名: Nakayama T, Kurobe H, Sugasawa N, Kinoshita H, Higashida M, Matsuoka Y, Yoshida Y, Hirata Y, Sakata M, Maxfield M, Shimabukuro M, Takahama Y, Sata M, Tamaki T, Kitagawa T, Tomita S.
  • 雑誌名: Cardiovasc Res. 巻: 99 ページ: 705-715
  • DOI: 10.1093/cvr/cvt146
  • 査読あり
• [雑誌論文] HMGB1 plays a critical role in vascular inflammation and lesion formation via toll-like receptor 9. (2013)
  • 著者名/発表者名: Y. Hirata, H. Kurobe, M. Higashida, D. Fukuda, M. Shimabukuro, Y. Higashikuni, T. Kitagawa, M. Sata
  • 雑誌名: Atherosclerosis. 巻: 231 ページ: 227-233
  • DOI: 10.1016/j.atherosclerosis.2013.09.010
  • 査読あり / 謝辞記載あり
• [雑誌論文] Telmisartan Ameliorates Insulin Sensitivity by Acting the AMPK/SIRT1 Pathway in Skeletal Muscle of Obese db/db Mice (2013)
  • 著者名/発表者名: Shiota A, Shimabukuro M, Fukuda D, Soeki T, Sato H, Uematsu E, Hirata Y, Kurobe H, Maeda N, Sakaue H, Masuzaki H, Shimomura I, Sata M.
  • 雑誌名: Cardiovasc Diabetol. 巻: 11 ページ: 139-139
  • DOI: 10.1186/1475-2840-11-139
  • 査読あり
• [雑誌論文] Lipid deposition in various sites of skeletal muscle and liver shows correlation with visceral fat accumulation in male patients with metabolic syndrome. (2013)
  • 著者名/発表者名: Taira S, Shimabukuro M, Higa M, Yabiku K, Kozuka C, Ueda R, Sunagawa S, Ohshiro Y, Doi M, Nanba T, Kawamoto E, Nakayama Y, Nakamura H, Iha T, Nakachi S, Tomoyose T, Ikema T, Yamakawa K, Masuzaki H.
  • 雑誌名: Intern Med 巻: 52 ページ: 1561-1571
  • 査読あり
• [雑誌論文] Ectopic fat deposition and global cardiometabolic risk: New paradigm in cardiovascular medicine. (2013)
  • 著者名/発表者名: Shimabukuro M et al.
  • 雑誌名: J Med Invest. 巻: 60 ページ: 1-14
  • NAID: 120005380896
  • 査読あり
• [雑誌論文] Epicardial adipose tissue volume and adipocytokine imbalance are strongly linked to human coronary atherosclerosis. (2013)
  • 著者名/発表者名: Shimabukuro M et al.
  • 雑誌名: Arterioscler Thromb Vasc Biol. 巻: 33 ページ: 1077-1084
  • 査読あり
• [雑誌論文] Perivascular adipose tissue-secreted angiopoietin-like protein 2 (Angptl2) accelerates neointimal hyperplasia after endovascular injury. (2013)
  • 著者名/発表者名: Tian Z et al.
  • 雑誌名: J Mol Cell Cardiol. 巻: 57 ページ: 1-12
  • 査読あり
• [雑誌論文] Exendin-4, a glucagon-like peptide-1 receptor agonist, attenuates neointimal hyperplasia after vascular injury. (2013)
  • 著者名/発表者名: Hirata Y et al.
  • 雑誌名: Eur J Pharmacol. 巻: 699(1-3) ページ: 106-11
  • 査読あり
• [雑誌論文] The Radioprotective 105/MD-1 Complex Contributes to Diet-Induced Obesity and Adipose Tissue Inflammation. (2012)
  • 著者名/発表者名: Y. Watanabe, T. Nakamura, S. Ishikawa, S. Fujisaka, I. Usui, K. Tsuneyama, Y. Ichihara, T. Wada, Y. Hirata, T. Suganami, H. Izaki, S. Akira, K. Miyake, H. Kanayama, M. Shimabukuro, M. Sata, T. Sasaoka, Y. Ogawa, K. Tobe, K. Takatsu, Y. Nagai
  • 雑誌名: Diabetes. 巻: 61 ページ: 1199-1209
  • DOI: 10.2337/db11-1182
  • 査読あり
• [雑誌論文] Brown rice and its component, γ-oryzanol, attenuate the preference for high-fat diet by decreasing hypothalamic endoplasmic reticulum stress in mice (2012)
  • 著者名/発表者名: Kozuka C, Oyadomari S
  • 雑誌名: Diabetes. 巻: 61 ページ: 3084-3093
  • DOI: 10.2337/db11-1767
  • NAID: 40019773446
  • 査読あり
• [雑誌論文] Activation of AMPK-Sirt1 Pathway by Telmisartan in White Adipose Tissue: A Possible Link to Anti-metabolic Effects (2012)
  • 著者名/発表者名: Shiota A, Shimabukuro M, Fukuda D, Soeki T, Sato H, Uematsu E, Hirata Y, Kurobe H, Sakaue H, Nakaya Y, Masuzaki H, Sata M
  • 雑誌名: Eur J Pharmacol. 巻: 692 ページ: 84-90
  • DOI: 10.1016/j.ejphar.2012.07.026
  • 査読あり
• [雑誌論文] Gender disparities in the association between epicardial adipose tissue volume and coronary atherosclerosis : A 3-dimensional cardiac computed tomography imaging study in Japanese subjects (2012)
  • 著者名/発表者名: Dagvasumberel M, Shimabukuro M, Nishiuchi T, Ueno J, Takao S, Fukuda D, Hirata Y, Kurobe H, Soeki T, Iwase T, Kusunose K, Niki T, Yamaguchi K, Taketani Y, Yagi S, Tomita N, Yamada H, Wakatsuki T, Harada M, Kitagawa T, Sata M
  • 雑誌名: Cardiovasc Diabetol. 巻: 11 ページ: 106-106
  • DOI: 10.1186/1475-2840-11-106
  • 査読あり
• [雑誌論文] Eicosapentaenoic acid supplementation changes fatty acid composition and corrects endothelial dysfunction in hyperlipidemic patients (2012)
  • 著者名/発表者名: Ken Yamakawa
  • 雑誌名: Cardiology Research and Pracitice 巻: 2012 ページ: 754181-754181
  • DOI: 10.1155/2012/754181
  • 査読あり
• [雑誌論文] Telmisartan ameliorates insulin sensitivity by activating the AMPK/SIRT1 pathway in skeletal muscle of obese db/db mice. (2012)
  • 著者名/発表者名: Shiota A et al.
  • 雑誌名: Cardiovasc Diabetol. 巻: 11 ページ: 139-139
  • 査読あり
• [雑誌論文] Gender disparities in the association between epicardial adipose tissue volume and coronary atherosclerosis: a 3-dimensional cardiac computed tomography imaging study in Japanese subjects. (2012)
  • 著者名/発表者名: Dagvasumberel M et al.
  • 雑誌名: Cardiovasc Diabetol. 巻: 11 ページ: 106-106
  • 査読あり
• [雑誌論文] The Radioprotective 105/MD-1 complex contributes to diet-induced obesity and adipose tissue inflammation. (2012)
  • 著者名/発表者名: Watanabe Y
  • 雑誌名: Diabetes 巻: 61 ページ: 1199-1209
  • 査読あり
• [雑誌論文] A synthetic prostacyclin agonist with thromboxane synthase inhibitory activity, ONO-1301, protects myocardium from ischemia/reperfusion injury. (2012)
  • 著者名/発表者名: Hirata Y
  • 雑誌名: Eur J Pharmacol 巻: 674 ページ: 352-358
  • 査読あり
• [雑誌論文] Distinct effects of pitavastatin and atorvastatin on lipoprotein subclasses in patients of type 2 diabetes mellitus (2011)
  • 著者名/発表者名: Shimabukuro M, et al
  • 雑誌名: Diabetic Med 巻: 28 ページ: 856-864
  • DOI: 10.1111/j.1464-5491.2011.03240.x
  • 査読あり
• [雑誌論文] Impaired glucose tolerance, but not impaired fasting glucose, underlies left ventricular diastolic dysfunction (2011)
  • 著者名/発表者名: Shimabukuro M, et al
  • 雑誌名: Diabetes Care 巻: 34 ページ: 686-690
  • DOI: 10.2337/dc10-1141
  • 査読あり
• [雑誌論文] Serum Levels of B-Cell Activating Factor of TNF Family (BAFF) as a Useful Indicator for the Activity of Graves'Disease (2011)
  • 著者名/発表者名: Sunagawa S, et al
  • 雑誌名: J Endocrinol Metab 巻: 1 ページ: 73-78
  • 査読あり
• [雑誌論文] A synthetic prostacycline agonist, ONO-1301, ameliorates ventricular remodeling after acute myocardial infarction via up-regulation of HGF in rat (2011)
  • 著者名/発表者名: Hirata Y, et al
  • 雑誌名: Biomed Aging Pathol 巻: 90-96 ページ: 1-1
  • 査読あり
• [雑誌論文] A synthetic prostacycline agonist, ONO-1301, ameliorates ventricular remodeling after acute myocardial infarction via up-regulation of HGF in rat (2011)
  • 著者名/発表者名: Hirata Y
  • 雑誌名: Biomed Aging Pathol 巻: 1 ページ: 90-96
• [雑誌論文] Impaired glucose tolerance, but not impaired fasting glucose, underlies left ventricular diastolic dysfunction. (2011)
  • 著者名/発表者名: Shimabukuro M
  • 雑誌名: Diabetes Care 巻: 34
• [学会発表] Post-Transcriptional Regulation of Adiponectin by Micro-RNA 378 in Human Visceral and Subcutaneous Adipose Tissue (2013)
  • 著者名/発表者名: Ishida M
  • 学会等名: AHA Scientific Sessions 2013
  • 発表場所: Dallas Convention Center(Dallas, USA) (一般演題)
• [学会発表] Macrophage Toll-like Receptor 9 Signaling Contributes to the Development of Insulin Resistance through the Promotion of Inflammation in Adipose Tissue (2013)
  • 著者名/発表者名: Nishimoto S
  • 学会等名: AHA Scientific Sessions 2013
  • 発表場所: Dallas Convention Center(Dallas, USA) (一般演題)
• [学会発表] Rivaroxaban, A Novel Oral Anticoagulant, Attenuates Plaque Progression in ApoE-Deficient Mice Through the Inhibition of Pro-Inflammatory Activation of Macrophages (2013)
  • 著者名/発表者名: Hara T
  • 学会等名: AHA Scientific Sessions 2013
  • 発表場所: Dallas Convention Center(Dallas, USA) (一般演題)
• [学会発表] Macrophage-Specific Hypoxia-Inducible Factor (HIF)-1α-Deficient Mice Suppress the Vascular Remodeling and Regulate M2 Macrophage Polarization (2013)
  • 著者名/発表者名: Nakayama T
  • 学会等名: AHA Scientific Sessions 2013
  • 発表場所: Dallas Convention Center(Dallas, USA) (一般演題)
• [学会発表] Cardiospecific microRNA plasma levels are associated with coronary plaque vulnerability (2013)
  • 著者名/発表者名: Soeki T
  • 学会等名: ESC Congress 2013
  • 発表場所: Amsterdam RAI Exhibition and Convention Centre (Amsterdam, Netherlands)(一般演題)
• [学会発表] MicroRNA miR-378 regulates adipocytokine fate by targeting transcriptional factors in human visceral and subctaneous adipose tissue (2013)
  • 著者名/発表者名: Ishida M
  • 学会等名: ESC Congress 2013
  • 発表場所: Amsterdam RAI Exhibition and Convention Centre (Amsterdam, Netherlands)(一般演題)
• [学会発表] Genetic ablation of TLR9 improves insulin resistance through macrophage accumulation in adipose tissue (2013)
  • 著者名/発表者名: Nishimoto S
  • 学会等名: ESC Congress 2013
  • 発表場所: Amsterdam RAI Exhibition and Convention Centre (Amsterdam, Netherlands)(一般演題)
• [学会発表] Visceral fat mass is associated with daily physical activity, leg skeletal muscle mass and fiber intake in healthy men (2013)
  • 著者名/発表者名: Nishikawa K
  • 学会等名: ESC Congress 2013
  • 発表場所: Amsterdam RAI Exhibition and Convention Centre (Amsterdam, Netherlands)(一般演題)
• [学会発表] Ghrelin ameliorates the progression of experimental autoimmune myocarditis (2013)
  • 著者名/発表者名: Bando S
  • 学会等名: ESC Congress 2013
  • 発表場所: Amsterdam RAI Exhibition and Convention Centre (Amsterdam, Netherlands)(一般演題)
• [学会発表] Gender-based risk stratification of coronary artery disease in asymptomatic diabetic subjects : a multi-clinic study using multi-detector computed tomography (2013)
  • 著者名/発表者名: Shimabukuro M, Saito T, Higa T, Nkamura K, Sata M
  • 学会等名: ESC Congress 2013
  • 発表場所: Amsterdam RAI Exhibition and Convention Centre (Amsterdam, Netherlands)(一般演題)