1998 Fiscal Year Annual Research Report

内臓脂肪特異的遺伝子の同定とその臨床応用の研究

Research Project

Project/Area Number	10557101
Research Institution	Osaka University
Principal Investigator	松澤佑次大阪大学, 医学部, 教授 (70116101)
Co-Investigator(Kenkyū-buntansha)	中澤宏住友化学(株), 生命工学研究所, 研究員木原進士大阪大学, 医学部・附属病院, 医員中村正大阪大学, 医学部, 助手 (90252668) 船橋徹大阪大学, 医学部, 助手 (60243234) 山下静也大阪大学, 医学部, 助手 (60243242)
Keywords	肥満 / 内臓脂肪 / 生活習慣病 / 動脈硬化
Research Abstract	現代社会において体脂肪の過剰蓄積は糖尿病、血管病等の様々な病態の基盤となっている。体脂肪蓄積による病態の発症は一様ではなく脂肪ﾟの蓄積部位、脂肪分布と密接に関連している。すなわち皮下脂肪よりも腹腔内内臓脂肪の蓄積が上記の病態と深く関わっている。本研究の目的は内臓脂肪と皮下脂肪の発現遺伝子を比較することによって内臓脂肪と皮下脂肪の本質的な生物学的差異を明らかにし、臨床に応用しようとするものである。内臓脂肪、皮下脂肪発現遺伝子の大規模シークエンス解析の比較により、皮下脂肪がリボゾーム蛋白や細胞骨格蛋白等の細胞維持に関わる比較的静的な遺伝子を多く発現していたのに対し、内臓脂肪は多くの生理活性物質を含む分泌蛋白遺伝子の発現が優位であった。さらにdifferential display法を用い皮下脂肪に比し内臓脂肪に比較的多く発現する遺伝子のクローニングを試みた。得られたクローンのうち、組織分布から内臓脂肪組織での発現が優位な未知のクローンを選択し、全長cDNAをクローニングした。本遺伝子の産物はある種の血球分化因子とホモロジーを有する分泌蛋白であった。レコンビナント蛋白に対して抗体を作成しウエスタンブロットを行ったところヒト血漿中での存在が確認された。血中濃度の定量的測定系を樹立し、肥満者において測定したところ、肥満者では高値を示し、特に内臓脂肪量との相関を認めた。次年度ではさらに本蛋白と糖尿病や血管病との関連を解析し、またその生理機能を検討する。平行して内臓脂肪特異的な新たな遺伝子の同定を進めていく予定である。

Research Products
(26 results)

All Other

All Publications (26 results)

[Publications] Y.Arita,S.Kihara,N.Ouchi,M.Takahashi et al.: "Paradoxical decrease of an adipose-specific protein,adiponectin,in obesity" Biochem.Biophys.Res.Commun.(in press). (1999)
[Publications] T.Yoshizumi,T.Nakamura,M.Yamane,W.Islam.A.H.M.,et al.: "A standardized technique for the measurement of abdominal fat based on computed tomography" Radiology. (in press). (1999)
[Publications] H.Kuriyama,S.Yamashita,I.Shimomura,T.Funahashi,et al.: "Enhanced expression of hepatic acyl-CoA synthetase and microsomal triglyceride transfer protein mRNAs in the obese and hypertriglyceridemic rat with visceral fat accumulation" Hepatology. 27(2). 562-557 (1998)
[Publications] S.Kihara,N.Ouchi,T.Funahashi,E.Shinohara,et al.: "Troglitazone enhances glucose uptake and inhibits mitogen-activated protein kinase in human aortic smooth muscle cells" Atherosclerosis. 136(1). 163-168 (1998)
[Publications] E.Shinohara,S.Kihara,N.Ouchi,T.Funahashi,et al.: "Troglitazone suppresses intimal formation following balloon injury in insulin-resistant Zucker fatty rats" Atherosclerosis. 136(2). 275-279 (1998)
[Publications] F.Matsuura,S.Yamashita,T.Nakamura,M.Nishida,et al.: "Effect of visceral fat accumulation on uric acid metabolism in male obese subjects:visceral fat obesity is linked more closely to overproduction of uric acid than subcutaneous fat obesity" Metabolism. 47(8). 929-933 (1998)
[Publications] T.Nakagawa,S.Nozaki,M.Nishida,J.M.Yakub,et al.: "Oxidized LDL increases and interferon-gamma decreases expression of CD36 in human monocyte-derived macrophages" Arterioscler.Thromb.Vasc.Biol.18(8). 1350-1357 (1998)
[Publications] T.Maruyama,Y.Miyake,T.Yamamura,S.Tajima,et al.: "A novel point mutation in a splice accceptor site of intron 1 of the human low density lipoprotein receptor gene which causes severe hypercholesterolemia:an unexpected absence of exon skippinng" Human Mutation. 12. 480-483 (1998)
[Publications] K.Fukuchi,S.Nozaki,T.Yoshizumi,T.Uehara,et al.: "Enhanced myocardial glucose uptake in individuals with a deficiency in long-chain fatty acid transport(CD36 deficiency)" J.Nucl.Med.,. (in press). (1999)
[Publications] S.Nozaki,T.Tanaka,S.Yamashita,K.Sohmiya,et al.: "CD36 mediates long-chain fatty acid transport in human myocardium:complete myocardial accumulation defect of radiolabeled long-chain fatty acid analog in subjects with CD36 deficiency." Mol.Cell.Biochem.(in press). (1999)
[Publications] A.Nakata,Y.Nakagawa,M.Nishida,S.Nozaki,et al.: "CD36,a novel receptor for oxidized low density lipoproteins,is highly expressed on lipid-laden macrophages in human atherosclerotic aorta" Arterioscler.Thromb.Vasc.(in press). (1999)
[Publications] F.Matsuura,S.Yamashita,H.Hirano,M.Ishigami,et al.: "Activation of monocytes in vivo causes intracellular accumulation of lipoprotein-derived lipids and marked hypocholesterolemia-possible pathogenesis of nerobiotic xanthogranuloma" Atherosclerosis. (in press). (1999)
[Publications] S.Takami,S.Yamashita,S.Kihara,M.Ishigami,et al.: "Lipoprotein(a) enhances the expression of intercellular adhesion molecule-1 in cultured human umbilical vein endothelial cells" Circulation. 97(8). 721-728 (1998)
[Publications] Yamagata-K;Yang-Q;Yamamoto-K;Iwahashi-H,et al.: "Mutation P291fsinsC in the transcription factor hepatocyte nuclear factor-1alpha is dominant negative." Diabetes. 47(8). 1231-1235 (1998)
[Publications] I.Toshiuchi,et al.: "Three new mutations in the hepatocyte nuclear factor-1 α gene in Japanese subjects with diabetes mellitus;Clinical features and functional characterization." Diabetologia. (in press). (1999)
[Publications] A.Imagawa et al: "In situ immunological abnormalities in islets parallelled further deteriolation of glycemic control in recent-onset type I(insulin-dependent)diabetes mellitus patients" Diabetologia. (in press). (1999)
[Publications] K.Aoyama et al: "Stromal cell CD9 regulates differentiation of hematopoietic stem/progenitor cells." Blood. (in press). (1999)
[Publications] H.Kashiwagi,Y.Tomiyama,S.Tadokoro et al.: "A mutation in the extracellular cystein-rich repeat region of the β3 subunit activates integrin αIIbβ3 and αvβ3." Blood. (in press). (1999)
[Publications] S.Tadokoro,Y.Tomiyama,S.Honda,M.Arai,et al.: "A Gln747->Pro substitution in the IIb subunit is responsible for a moderate IIbbeta3 deficiency in Glanzmann thrombasthenia." Blood. 92(8). 2750-2758 (1998)
[Publications] M.Shiraga,Y.Tomiyama,S.Honada,et al.: "Involvement of Na+/Ca2+ exchanger in inside-out signaling through the platelet integrin IIbbeta3" Blood. 92(10). 3710-3720 (1998)
[Publications] S.Honda,Y.Tomiyama,T.Aoki,M.Shiraga,et al.: "Association between ligand-induced conformational changes of integrin IIb β3 and IIbβ3-mediated intracellular Ca2+ signaling." Blood. 92(10). 3675-3683 (1998)
[Publications] S.Honda,Y.Tomiyama,M.Shiraga,S.Tadokoro,et al.: "A two-amino acid insertion in the Cys146-Cys167 loop of the alphaIIb subunit is associated with a variant of Glanzmann thrombasthenia.Critical role of Asp163 in ligand binding." J.Clin.Invest.102(6). 1183-1192 (1998)
[Publications] Y.Okajima,I.Matsumura,T.Nishiura,K.Hashimoto,et al.: "Insulin-like growth factor-I augments erythropoietin-induced proliferation through enhanced tyrosine phosphorylation of STAT5." J.Biol.Chem.273(36). 22877-22883 (1998)
[Publications] T.Yokota,K.Oritani,H.Mitsui,K.Aoyama,et al.: "Growth-supporting activities of fibronectin on hematopoietic stem/progenitor cells in vitro and in vivo:structural requirement for fibronectin activities of CS1 and cell-binding domains." Blood. 91(9). 3263-3272 (1998)
[Publications] Fukuda,S.Kawata,S.Tamura,Y.Matsuda,et al.: "Transforming growth factor-β1-induced degradation of activated Src tyrosine kinase in rat fibroblasts" Oncogene. 17(26). 3349-3356 (1998)
[Publications] K.Fukuda,S.Kawata,S.Tamura,Y.Matsuda,et al.: "Altered regulation of Src tyrosine kinase by transforming growth factor- β1 in a human hepatoma cell line." Hepatology. 28(9). 796-804 (1998)

1998 Fiscal Year Annual Research Report

内臓脂肪特異的遺伝子の同定とその臨床応用の研究

Principal Investigator

松澤 佑次 大阪大学, 医学部, 教授 (70116101)

Research Products

[Publications] Y.Arita,S.Kihara,N.Ouchi,M.Takahashi et al.: "Paradoxical decrease of an adipose-specific protein,adiponectin,in obesity" Biochem.Biophys.Res.Commun.(in press). (1999)

[Publications] T.Yoshizumi,T.Nakamura,M.Yamane,W.Islam.A.H.M.,et al.: "A standardized technique for the measurement of abdominal fat based on computed tomography" Radiology. (in press). (1999)

[Publications] H.Kuriyama,S.Yamashita,I.Shimomura,T.Funahashi,et al.: "Enhanced expression of hepatic acyl-CoA synthetase and microsomal triglyceride transfer protein mRNAs in the obese and hypertriglyceridemic rat with visceral fat accumulation" Hepatology. 27(2). 562-557 (1998)

[Publications] S.Kihara,N.Ouchi,T.Funahashi,E.Shinohara,et al.: "Troglitazone enhances glucose uptake and inhibits mitogen-activated protein kinase in human aortic smooth muscle cells" Atherosclerosis. 136(1). 163-168 (1998)

[Publications] E.Shinohara,S.Kihara,N.Ouchi,T.Funahashi,et al.: "Troglitazone suppresses intimal formation following balloon injury in insulin-resistant Zucker fatty rats" Atherosclerosis. 136(2). 275-279 (1998)

[Publications] F.Matsuura,S.Yamashita,T.Nakamura,M.Nishida,et al.: "Effect of visceral fat accumulation on uric acid metabolism in male obese subjects:visceral fat obesity is linked more closely to overproduction of uric acid than subcutaneous fat obesity" Metabolism. 47(8). 929-933 (1998)

[Publications] T.Nakagawa,S.Nozaki,M.Nishida,J.M.Yakub,et al.: "Oxidized LDL increases and interferon-gamma decreases expression of CD36 in human monocyte-derived macrophages" Arterioscler.Thromb.Vasc.Biol.18(8). 1350-1357 (1998)

[Publications] T.Maruyama,Y.Miyake,T.Yamamura,S.Tajima,et al.: "A novel point mutation in a splice accceptor site of intron 1 of the human low density lipoprotein receptor gene which causes severe hypercholesterolemia:an unexpected absence of exon skippinng" Human Mutation. 12. 480-483 (1998)

[Publications] K.Fukuchi,S.Nozaki,T.Yoshizumi,T.Uehara,et al.: "Enhanced myocardial glucose uptake in individuals with a deficiency in long-chain fatty acid transport(CD36 deficiency)" J.Nucl.Med.,. (in press). (1999)

[Publications] S.Nozaki,T.Tanaka,S.Yamashita,K.Sohmiya,et al.: "CD36 mediates long-chain fatty acid transport in human myocardium:complete myocardial accumulation defect of radiolabeled long-chain fatty acid analog in subjects with CD36 deficiency." Mol.Cell.Biochem.(in press). (1999)

[Publications] A.Nakata,Y.Nakagawa,M.Nishida,S.Nozaki,et al.: "CD36,a novel receptor for oxidized low density lipoproteins,is highly expressed on lipid-laden macrophages in human atherosclerotic aorta" Arterioscler.Thromb.Vasc.(in press). (1999)

[Publications] F.Matsuura,S.Yamashita,H.Hirano,M.Ishigami,et al.: "Activation of monocytes in vivo causes intracellular accumulation of lipoprotein-derived lipids and marked hypocholesterolemia-possible pathogenesis of nerobiotic xanthogranuloma" Atherosclerosis. (in press). (1999)

[Publications] S.Takami,S.Yamashita,S.Kihara,M.Ishigami,et al.: "Lipoprotein(a) enhances the expression of intercellular adhesion molecule-1 in cultured human umbilical vein endothelial cells" Circulation. 97(8). 721-728 (1998)

[Publications] Yamagata-K;Yang-Q;Yamamoto-K;Iwahashi-H,et al.: "Mutation P291fsinsC in the transcription factor hepatocyte nuclear factor-1alpha is dominant negative." Diabetes. 47(8). 1231-1235 (1998)

[Publications] I.Toshiuchi,et al.: "Three new mutations in the hepatocyte nuclear factor-1 α gene in Japanese subjects with diabetes mellitus;Clinical features and functional characterization." Diabetologia. (in press). (1999)

[Publications] A.Imagawa et al: "In situ immunological abnormalities in islets parallelled further deteriolation of glycemic control in recent-onset type I(insulin-dependent)diabetes mellitus patients" Diabetologia. (in press). (1999)

[Publications] K.Aoyama et al: "Stromal cell CD9 regulates differentiation of hematopoietic stem/progenitor cells." Blood. (in press). (1999)

[Publications] H.Kashiwagi,Y.Tomiyama,S.Tadokoro et al.: "A mutation in the extracellular cystein-rich repeat region of the β3 subunit activates integrin αIIbβ3 and αvβ3." Blood. (in press). (1999)

[Publications] S.Tadokoro,Y.Tomiyama,S.Honda,M.Arai,et al.: "A Gln747->Pro substitution in the IIb subunit is responsible for a moderate IIbbeta3 deficiency in Glanzmann thrombasthenia." Blood. 92(8). 2750-2758 (1998)

[Publications] M.Shiraga,Y.Tomiyama,S.Honada,et al.: "Involvement of Na+/Ca2+ exchanger in inside-out signaling through the platelet integrin IIbbeta3" Blood. 92(10). 3710-3720 (1998)

[Publications] S.Honda,Y.Tomiyama,T.Aoki,M.Shiraga,et al.: "Association between ligand-induced conformational changes of integrin IIb β3 and IIbβ3-mediated intracellular Ca2+ signaling." Blood. 92(10). 3675-3683 (1998)

[Publications] S.Honda,Y.Tomiyama,M.Shiraga,S.Tadokoro,et al.: "A two-amino acid insertion in the Cys146-Cys167 loop of the alphaIIb subunit is associated with a variant of Glanzmann thrombasthenia.Critical role of Asp163 in ligand binding." J.Clin.Invest.102(6). 1183-1192 (1998)

[Publications] Y.Okajima,I.Matsumura,T.Nishiura,K.Hashimoto,et al.: "Insulin-like growth factor-I augments erythropoietin-induced proliferation through enhanced tyrosine phosphorylation of STAT5." J.Biol.Chem.273(36). 22877-22883 (1998)

[Publications] T.Yokota,K.Oritani,H.Mitsui,K.Aoyama,et al.: "Growth-supporting activities of fibronectin on hematopoietic stem/progenitor cells in vitro and in vivo:structural requirement for fibronectin activities of CS1 and cell-binding domains." Blood. 91(9). 3263-3272 (1998)

[Publications] Fukuda,S.Kawata,S.Tamura,Y.Matsuda,et al.: "Transforming growth factor-β1-induced degradation of activated Src tyrosine kinase in rat fibroblasts" Oncogene. 17(26). 3349-3356 (1998)

[Publications] K.Fukuda,S.Kawata,S.Tamura,Y.Matsuda,et al.: "Altered regulation of Src tyrosine kinase by transforming growth factor- β1 in a human hepatoma cell line." Hepatology. 28(9). 796-804 (1998)

松澤佑次大阪大学, 医学部, 教授 (70116101)