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論文 |
論文
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Ishikura, Kazuhide ; Misu, Hirofumi ; Kumazaki, Masafumi ; Takayama, Hiroaki ; Matsuzawa-Nagata, Naoto ; Tajima, Natsumi ; Chikamoto, Keita ; Lan, Fei ; Ando, Hitoshi ; Ota, Tsuguhito ; Sakurai, Masaru ; Takeshita, Yumie ; Kato, Kenichiro ; Fujimura, Akio ; Miyamoto, Ken-ichi ; Saito, Yoshiro ; Kameo, Satomi ; Okamoto, Yasuo ; Takuwa, Yoh ; Takahashi, Kazuhiko ; Kidoya, Hiroyasu ; Takakura, Nobuyuki ; Kaneko, Shuichi ; Takamaura, Toshinari
概要:
Aims/hypothesis Impaired angiogenesis induced by vascular endothelial growth factor (VEGF) resistance is a hallmark of v
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ascular complications in type 2 diabetes; however, its molecular mechanism is not fully understood. We have previously identified selenoprotein P (SeP, encoded by the SEPP1 gene in humans) as a liver-derived secretory protein that induces insulin resistance. Levels of serum SeP and hepatic expression of SEPP1 are elevated in type 2 diabetes. Here, we investigated the effects of SeP on VEGF signalling and angiogenesis. Methods We assessed the action of glucose on Sepp1 expression in cultured hepatocytes. We examined the actions of SeP on VEGF signalling and VEGF-induced angiogenesis in HUVECs. We assessed wound healing in mice with hepatic SeP overexpression or SeP deletion. The blood flow recovery after ischaemia was also examined by using hindlimb ischaemia model with Sepp1-heterozygous-knockout mice. Results Treatment with glucose increased gene expression and transcriptional activity for Sepp1 in H4IIEC hepatocytes. Physiological concentrations of SeP inhibited VEGF-stimulated cell proliferation, tubule formation and migration in HUVECs. SeP suppressed VEGF-induced reactive oxygen species (ROS) generation and phosphorylation of VEGF receptor 2 (VEGFR2) and extracellular signal-regulated kinase 1/2 (ERK1/2) in HUVECs. Wound closure was impaired in the mice overexpressing Sepp1, whereas it was improved in SeP-/-mice. SeP+/-mice showed an increase in blood flow recovery and vascular endothelial cells after hindlimb ischaemia. Conclusions/interpretation The hepatokine SeP may be a novel therapeutic target for impaired angiogenesis in type 2 diabetes. © 2014 Springer-Verlag Berlin Heidelberg.
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| 2.
図書 |
図書
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Takamura, Toshinari ; Misu, Hirofumi ; Kaneko, Shuichi
概要:
Liver fat is associated not only with enhanced hepatic glucose production but also with skeletal muscle insulin resistan
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ce, supporting a central role of fatty liver in systemic insulin resistance and existence of a network between the liver and skeletal muscle. Palmitate and cholesterol act as toxic lipids to cause hepatic insulin resistance via mitochondria-derived oxidative stress. Obesity-mediated disruption in crosstalk among protein-, glucose- and lipid-metabolism pathways results in hepatic insulin resistance, enhanced gluconeogenesis and liver steatosis by impairing proteasome function. The liver plays as an endocrine organ to produce functional hepatokines and thereby mediates fatty liver-associated skeletal muscle insulin resistance through unique mechanisms. Selenoprotein P is upregulated through FoxOs and hyperglycemia and causes resistance to insulin, angiogenesis and exercise through reductive stress. LECT2 is upregulated in satiety through AMPK inactivation and contributes to the development of muscle insulin resistance and obesity by activating JNK and by impairing myogenesis, respectively. Therefore, overnutrition evokes remodeling of nutrient homeostasis by toxic lipids and proteasome dysfunction in the liver. The remodeling also results in the overproduction of hepatokines that disrupt inter-organ network leading to pathology of diabetes. © Springer Japan 2016.<br />Book Chapter / Embargo Period 12 months
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