2013 Fiscal Year Final Research Report
Significance of proteasome dysfunction in the development of obesity-mediated hepatic insulin resistance
| Project/Area Number |
23591301
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | Kanazawa University |
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Principal Investigator |
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| Co-Investigator(Renkei-kenkyūsha) |
MURATA Shigeo 東京大学, 薬学研究科(研究院), 教授 (20344070)
ISEKI Shoichi 金沢大学, 医学系, 教授 (50167251)
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| Project Period (FY) |
2011 – 2013
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| Keywords | インスリン抵抗性 / 肝臓 / 肥満 / 小胞体ストレス / プロテアソーム / エネルギー / 糖質代謝異常 |
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| Research Abstract |
Chronic endoplasmic reticulum (ER) stress is a major contributor to obesity-induced insulin resistance in the liver. Here, we investigated the molecular link between obesity and ER stress. Mouse models of obesity and diabetes and proteasome activator 28 (PA28)-null mice showed 30-40% reduction in proteasome activity and accumulation of poly-ubiquitinated proteins in the liver. PA28-null mice also showed hepatic steatosis, decreased hepatic insulin signaling, and increased hepatic glucose production. The link between proteasome dysfunction and hepatic insulin resistance involves ER stress leading to hyperactivation of c-Jun N-terminal kinase and forkhead box O1 (FoxO1) activation in the liver. Taken together, our data suggest that proteasome dysfunction mediates obesity-induced ER stress, leading to insulin resistance in the liver.
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Research Products
(40 results)
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[Journal Article] LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance2014
Author(s)
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
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Journal Title
Diabetes
Volume: 63
Pages: 1649-64
Peer Reviewed
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[Journal Article] The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism : a randomised controlled trial2014
Author(s)
Takeshita Y, Takamura T, Honda M, Kita Y, Zen Y, Kato KI, Misu H, Ota T, Nakamura M, Yamada K, Sunagozaka H, Arai K, Yamashita T, Mizukoshi E, Kaneko S
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Journal Title
Diabetologia
Volume: 57
Pages: 878-90
Peer Reviewed
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[Journal Article] Metformin Suppresses Expression of the Selenoprotein P Gene via an AMP-activated Kinase (AMPK)/FoxO3a Pathway in H4IIEC3 Hepatocytes2014
Author(s)
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
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Journal Title
J Biol Chem
Volume: 289
Pages: 335-45
Peer Reviewed
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[Journal Article] Ectopic fat accumulation and distant organ-specific insulin resistance in Japanese people with nonalcoholic Fatty liver disease2014
Author(s)
Kato K, Takamura T, Takeshita Y, Ryu Y, Misu H, Ota T, Tokuyama K, Nagasaka S, Matsuhisa M, Matsui O, Kaneko S
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Journal Title
PLOS ONE
Volume: 20;9
Pages: e92170
Peer Reviewed
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[Journal Article] Proteasome Dysfunction Mediates Obesity-Induced Endoplasmic Reticulum Stress and Insulin Resistance in the Liver2013
Author(s)
Otoda T, Takamura T, 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
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Journal Title
Diabetes
Volume: 62
Pages: 811-24
Peer Reviewed
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[Journal Article] Adipose tissue-derived stem cells as a regenerative therapy for a murine steatohepatitis-induced cirrhosis model2013
Author(s)
Seki A, Sakai Y, Komura T, Nasti A, Yoshida K, Higashimoto M, Honda M, Usui S, Takamura M, Takamura T, Ochiya T, Furuichi K, Wada T, Kaneko S
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Journal Title
Hepatology
Volume: 58
Pages: 1133-42
Peer Reviewed
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[Journal Article] Metformin prevents and reverses inflammation in a non-diabetic mouse model of nonalcoholic steatohepatitis2012
Author(s)
Kita Y, Takamura T, Misu H, Ota T, Kurita S, Takeshita Y, Uno M, Matsuzawa-Nagata N, Kato K, Ando H, Fujimura A, Hayashi K, Kimura T, Ni Y, Otoda T, Miyamoto K, Zen Y, Nakanuma Y, Kaneko S
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Journal Title
PLOS ONE
Volume: 7
Pages: e43056
Peer Reviewed
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[Journal Article] CCR5 plays a critical role in obesity-induced adipose tissue inflammation and insulin resistance by regulating both macrophage recruitment and M1/M2 status2012
Author(s)
H Kitade, K Sawamoto, M Nagashimada, H Inoue, Y Yamamoto, Y Sai, T Takamura, H Yamamoto, K Miyamoto, H N. Ginsberg, N Mukaida, S Kaneko, T Ota
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Journal Title
Diabetes
Volume: 61
Pages: 1680-90
Peer Reviewed
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[Journal Article] Selenoprotein P as a diabetes-associated hepatokine that impairs angiogenesis by inducing VEGF resistance in vascular endothelial cells
Author(s)
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
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Journal Title
Diabetologia
Volume: (in press) (2014予定)
Peer Reviewed
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