Proteasome Dysfunction Mediates Obesity-Induced Endoplasmic Reticulum Stress and Insulin Resistance in the Liver
- Toshiki Otoda1,
- Toshinari Takamura1⇓,
- Hirofumi Misu1,
- Tsuguhito Ota2,
- Shigeo Murata3,
- Hiroto Hayashi1,
- Hiroaki Takayama1,
- Akihiro Kikuchi1,
- Takehiro Kanamori1,
- Kosuke R. Shima1,
- Fei Lan1,
- Takashi Takeda1,
- Seiichiro Kurita1,
- Kazuhide Ishikura1,
- Yuki Kita1,
- Kaito Iwayama4,
- Ken-ichiro Kato1,
- Masafumi Uno1,
- Yumie Takeshita1,
- Miyuki Yamamoto5,
- Kunpei Tokuyama4,
- Shoichi Iseki5,
- Keiji Tanaka6 and
- Shuichi Kaneko1
- 1Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Sciences, Ishikawa, Japan
- 2Frontier Science Organization, Kanazawa University, Ishikawa, Japan
- 3Laboratory of Protein Metabolism, Department of Integrated Biology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan
- 4Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Japan
- 5Department of Histology and Embryology, Kanazawa University Graduate School of Medical Sciences, Ishikawa, Japan
- 6Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
- Corresponding author: Toshinari Takamura, .
T.Oto. and T.Taka. contributed equally to this work.
Chronic endoplasmic reticulum (ER) stress is a major contributor to obesity-induced insulin resistance in the liver. However, the molecular link between obesity and ER stress remains to be identified. Proteasomes are important multicatalytic enzyme complexes that degrade misfolded and oxidized proteins. Here, we report that both mouse models of obesity and diabetes and proteasome activator (PA)28-null mice showed 30–40% reduction in proteasome activity and accumulation of polyubiquitinated 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 NH2-terminal kinase in the liver. Administration of a chemical chaperone, phenylbutyric acid (PBA), partially rescued the phenotypes of PA28-null mice. To confirm part of the results obtained from in vivo experiments, we pretreated rat hepatoma-derived H4IIEC3 cells with bortezomib, a selective inhibitor of the 26S proteasome. Bortezomib causes ER stress and insulin resistance in vitro—responses that are partly blocked by PBA. Taken together, our data suggest that proteasome dysfunction mediates obesity-induced ER stress, leading to insulin resistance in the liver.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-1652/-/DC1.
See accompanying commentary, p. 691.
- Received November 25, 2011.
- Accepted October 9, 2012.
- © 2013 by the American Diabetes Association.
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