Proteasome dysfunction mediates obesity-induced endoplasmic reticulum stress and insulin resistance in the liver.
Proteasome dysfunction mediates obesity-induced endoplasmic reticulum stress and insulin resistance in the liver.
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作者：
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 K;Uno M;Takeshita Y;Yamamoto M;Tokuyama K;Iseki S;Tanaka K;Kaneko S
慢性内质网应激是肥胖诱导的肝脏胰岛素抵抗的主要原因。然而，肥胖和内质网应激之间的分子联系仍有待确定。蛋白酶体是降解错误折叠和氧化蛋白质的重要多催化酶复合体。在这里，我们报告了肥胖和糖尿病的小鼠模型和蛋白酶体激活物(PA)28缺失的小鼠显示蛋白酶体活性降低30%-40%和肝脏中多泛素化蛋白的积累。PA28基因缺失的小鼠也表现出肝脏脂肪变性，肝脏胰岛素信号减弱，肝脏葡萄糖产生增加。蛋白酶体功能障碍与肝脏胰岛素抵抗之间的联系涉及内质网应激导致肝脏中c-jun NH2末端激酶的过度激活。给予化学伴侣苯丁酸(PBA)，部分挽救了PA28基因缺失小鼠的表型。为了证实体内实验获得的部分结果，我们用26S蛋白酶体的选择性抑制剂Bortezomib处理大鼠肝癌来源的H4IIEC3细胞。Bortezomib在体外会导致内质网应激和胰岛素抵抗--这些反应可以被PBA部分阻断。综上所述，我们的数据表明，蛋白酶体功能障碍介导了肥胖诱导的内质网应激，导致肝脏中的胰岛素抵抗。
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.
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影响因子：
7.7
作者：
Kozuka C;Yabiku K;Sunagawa S;Ueda R;Taira S;Ohshiro H;Ikema T;Yamakawa K;Higa M;Tanaka H;Takayama C;Matsushita M;Oyadomari S;Shimabukuro M;Masuzaki H
通讯作者：
Masuzaki H
影响因子：
4.5
作者：
Fu S;Fan J;Blanco J;Gimenez-Cassina A;Danial NN;Watkins SM;Hotamisligil GS
通讯作者：
Hotamisligil GS
DOI：
10.1073/pnas.0406789102
发表时间：
2005-02-01
影响因子：
11.1
作者：
Huang, H;Regan, KM;Tindall, DJ
通讯作者：
Tindall, DJ
DOI：
10.1016/j.bbrc.2009.01.150
发表时间：
2009-03-13
影响因子：
3.1
作者：
Ando, Hitoshi;Takamura, Toshinari;Kaneko, Shuichi
通讯作者：
Kaneko, Shuichi
DOI：
10.1073/pnas.0405454101
发表时间：
2004-09-14
影响因子：
11.1
作者：
Aoki, M;Hao, J;Vogt, PK
通讯作者：
Vogt, PK