The serine protease prostasin regulates hepatic insulin sensitivity by modulating TLR4 signalling.
The serine protease prostasin regulates hepatic insulin sensitivity by modulating TLR4 signalling.
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DOI：
10.1038/ncomms4428
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发表时间：
2014-03-11
影响因子：
16.6
通讯作者：
Kitamura, Kenichiro
中科院分区：
文献类型：
--
作者：
Uchimura, Kohei;Hayata, Manabu;Mizumoto, Teruhiko;Miyasato, Yoshikazu;Kakizoe, Yutaka;Morinaga, Jun;Onoue, Tomoaki;Yamazoe, Rika;Ueda, Miki;Adachi, Masataka;Miyoshi, Taku;Shiraishi, Naoki;Ogawa, Wataru;Fukuda, Kazuki;Kondo, Tatsuya;Matsumura, Takeshi;Araki, Eiichi;Tomita, Kimio;Kitamura, Kenichiro
高脂饮食（HFD）和餐后内毒素血症对2型糖尿病发展的影响尚未完全了解。在这里，我们表明，丝氨酸蛋白酶前列腺素（PRSS 8）调节肝脏胰岛素敏感性，通过调节Toll样受体4（TLR 4）介导的信号。HFD通过诱导内质网（ER）应激触发PRSS 8表达的抑制并增加肝脏中的TLR 4水平。PRSS 8通过切割TLR 4释放其胞外域，这导致全长形式的减少并减少TLR 4的活化。肝脏特异性PRSS 8敲除（LKO）小鼠发展与肝脏TLR 4增加相关的胰岛素抵抗。HFD、LKO和db/db小鼠肝脏中PRSS 8表达的恢复降低了TLR 4水平并改善了胰岛素抵抗。这些结果确定了PRSS 8在肝脏中的新生理作用，并为HFD或代谢性内毒素血症导致的糖尿病的发展提供了新的见解。 肝脏胰岛素抵抗是糖尿病的标志，但其病因尚不完全清楚。在这里，内村及其同事表明，丝氨酸蛋白酶前列腺素切割Toll样受体4（TLR 4），并通过调节TLR 4介导的信号转导来调节肝脏胰岛素敏感性。
The effects of high-fat diet (HFD) and postprandial endotoxemia on the development of type 2 diabetes are not fully understood. Here we show that the serine protease prostasin (PRSS8) regulates hepatic insulin sensitivity by modulating Toll-like receptor 4 (TLR4)-mediated signalling. HFD triggers the suppression of PRSS8 expression by inducing endoplasmic reticulum (ER) stress and increases the TLR4 level in the liver. PRSS8 releases the ectodomain of TLR4 by cleaving it, which results in a reduction in the full-length form and reduces the activation of TLR4. Liver-specific PRSS8 knockout (LKO) mice develop insulin resistance associated with the increase in hepatic TLR4. Restoration of PRSS8 expression in livers of HFD, LKO and db/db mice decreases the TLR4 level and ameliorates insulin resistance. These results identify a novel physiological role for PRSS8 in the liver and provide new insight into the development of diabetes resulting from HFD or metabolic endotoxemia. Hepatic insulin resistance is a hallmark of diabetes, but its aetiology is incompletely understood. Here, Uchimura and colleagues show that the serine protease prostasin cleaves Toll-like receptor 4 (TLR4) and regulates hepatic insulin sensitivity by modulating TLR4-mediated signalling.
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影响因子：
7.7
作者：
Cani, Patrice D.;Amar, Jacques;Burcelin, Remy
通讯作者：
Burcelin, Remy
与肝脂肪变性和胰岛素抵抗有关的脂肪生成与脂质过量的过多相对于脂质过量的反应不同。
影响因子：
3.7
作者：
Ren LP;Chan SM;Zeng XY;Laybutt DR;Iseli TJ;Sun RQ;Kraegen EW;Cooney GJ;Turner N;Ye JM
通讯作者：
Ye JM
影响因子：
7.7
作者：
Oliveira AG;Carvalho BM;Tobar N;Ropelle ER;Pauli JR;Bagarolli RA;Guadagnini D;Carvalheira JB;Saad MJ
通讯作者：
Saad MJ
影响因子：
3.7
作者：
Pierre N;Deldicque L;Barbé C;Naslain D;Cani PD;Francaux M
通讯作者：
Francaux M
影响因子：
8.2
作者：
Poggi, M.;Bastelica, D.;Alessi, M. C.
通讯作者：
Alessi, M. C.