The serine protease prostasin regulates hepatic insulin sensitivity by modulating TLR4 signalling

Kohei Uchimura, Manabu Hayata, Teruhiko Mizumoto, Yoshikazu Miyasato, Yutaka Kakizoe, Jun Morinaga, Tomoaki Onoue, Rika Yamazoe, Miki Ueda, Masataka Adachi, Taku Miyoshi, Naoki Shiraishi, Wataru Ogawa, Kazuki Fukuda, Tatsuya Kondo, Takeshi Matsumura, Eiichi Araki, Kimio Tomita and Kenichiro Kitamura ()
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Kohei Uchimura: Kumamoto University Graduate School of Medical Sciences
Manabu Hayata: Kumamoto University Graduate School of Medical Sciences
Teruhiko Mizumoto: Kumamoto University Graduate School of Medical Sciences
Yoshikazu Miyasato: Kumamoto University Graduate School of Medical Sciences
Yutaka Kakizoe: Kumamoto University Graduate School of Medical Sciences
Jun Morinaga: Kumamoto University Graduate School of Medical Sciences
Tomoaki Onoue: Kumamoto University Graduate School of Medical Sciences
Rika Yamazoe: Kumamoto University Graduate School of Medical Sciences
Miki Ueda: Kumamoto University Graduate School of Medical Sciences
Masataka Adachi: Kumamoto University Graduate School of Medical Sciences
Taku Miyoshi: Kumamoto University Graduate School of Medical Sciences
Naoki Shiraishi: Kumamoto University Graduate School of Medical Sciences
Wataru Ogawa: Kobe University Graduate School of Medicine
Kazuki Fukuda: Kumamoto University Graduate School of Medical Sciences
Tatsuya Kondo: Kumamoto University Graduate School of Medical Sciences
Takeshi Matsumura: Kumamoto University Graduate School of Medical Sciences
Eiichi Araki: Kumamoto University Graduate School of Medical Sciences
Kimio Tomita: Kumamoto University Graduate School of Medical Sciences
Kenichiro Kitamura: Kumamoto University Graduate School of Medical Sciences

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract 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.

Date: 2014
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DOI: 10.1038/ncomms4428

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