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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Kohei Uchimura & Manabu Hayata & Teruhiko Mizumoto & Yoshikazu Miyasato & Yutaka Kakizoe & Jun Morinaga & Tomoaki Onoue & Rika Yamazoe & Miki Ueda & Masataka Adachi & Taku Miyoshi & Naoki Shiraishi & , 2014. "The serine protease prostasin regulates hepatic insulin sensitivity by modulating TLR4 signalling," Nature Communications, Nature, vol. 5(1), pages 1-13, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4428
    DOI: 10.1038/ncomms4428
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