Research Abstract


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

2014年3月11日 Nature Communications 5 : 3428 doi: 10.1038/ncomms4428


内村 幸平1, 早田 学1, 水本 輝彦1, 宮里 賢和1, 柿添 豊1, 森永 潤1, 尾上 友朗1, 山添 リカ1, 植田 美紀1, 安達 政隆1, 實吉 拓1, 白石 直樹1, 小川 渉2, 福田 一起3, 近藤 龍也3, 松村 剛3, 荒木 栄一3, 冨田 公夫1 & 北村 健一郎1

  1. 熊本大学大学院 生命科学研究部 腎臓内科学分野
  2. 神戸大学大学院 医学研究科 糖尿病・内分泌内科
  3. 熊本大学大学院 生命科学研究部 代謝内科学分野
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.