El Ouaamari Abdelfattah, Dirice Ercument, Gedeon Nicholas, Hu Jiang, Zhou Jian-Ying, Shirakawa Jun, Hou Lifei, Goodman Jessica, Karampelias Christos, Qiang Guifeng, Boucher Jeremie, Martinez Rachael, Gritsenko Marina A, De Jesus Dario F, Kahraman Sevim, Bhatt Shweta, Smith Richard D, Beer Hans-Dietmar, Jungtrakoon Prapaporn, Gong Yanping, Goldfine Allison B, Liew Chong Wee, Doria Alessandro, Andersson Olov, Qian Wei-Jun, Remold-O'Donnell Eileen, Kulkarni Rohit N
Islet Cell and Regenerative Medicine, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA.
Biological Sciences Division and Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA 99352, USA.
Cell Metab. 2016 Jan 12;23(1):194-205. doi: 10.1016/j.cmet.2015.12.001. Epub 2015 Dec 15.
Although compensatory islet hyperplasia in response to insulin resistance is a recognized feature in diabetes, the factor(s) that promote β cell proliferation have been elusive. We previously reported that the liver is a source for such factors in the liver insulin receptor knockout (LIRKO) mouse, an insulin resistance model that manifests islet hyperplasia. Using proteomics we show that serpinB1, a protease inhibitor, which is abundant in the hepatocyte secretome and sera derived from LIRKO mice, is the liver-derived secretory protein that regulates β cell proliferation in humans, mice, and zebrafish. Small-molecule compounds, that partially mimic serpinB1 effects of inhibiting elastase activity, enhanced proliferation of β cells, and mice lacking serpinB1 exhibit attenuated β cell compensation in response to insulin resistance. Finally, SerpinB1 treatment of islets modulated proteins in growth/survival pathways. Together, these data implicate serpinB1 as an endogenous protein that can potentially be harnessed to enhance functional β cell mass in patients with diabetes.
尽管胰岛对胰岛素抵抗的代偿性增生是糖尿病的一个公认特征，但促进β细胞增殖的因素一直难以捉摸。我们之前报道，肝脏是肝脏胰岛素受体敲除（LIRKO）小鼠（一种表现为胰岛增生的胰岛素抵抗模型）中此类因子的来源。利用蛋白质组学，我们发现丝氨酸蛋白酶抑制剂B1（SerpinB1），一种在LIRKO小鼠的肝细胞分泌组和血清中含量丰富的蛋白酶抑制剂，是调节人类、小鼠和斑马鱼β细胞增殖的肝脏来源分泌蛋白。部分模拟SerpinB1抑制弹性蛋白酶活性作用的小分子化合物可增强β细胞增殖，而缺乏SerpinB1的小鼠对胰岛素抵抗的β细胞代偿作用减弱。最后，用SerpinB1处理胰岛可调节生长/存活途径中的蛋白质。总之，这些数据表明SerpinB1是一种内源性蛋白质，有可能被用于增加糖尿病患者功能性β细胞数量。
