Bleich D, Chen S, Gu J L, Nadler J L
Division of Diabetes, Endocrinology and Metabolism, City of Hope National Medical Center, Duarte, CA 91010, USA.
Int J Mol Med. 1998 Jan;1(1):265-72.
Leukocyte type 12-lipoxygenase (12-LO) catalyzes the conversion of arachidonic acid (AA; C20:4) to 12-hydroperoxyeicosatetraenoic acid (12-HPETE) and linoleic acid (LA; C18:2) to 13-hydroperoxyoctadecadienoic acid (13-HPODE). Previous studies have demonstrated that 12-LO, but not 5- or 15-lipoxygenase (5-LO, 15-LO respectively), is specifically expressed in pancreatic -cells and is involved in regulating glucose-stimulated insulin secretion. Lipoxygenase products also have been linked with inflammatory pathways in endothelial cells, kidney mesangial cells, inflammatory bowel disease, and corneal epithelial cells. Therefore, 12-LO may play a role in cytokine mediated inflammation in pancreatic beta-cells (i.e. beta -cell dysfunction and cytotoxicity). Cytokines such as IL-1 stimulate both de novo 12-LO protein synthesis and enzyme activity in pancreatic beta-cells. The products generated by 12-LO may ultimately be involved in cellular events that lead to lipid peroxidation. Hydroperoxide and free radical production in beta-cells can activate intracellular signaling pathways that lead to cell death or may directly damage mitochondrial and plasma membranes. Increased 12-LO expression has also been found in islets from prediabetic Zucker fatty rats, a model that demonstrates insulin secretory defects similar to human type 2 diabetes. In this review, we present an overview of the 12-LO pathway in regulating glucose-stimulated insulin secretion in beta-cells as well as more recent data which supports the hypothesis that the 12-LO pathway participates in cytokine mediated beta-cell dysfunction and cytotoxicity.
白细胞12-脂氧合酶（12-LO）催化花生四烯酸（AA；C20:4）转化为12-氢过氧化二十碳四烯酸（12-HPETE），以及亚油酸（LA；C18:2）转化为13-氢过氧化十八碳二烯酸（13-HPODE）。先前的研究表明，12-LO而非5-或15-脂氧合酶（分别为5-LO、15-LO）在胰腺β细胞中特异性表达，并参与调节葡萄糖刺激的胰岛素分泌。脂氧合酶产物还与内皮细胞、肾系膜细胞、炎症性肠病和角膜上皮细胞中的炎症途径有关。因此，12-LO可能在细胞因子介导的胰腺β细胞炎症中发挥作用（即β细胞功能障碍和细胞毒性）。诸如白细胞介素-1等细胞因子可刺激胰腺β细胞中从头合成12-LO蛋白并提高其酶活性。12-LO产生的产物最终可能参与导致脂质过氧化的细胞事件。β细胞中氢过氧化物和自由基的产生可激活细胞内信号通路，导致细胞死亡或可能直接损伤线粒体膜和质膜。在糖尿病前期Zucker肥胖大鼠的胰岛中也发现12-LO表达增加，该模型显示出与人类2型糖尿病相似的胰岛素分泌缺陷。在本综述中，我们概述了12-LO途径在调节β细胞中葡萄糖刺激的胰岛素分泌方面的作用，以及支持12-LO途径参与细胞因子介导的β细胞功能障碍和细胞毒性这一假说的最新数据。
