Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA, United States.
Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, United States.
Pharmacol Ther. 2019 Mar;195:100-110. doi: 10.1016/j.pharmthera.2018.10.010. Epub 2018 Oct 19.
12-lipoxygenase (12-LOX) is one of several enzyme isoforms responsible for the metabolism of arachidonic acid and other poly-unsaturated fatty acids to both pro- and anti-inflammatory lipid mediators. Mounting evidence has shown that 12-LOX plays a critical role in the modulation of inflammation at multiple checkpoints during diabetes development. Due to this, interventions to limit pro-inflammatory 12-LOX metabolites either by isoform-specific 12-LOX inhibition, or by providing specific fatty acid substrates via dietary intervention, has the potential to significantly and positively impact health outcomes of patients living with both type 1 and type 2 diabetes. To date, the development of truly specific and efficacious inhibitors has been hampered by homology of LOX family members; however, improvements in high throughput screening have improved the inhibitor landscape. Here, we describe the function and role of human 12-LOX, and mouse 12-LOX and 12/15-LOX, in the development of diabetes and diabetes-related complications, and describe promise in the development of strategies to limit pro-inflammatory metabolites, primarily via new small molecule 12-LOX inhibitors.
12-脂氧合酶（12-LOX）是负责代谢花生四烯酸和其他多不饱和脂肪酸为促炎和抗炎脂质介质的几种酶同工型之一。越来越多的证据表明，12-LOX 在糖尿病发展过程中的多个检查点调节炎症中起着关键作用。因此，通过同工型特异性 12-LOX 抑制或通过饮食干预提供特定的脂肪酸底物来限制促炎 12-LOX 代谢物的干预措施有可能显著积极地影响 1 型和 2 型糖尿病患者的健康结果。迄今为止，真正特异性和有效的抑制剂的开发受到 LOX 家族成员同源性的阻碍；然而，高通量筛选的改进改善了抑制剂的前景。在这里，我们描述了人 12-LOX 以及鼠 12-LOX 和 12/15-LOX 在糖尿病及其相关并发症发展中的作用和作用，并描述了通过新型小分子 12-LOX 抑制剂限制促炎代谢物的策略的发展前景。
