Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Queen Rania St, Amman, 11942, Jordan.
Department of Clinical Pharmacy and Biopharmaceutics, School of Pharmacy, The University of Jordan, Amman, Jordan.
Pharmacol Rep. 2020 Apr;72(2):435-442. doi: 10.1007/s43440-019-00013-0. Epub 2019 Dec 19.
Currently, there is overwhelming evidence linking elevated plasma free fatty acids with insulin resistance and inflammation. Monoglyceride lipase (MGL) plays a crucial metabolic role in lipolysis by mediating the release of fatty acids. Therefore, inhibiting MGL should be a promising pharmacological approach for treating type 2 diabetes and inflammatory disorders. Proton pump inhibitors (PPIs) have been reported to improve glycemic control in type 2 diabetes albeit via largely unknown mechanism.
The anti-MGL bioactivities of three PPIs, namely, lansoprazole, rabeprazole, and pantoprazole, were investigated using docking experiments and in vitro bioassay.
The three PPIs inhibited MGL in low micromolar range with rabeprazole exhibiting the best IC at 4.2 µM. Docking experiments showed several binding interactions anchoring PPIs within MGL catalytic site.
Our study provides evidence for a new mechanism by which PPIs improve insulin sensitivity independent of serum gastrin. The three PPIs effectively inhibit MGL and, therefore, serve as promising leads for the development of new clinical MGL inhibitors.
目前，大量证据表明血浆游离脂肪酸与胰岛素抵抗和炎症有关。单甘油酯脂肪酶（MGL）在脂肪分解中发挥着关键的代谢作用，介导脂肪酸的释放。因此，抑制 MGL 应该是治疗 2 型糖尿病和炎症性疾病的一种有前途的药理学方法。质子泵抑制剂（PPIs）已被报道可改善 2 型糖尿病患者的血糖控制，尽管其机制尚不清楚。
采用对接实验和体外生物测定法研究了三种质子泵抑制剂（兰索拉唑、雷贝拉唑和泮托拉唑）的抗 MGL 活性。
三种质子泵抑制剂以低微摩尔浓度抑制 MGL，其中雷贝拉唑的 IC 为 4.2µM。对接实验表明，几种结合相互作用将质子泵抑制剂锚定在 MGL 催化位点内。
我们的研究为质子泵抑制剂通过独立于血清胃泌素提高胰岛素敏感性提供了新的机制证据。这三种质子泵抑制剂能有效抑制 MGL，因此可作为开发新型临床 MGL 抑制剂的有希望的先导化合物。
