Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S., Nagar, Punjab, 160062, India.
Naunyn Schmiedebergs Arch Pharmacol. 2020 Apr;393(4):705-716. doi: 10.1007/s00210-019-01773-5. Epub 2019 Dec 13.
The prevalence of non-alcoholic fatty liver disease (NAFLD) is much higher in diabetic and obese individuals. Combined exposure of high-fat diet (HFD) and single low-dose streptozotocin (STZ) was used to induce type II diabetes-associated NAFLD, as it better replicates the human pathology of fatty liver. Glibenclamide (GLB) is a potent NLRP3 inflammasome inhibitor and possesses anti-inflammatory and anti-oxidant properties. So it was pertinent to investigate its hepatoprotective potential against NAFLD in rat. HFD was provided to rat for 17 consecutive weeks and glibenclamide (GLB; 0.5 and 2.5 mg/kg/day, orally) was administered for the last 12 consecutive weeks. Establishment of NAFLD was clearly indicated by significant increase in liver weight, glucose, triglyceride, cholesterol, % glycosylated haemoglobin and insulin levels, and GLB intervention reduced the same. GLB restored HFD-induced significant increase in ROS, MDA and decrease in GSH. Histopathological studies revealed the macro- and micro-vascular steatosis and mild degree of inflammation in HFD-fed rat compared with control, and GLB intervention reduced the same. HFD exposure significantly increased the DNA damage and apoptosis compared with control, and GLB intervention reduced the same. Immunohistochemical and immunoblotting findings showed that GLB improved the hepatic expressions of inflammatory markers (NLRP3, ASC, caspase-1, IL-1β, NF-κB), anti-oxidant markers (SOD, catalase) and insulin signalling markers (p-AKT, p-GSK-3β, p-IRS). Hepatoprotective effects of GLB was mediated by decreasing the levels of glucose, triglycerides, cholesterol, DNA damage, apoptosis and inflammatory markers, and by improving the anti-oxidant status and insulin signalling pathway in HFD fed rat.
非酒精性脂肪性肝病（NAFLD）在糖尿病和肥胖个体中的患病率要高得多。联合高脂肪饮食（HFD）和单次低剂量链脲佐菌素（STZ）暴露用于诱导与 2 型糖尿病相关的非酒精性脂肪性肝病，因为它更好地模拟了脂肪肝的人类病理学。格列本脲（GLB）是一种有效的 NLRP3 炎性体抑制剂，具有抗炎和抗氧化特性。因此，研究其对大鼠非酒精性脂肪性肝病的保肝潜力是很有必要的。连续 17 周给予大鼠 HFD，最后 12 周连续给予格列本脲（GLB；0.5 和 2.5mg/kg/天，口服）。肝重、血糖、甘油三酯、胆固醇、%糖化血红蛋白和胰岛素水平的显著增加清楚地表明了非酒精性脂肪性肝病的建立，GLB 干预降低了这些水平。GLB 恢复了 HFD 诱导的 ROS、MDA 显著增加和 GSH 显著减少。组织病理学研究显示，与对照组相比，HFD 喂养的大鼠出现大血管和微血管脂肪变性以及轻度炎症，GLB 干预减轻了这种情况。HFD 暴露与对照组相比显著增加了 DNA 损伤和细胞凋亡，GLB 干预减轻了这种情况。免疫组化和免疫印迹结果显示，GLB 改善了肝脏炎症标志物（NLRP3、ASC、caspase-1、IL-1β、NF-κB）、抗氧化标志物（SOD、过氧化氢酶）和胰岛素信号标志物（p-AKT、p-GSK-3β、p-IRS）的表达。GLB 的保肝作用是通过降低血糖、甘油三酯、胆固醇、DNA 损伤、细胞凋亡和炎症标志物的水平，改善 HFD 喂养大鼠的抗氧化状态和胰岛素信号通路来介导的。
