DGAT1 inhibitors protect pancreatic β-cells from palmitic acid-induced apoptosis

• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2021,（2）
• 所属期刊栏目: Endocrine Pharmacology
• 页码范围: 264-271
• 页数: 8页
• 语种: 英文
• DOI: 10.1038/s41401-020-0482-7

摘要

Previous studies demonstrated that prolonged exposure to elevated levels of free fatty acids(FFA),especially saturated fatty acids,could lead to pancreatic β-cell apoptosis,which plays an important role in the progression of type 2 diabetes(T2D).Diacylglycerol acyltransferase 1(DGAT1),an enzyme that catalyzes the final step of triglyceride(TG)synthesis,has been reported as a novel target for the treatment of multiple metabolic diseases.In this study we evaluated the potential beneficial effects of DGAT1 inhibitors on pancreatic P-cells,and further verified their antidiabetic effects in db/db mice.We showed that DGAT1 inhibitors(4a and LCQ908)at the concentration of 1 μM significantly ameliorated palmitic acid(PA)-induced apoptosis in MIN6 pancreatic β-cells and primary cultured mouse islets;oral administration of a DGAT1 inhibitor(4a)(100 mg/kg)for 4 weeks significantly reduced the apoptosis of pancreatic islets in db/db mice.Meanwhile,4a administration significantly decreased fasting blood glucose and TG levels,and improved glucose tolerance and insulin tolerance in db/db mice.Furthermore,we revealed that pretreatment with 4a(1 μM)significantly alleviated PA-induced intracellular lipid accumulation,endoplasmic reticulum(ER)stress,and proinflammatory responses in MIN6 cells,which might contribute to the protective effects of DGAT1 inhibitors on pancreatic β-cells.These findings provided a better understanding of the antidiabetic effects of DGAT1 inhibitors.