Article

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

Authors: Jun-shang Huang1,2, Bin-bin Guo1, Gai-hong Wang1, Li-min Zeng1, You-hong Hu1,2, Ting Wang1, He-yao Wang1,2
1 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 University of Chinese Academy of Sciences, Beijing 100049, China
Correspondence to: Ting Wang: wangting@simm.ac.cn, He-yao Wang: hywang@simm.ac.cn,
DOI: 10.1038/s41401-020-0482-7
Received: 6 November 2019
Accepted: 14 July 2020
Advance online: 31 July 2020

Abstract

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 β-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.
Keywords: type 2 diabetes; DGAT1 inhibitors; pancreatic β-cells; apoptosis; ER stress; inflammation

Article Options

Download Citation

Cited times in Scopus