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

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.

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Fig. 1: DGAT1 inhibitors dose-dependently increase cell viability in PA-treated MIN6 cells.
Fig. 2: Inhibition of DGAT1 ameliorates PA-induced apoptosis in MIN6 cells.
Fig. 3: 4a reduces the apoptosis of islet cells both in vitro and in vivo.
Fig. 4: Long-term administration of 4a improves glucose and lipid metabolism in db/db mice.
Fig. 5: DGAT1 inhibitors decrease PA-induced lipid accumulation, ER stress, and proinflammatory responses in MIN6 cells.

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Acknowledgements

We gratefully acknowledge the kind provision of MIN6 cells by Professor S. Seino (Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Kobe, Japan). This work was supported by grants from the National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program,” China (2018ZX09711002-002-007); the “Personalized Medicines-Molecular Signature-based Drug Discovery and Development,” the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12040336); the National Natural Science Foundation of China (81503124, 81773791, and 81473262); and the Institutes for Drug Discovery and Development, Chinese Academy of Sciences (CASIMM0120162025).

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HYW and TW designed the research; JSH, BBG, and GHW performed the research and analyzed the data; LMZ and YHH synthesized the compounds; JSH, TW, and HYW wrote the paper.

Corresponding authors

Correspondence to Ting Wang or He-yao Wang.

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The authors declare no competing interests.

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Huang, J., Guo, B., Wang, G. et al. DGAT1 inhibitors protect pancreatic β-cells from palmitic acid-induced apoptosis. Acta Pharmacol Sin (2020). https://doi.org/10.1038/s41401-020-0482-7

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Keywords

  • type 2 diabetes
  • DGAT1 inhibitors
  • pancreatic β-cells
  • apoptosis
  • ER stress
  • inflammation