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Protective Role of PPARdelta in Lipoapoptosis of Pancreatic β Cells

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Lipids

Abstract

Lipoapoptosis plays an important role in the pathogenesis of type 2 diabetes. Peroxisome proliferator-activated receptor delta (PPARdelta), a vital regulator of glucose and lipid metabolism, may reduce fatty acid-induced pancreatic β cell lipotoxicity in diabetes. However, the detailed molecular mechanisms underlying this process are not fully understood. In this study, we investigated the effect of activation of PPARdelta on palmitate-induced β cell apoptosis, and we explored the potential mechanism of the antiapoptotic effect. The cell apoptosis was determined by DNA fragmentation analysis and Hoechst 33342 staining. The expressing of glucagon-like peptide-1 receptor (GLP-1R) in INS-1 cells was assessed by Western blotting, quantification of PCR, and was further confirmed by immunofluorescence staining. The potential of PPARdelta to interact with homologous PPRE in the GLP-1R gene was determined by Chromatin immunoprecipitation (ChIP). Our results showed that exposure of INS-1 cells to palmitate for 24 h caused a significant increase in cell apoptosis, which was inhibited by GW501516. PPARdelta exerted anti-apoptotic effects in pancreatic β cells via the PI3 K/PKB/FoxO1 signaling pathway. Moreover, PPARdelta upregulated the GLP-1R expression under lipotoxic conditions. The ChIP assay revealed a direct binding of PPARdelta to a noncanonical PPRE motif of the GLP-1R gene in INS-1 cells. Our study suggested that the anti-apoptotic action of PPARdelta may involve its transcriptional regulation of GLP-1R and PI3 K/PKB/FoxO1 signaling. GW501516 and possible other GW-based strategies may confer additional benefit beyond improved glycemic control.

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Abbreviations

BSA:

Bovine serum albumin

ChIP:

Chromatin immunoprecipitation

FFA:

Free fatty acids

FoxO1:

Forkhead box O1

GLP-1:

Glucagon-like peptide-1

GLP-1R:

Glucagon-like peptide-1 receptor

PAM:

Palmitate

PI3K:

Phosphoinositide 3-kinase

PKB:

Protein kinase B

PPARdelta:

Peroxisome proliferator-activated receptor delta

RT-qPCR:

Real-time quantitative PCR

T2D:

Type 2 diabetes

References

  1. Unger RH, Zhou YT (2001) Lipotoxicity of beta-cells in obesity and in other causes of fatty acid spillover. Diabetes 50(Suppl 1):S118–S121

    Article  CAS  PubMed  Google Scholar 

  2. Wilding JP (2007) The importance of free fatty acids in the development of Type 2 diabetes. Diabet Med 24(9):934–945

    Article  CAS  PubMed  Google Scholar 

  3. Laybutt DR, Preston AM, Akerfeldt MC, Kench JG, Busch AK, Biankin AV, Biden TJ (2007) Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia 50(4):752–763

    Article  CAS  PubMed  Google Scholar 

  4. Shimabukuro M, Zhou YT, Levi M, Unger RH (1998) Fatty acid-induced beta cell apoptosis: a link between obesity and diabetes. Proc Natl Acad Sci USA 95(5):2498–2502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lupi R, Dotta F, Marselli L, Del Guerra S, Masini M, Santangelo C, Patané G, Boggi U, Piro S, Anello M, Bergamini E, Mosca F, Di Mario U, Del Prato S, Marchetti P (2002) Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. Diabetes 51(5):1437–1442

    Article  CAS  PubMed  Google Scholar 

  6. Vilsbøll T, Krarup T, Deacon CF, Madsbad S, Holst JJ (2001) Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 50(3):609–613

    Article  PubMed  Google Scholar 

  7. Thorens B (1992) Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1. Proc Natl Acad Sci USA 89(18):8641–8645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Thorens B, Porret A, Bühler L, Deng SP, Morel P, Widmann C (1993) Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9–39) an antagonist of the receptor. Diabetes 42(11):1678–1682

    Article  CAS  PubMed  Google Scholar 

  9. Xu G, Kaneto H, Laybutt DR, Duvivier-Kali VF, Trivedi N, Suzuma K, King GL, Weir GC, Bonner-Weir S (2007) Downregulation of GLP-1 and GIP receptor expression by hyperglycemia: possible contribution to impaired incretin effects in diabetes. Diabetes 56(6):1551–1558

    Article  CAS  PubMed  Google Scholar 

  10. Farilla L, Bulotta A, Hirshberg B, Li Calzi S, Khoury N, Noushmehr H, Bertolotto C, Di Mario U, Harlan DM, Perfetti R (2003) Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology 144(12):5149–5158

    Article  CAS  PubMed  Google Scholar 

  11. Meier JJ, Nauck MA (2005) Glucagon-like peptide 1(GLP-1) in biology and pathology. Diabete Metab Res Rev 21(2):91–117

    Article  CAS  Google Scholar 

  12. Drucker DJ (2007) The role of gut hormones in glucose homeostasis. J Clin Invest 117(1):24–32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ravnskjaer K, Frigerio F, Boergesen M, Nielsen T, Maechler P, Mandrup S (2010) PPARdelta is a fatty acid sensor that enhances mitochondrial oxidation in insulin-secreting cells and protects against fatty acid-induced dysfunction. J Lipid Res 51(6):1370–1379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wan J, Jiang L, Lü Q, Ke L, Li X, Tong N (2010) Activation of PPARdelta up-regulates fatty acid oxidation and energy uncoupling genes of mitochondria and reduces palmitate-induced apoptosis in pancreatic beta-cells. Biochem Biophys Res Commun 391(3):1567–1572

    Article  CAS  PubMed  Google Scholar 

  15. Kersten S, Desvergne B, Wahli W (2000) Roles of PPARs in health and disease. Nature 405(6785):421–424

    Article  CAS  PubMed  Google Scholar 

  16. Elghazi L, Balcazar N, Bernal-Mizrachi E (2006) Emerging role of protein kinaseB/Akt signaling in pancreatic β-cell mass and function. Int J Biochem Cell Biol 38(2):157–163

    CAS  PubMed  Google Scholar 

  17. Kharroubi I, Ladriere L, Cardozo AK, Dogusan Z, Cnop M, Eizirik DL (2004) Free fatty acids and cytokines induce pancreatic β-cell apoptosis by different mechanisms: role of nuclear factor-кB and endoplasmic reticulum stress. Endocrinology 145(11):5087–5096

    Article  CAS  PubMed  Google Scholar 

  18. McGarry JD, Dobbins RL (1999) Fatty acid, lipotoxicity and insulin secretion. Diabetologia 42(2):128–138

    Article  CAS  PubMed  Google Scholar 

  19. Franke TF, Hornik CP, Segev L, Shostak GA, Sugimoto C (2003) PI3 K/Akt and apoptosis: size matters. Oncogene 22(56):8983–8998

    Article  CAS  PubMed  Google Scholar 

  20. Wrede CE, Dickson LM, Lingohr MK, Briaud I, Rhodes CJ (2002) Protein kinase B/Akt prevents fatty acid-induced apoptosis in pancreatic beta-cells (INS-1). J Biol Chem 277(51):49676–49684

    Article  CAS  PubMed  Google Scholar 

  21. Hirabara SM, Curi R, Maechler P (2010) Saturated fatty acid-induced insulin resistance is associated with mitochondrial dysfunction in skeletal muscle cells. J Cell Physiol 222(1):187–194

    Article  CAS  PubMed  Google Scholar 

  22. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96(6):857–868

    Article  CAS  PubMed  Google Scholar 

  23. Cypess AM, Zhang H, Schulz TJ, Huang TL, Espinoza DO, Kristiansen K, Unterman TG, Tseng YH (2011) Insulin/IGF-I regulation of necdin and brown adipocyte differentiation via CREB- and FoxO1-associated pathways. Endocrinology 152(10):3680–3689

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Nakae J, Oki M, Cao Y (2008) The FoxO transcription factors and metabolic regulation. FEBS Lett 582(1):54–67

    Article  CAS  PubMed  Google Scholar 

  25. Zhang X, Yong W, Lv J, Zhu Y, Zhang J, Chen F, Zhang R, Yang T, Sun Y, Han X (2009) Inhibition of forkhead boxO1 protects pancreatic beta-cells against dexamethasone-induced dysfunction. Endocrinology 150(9):4065–4073

    Article  CAS  PubMed  Google Scholar 

  26. Wang Q, Li L, Xu E, Wong V, Rhodes C, Brubaker PL (2004) Glucagon-like peptide-1 regulates proliferation and apoptosis via activation of protein kinaseB in pancreatic INS-1 beta cells. Diabetologia 47(3):478–487

    Article  CAS  PubMed  Google Scholar 

  27. Buteau J, Spatz ML, Accili D (2006) Transcription factor FoxO1 mediates glucagon-like peptide-1 effects on pancreatic beta-cell mass. Diabetes 55(5):1190–1196

    Article  CAS  PubMed  Google Scholar 

  28. Wang HW, Mizuta M, Saitoh Y, Noma K, Ueno H, Nakazato M (2011) Glucagon-like peptide-1 and candesartan additively improve glucolipotoxicity in pancreatic β-cells. Metabolism 60(8):1081–1089

    Article  CAS  PubMed  Google Scholar 

  29. Shi Y, Hon M, Evans RM (2002) The peroxisome proliferator-activated receptor δ, an integrator of transcriptional repression and nuclear receptor signaling. Proc Natl Acad Sci USA 99(5):2613–2618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Khozoie C, Borland MG, Zhu B, Baek S, John S, Hager GL, Shah YM, Gonzalez FJ, Peters JM (2012) Analysis of the peroxisome proliferator-activated receptor -β/δ (PPARβ/δ) cistrome reveals novel co-regulatory role of ATF4. BMC Genom 13:665

    Article  CAS  Google Scholar 

  31. Biddie SC, Hager GL (2009) Glucocorticoid receptor dynamics and gene regulation. Stress 12(3):193–205

    Article  CAS  PubMed  Google Scholar 

  32. Biddie SC, John S, Hager GL (2010) Genome-wide mechanisms of nuclear receptor action. Trends Endocrinol Metab 2(1):3–9

    Article  Google Scholar 

  33. Gupta D, Peshavaria M, Monga N, Jetton TL, Leahy JL (2010) Physiologic and pharmacologic modulation of glucose-dependent insulinotropicpolypeptide (GIP)receptor expression in beta-cells by peroxisome proliferator-activated receptor (PPAR)-gamma signaling:possible mechanism for the GIP resistance in type 2 diabetes. Diabetes 59(6):1445–1450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was funded by grants from the National Natural Science Foundation of China (No. 81170777).

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Authors and Affiliations

  1. Department of Diabetes, The Second Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China

    Yan Yang, Jiangong Ren & Xuejian Hu

  2. Department of Endocrinology, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China

    Yan Yang, Yuzhen Tong, Qingguo Lv & Nanwei Tong

Authors
  1. Yan Yang
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  2. Jiangong Ren
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  3. Yuzhen Tong
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  4. Xuejian Hu
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  6. Nanwei Tong
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Correspondence to Nanwei Tong.

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Yang, Y., Ren, J., Tong, Y. et al. Protective Role of PPARdelta in Lipoapoptosis of Pancreatic β Cells. Lipids 51, 1259–1268 (2016). https://doi.org/10.1007/s11745-016-4190-5

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  • DOI: https://doi.org/10.1007/s11745-016-4190-5

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