Monounsaturated fatty acids protect against palmitate-induced lipoapoptosis in human umbilical vein endothelial cells


Autoři: Dustin M. Lee aff001;  Kyle J. Sevits aff001;  Micah L. Battson aff001;  Yuren Wei aff001;  Kimberly A. Cox-York aff001;  Christopher L. Gentile aff001
Působiště autorů: Department of Food Science & Human Nutrition, Colorado State University, Fort Collins, CO, United States of America aff001
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0226940

Souhrn

Diets high in saturated fatty acids are linked to increased cardiovascular disease risk, whereas monounsaturated fatty acids have been associated with improved cardiovascular outcomes. Accordingly, cell culture studies have demonstrated that saturated fatty acids, particularly long chain saturated fatty acids such as palmitate, induce dysfunction and cell death in a variety of cell types, and monounsaturated fatty acids may confer protection against palmitate-mediated damage. The aim of the present study was to examine whether monounsaturated fatty acids could protect against palmitate-mediated cell death in endothelial cells, to determine if AMPK inactivation and activation (via compound C and AICAR, respectively) underlies both palmitate-induced damage and monounsaturated fatty acid-mediated protection, and to explore the role of ER stress in this context. Human umbilical vein endothelial cells were examined for cell viability and apoptosis following treatment for 24 hours with palmitate (0.25 and 0.5mM) alone or in combination with the monounsaturated fatty acids oleate or palmitoleate (0.25 and 0.5mM), AICAR, compound C, 4μ8C, or TUDCA. Compared to control cells, palmitate significantly decreased cell viability and increased apoptosis in a dose-dependent manner. The monounsaturated fatty acids oleate and palmitoleate completely prevented the cytotoxic effects of palmitate. Although palmitate induced markers of ER stress, chemical inhibition of ER stress did not prevent palmitate-induced lipoapoptosis. Conversely, the AMPK activator AICAR (0.1 and 0.5mM) conferred protection from palmitate mediated-alterations in viability, apoptosis and ER stress, whereas the AMPK inhibitor compound C (20 and 40μM) significantly exacerbated palmitate-mediated damage. Lastly, co-incubation with palmitate, monounsaturated fatty acids, and compound C significantly mitigated the protective effects of both oleate and palmitoleate. In conclusion, monounsaturated fatty acids confer protection against the cytotoxic effects of palmitate in vascular endothelial cells; and palmitate-mediated damage, as well as monounsaturated-mediated protection, are due in part to inactivation and activation, respectively, of the metabolic regulator AMPK. These results may have implications for understanding the deleterious effects of high saturated fat diets on cardiovascular dysfunction and disease risk.

Klíčová slova:

Apoptosis – Cell cultures – Cell death – Endoplasmic reticulum – Endothelial cells – Fatty acids – Metabolic disorders – Oleates


Zdroje

1. Perticone F, Ceravolo R, Pujia A, Ventura G, Iacopino S, Scozzafava A, et al. Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation. 2001;104(2):191–6. doi: 10.1161/01.cir.104.2.191 11447085.

2. Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation. 2001;104(22):2673–8. doi: 10.1161/hc4601.099485 11723017.

3. Winn RK, Harlan JM. The role of endothelial cell apoptosis in inflammatory and immune diseases. J Thromb Haemost. 2005;3(8):1815–24. Epub 2005/08/17. doi: 10.1111/j.1538-7836.2005.01378.x 16102048.

4. Tricot O, Mallat Z, Heymes C, Belmin J, Leseche G, Tedgui A. Relation between endothelial cell apoptosis and blood flow direction in human atherosclerotic plaques. Circulation. 2000;101(21):2450–3. Epub 2000/06/01. doi: 10.1161/01.cir.101.21.2450 10831515.

5. Mathew M, Tay E, Cusi K. Elevated plasma free fatty acids increase cardiovascular risk by inducing plasma biomarkers of endothelial activation, myeloperoxidase and PAI-1 in healthy subjects. Cardiovascular Diabetology. 2010;9. Artn 9 10.1186/1475-2840-9-9. WOS:000275684700001.

6. Kim JY, Park JY, Kim OY, Ham BM, Kim HJ, Kwon DY, et al. Metabolic profiling of plasma in overweight/obese and lean men using ultra performance liquid chromatography and Q-TOF mass spectrometry (UPLC-Q-TOF MS). J Proteome Res. 2010;9(9):4368–75. Epub 2010/06/22. doi: 10.1021/pr100101p 20560578.

7. Steinberg HO, Tarshoby M, Monestel R, Hook G, Cronin J, Johnson A, et al. Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest. 1997;100(5):1230–9. doi: 10.1172/JCI119636 9276741.

8. Pilz S, Scharnagl H, Tiran B, Seelhorst U, Wellnitz B, Boehm BO, et al. Free fatty acids are independently associated with all-cause and cardiovascular mortality in subjects with coronary artery disease. J Clin Endocrinol Metab. 2006;91(7):2542–7. Epub 2006/04/06. doi: 10.1210/jc.2006-0195 16595593.

9. Unger RH, Orci L. Lipoapoptosis: its mechanism and its diseases. Biochim Biophys Acta. 2002;1585(2–3):202–12. doi: 10.1016/s1388-1981(02)00342-6 12531555.

10. Szmitko PE, Wang CH, Weisel RD, de Almeida JR, Anderson TJ, Verma S. New markers of inflammation and endothelial cell activation: Part I. Circulation. 2003;108(16):1917–23. Epub 2003/10/22. doi: 10.1161/01.CIR.0000089190.95415.9F 14568885.

11. Ozcan L, Tabas I. Role of endoplasmic reticulum stress in metabolic disease and other disorders. Annu Rev Med. 2012;63:317–28. Epub 2012/01/18. doi: 10.1146/annurev-med-043010-144749 22248326; PubMed Central PMCID: PMC3290993.

12. Battson ML, Lee DM, Gentile CL. Endoplasmic reticulum stress and the development of endothelial dysfunction. Am J Physiol Heart Circ Physiol. 2017;312(3):H355–H67. doi: 10.1152/ajpheart.00437.2016 27923788.

13. Tummala PE, Chen XL, Sundell CL, Laursen JB, Hammes CP, Alexander RW, et al. Angiotensin II induces vascular cell adhesion molecule-1 expression in rat vasculature: A potential link between the renin-angiotensin system and atherosclerosis. Circulation. 1999;100(11):1223–9. Epub 1999/09/14. doi: 10.1161/01.cir.100.11.1223 10484544.

14. Engin F, Hotamisligil GS. Restoring endoplasmic reticulum function by chemical chaperones: an emerging therapeutic approach for metabolic diseases. Diabetes Obes Metab. 2010;12 Suppl 2:108–15. doi: 10.1111/j.1463-1326.2010.01282.x 21029307.

15. Battson ML, Lee DM, Jarrell DK, Hou S, Ecton KE, Phan AB, et al. Tauroursodeoxycholic Acid Reduces Arterial Stiffness and Improves Endothelial Dysfunction in Type 2 Diabetic Mice. J Vasc Res. 2017;54(5):280–7. doi: 10.1159/000479967 28930750.

16. Farvid MS, Ding M, Pan A, Sun Q, Chiuve SE, Steffen LM, et al. Dietary linoleic acid and risk of coronary heart disease: a systematic review and meta-analysis of prospective cohort studies. Circulation. 2014;130(18):1568–78. Epub 2014/08/28. doi: 10.1161/CIRCULATIONAHA.114.010236 25161045; PubMed Central PMCID: PMC4334131.

17. Mayneris-Perxachs J, Guerendiain M, Castellote AI, Estruch R, Covas MI, Fito M, et al. Plasma fatty acid composition, estimated desaturase activities, and their relation with the metabolic syndrome in a population at high risk of cardiovascular disease. Clin Nutr. 2014;33(1):90–7. Epub 2013/04/18. doi: 10.1016/j.clnu.2013.03.001 23591154.

18. Kim JE, Kim YW, Lee IK, Kim JY, Kang YJ, Park SY. AMP-activated protein kinase activation by 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) inhibits palmitate-induced endothelial cell apoptosis through reactive oxygen species suppression. J Pharmacol Sci. 2008;106(3):394–403. Epub 2008/03/25. doi: 10.1254/jphs.fp0071857 18360094.

19. Wei Y, Wang D, Gentile CL, Pagliassotti MJ. Reduced endoplasmic reticulum luminal calcium links saturated fatty acid-mediated endoplasmic reticulum stress and cell death in liver cells. Mol Cell Biochem. 2009;331(1–2):31–40. doi: 10.1007/s11010-009-0142-1 19444596.

20. Wang D, Wei Y, Frye M, Gentile CL, Pagliassotti MJ. Saturated Fatty Acid-induced cytotoxicity in liver cells does not involve phosphatase and tensin homologue deleted on chromosome 10. J Nutr Metab. 2013;2013:514206. Epub 2013/05/22. doi: 10.1155/2013/514206 23691291; PubMed Central PMCID: PMC3649318.

21. Maedler K, Oberholzer J, Bucher P, Spinas GA, Donath MY. Monounsaturated fatty acids prevent the deleterious effects of palmitate and high glucose on human pancreatic beta-cell turnover and function. Diabetes. 2003;52(3):726–33. Epub 2003/02/28. doi: 10.2337/diabetes.52.3.726 12606514.

22. Li Y, Yang J, Chen MH, Wang Q, Qin MJ, Zhang T, et al. Ilexgenin A inhibits endoplasmic reticulum stress and ameliorates endothelial dysfunction via suppression of TXNIP/NLRP3 inflammasome activation in an AMPK dependent manner. Pharmacol Res. 2015;99:101–15. doi: 10.1016/j.phrs.2015.05.012 26054569.

23. Harvey KA, Walker CL, Xu Z, Whitley P, Pavlina TM, Hise M, et al. Oleic acid inhibits stearic acid-induced inhibition of cell growth and pro-inflammatory responses in human aortic endothelial cells. J Lipid Res. 2010;51(12):3470–80. Epub 2010/09/21. doi: 10.1194/jlr.M010371 20852092; PubMed Central PMCID: PMC2975719.

24. Herzig S, Shaw RJ. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol. 2018;19(2):121–35. doi: 10.1038/nrm.2017.95 28974774; PubMed Central PMCID: PMC5780224.

25. Yang WM, Lee W. CTRP5 ameliorates palmitate-induced apoptosis and insulin resistance through activation of AMPK and fatty acid oxidation. Biochem Biophys Res Commun. 2014;452(3):715–21. doi: 10.1016/j.bbrc.2014.08.145 25195818.

26. Sun Y, Ren M, Gao GQ, Gong B, Xin W, Guo H, et al. Chronic palmitate exposure inhibits AMPKalpha and decreases glucose-stimulated insulin secretion from beta-cells: modulation by fenofibrate. Acta Pharmacol Sin. 2008;29(4):443–50. doi: 10.1111/j.1745-7254.2008.00717.x 18358090.

27. Liu TY, Xiong XQ, Ren XS, Zhao MX, Shi CX, Wang JJ, et al. FNDC5 Alleviates Hepatosteatosis by Restoring AMPK/mTOR-Mediated Autophagy, Fatty Acid Oxidation, and Lipogenesis in Mice. Diabetes. 2016;65(11):3262–75. doi: 10.2337/db16-0356 27504012.

28. Kim J, Yang G, Kim Y, Kim J, Ha J. AMPK activators: mechanisms of action and physiological activities. Exp Mol Med. 2016;48:e224. Epub 2016/04/02. doi: 10.1038/emm.2016.16 27034026; PubMed Central PMCID: PMC4855276.

29. Kabagambe EK, Baylin A, Siles X, Campos H. Individual saturated fatty acids and nonfatal acute myocardial infarction in Costa Rica. Eur J Clin Nutr. 2003;57(11):1447–57. Epub 2003/10/25. doi: 10.1038/sj.ejcn.1601709 14576758.

30. Praagman J, de Jonge EA, Kiefte-de Jong JC, Beulens JW, Sluijs I, Schoufour JD, et al. Dietary Saturated Fatty Acids and Coronary Heart Disease Risk in a Dutch Middle-Aged and Elderly Population. Arterioscler Thromb Vasc Biol. 2016;36(9):2011–8. Epub 2016/07/16. doi: 10.1161/ATVBAHA.116.307578 27417581.

31. Sarabi M, Vessby B, Millgard J, Lind L. Endothelium-dependent vasodilation is related to the fatty acid composition of serum lipids in healthy subjects. Atherosclerosis. 2001;156(2):349–55. doi: 10.1016/s0021-9150(00)00658-4 11395031.

32. Bharath LP, Ruan T, Li Y, Ravindran A, Wan X, Nhan JK, et al. Ceramide-Initiated Protein Phosphatase 2A Activation Contributes to Arterial Dysfunction In Vivo. Diabetes. 2015;64(11):3914–26. Epub 2015/08/09. doi: 10.2337/db15-0244 26253611; PubMed Central PMCID: PMC4613970.

33. Akazawa Y, Cazanave S, Mott JL, Elmi N, Bronk SF, Kohno S, et al. Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis. J Hepatol. 2010;52(4):586–93. Epub 2010/03/09. S0168-8278(10)00011-5 [pii] doi: 10.1016/j.jhep.2010.01.003 20206402; PubMed Central PMCID: PMC2847010.

34. Jung IR, Choi SE, Hong SA, Hwang Y, Kang Y. Sodium fluorocitrate having protective effect on palmitate-induced beta cell death improves hyperglycemia in diabetic db/db mice. Sci Rep. 2017;7(1):12916. Epub 2017/10/12. doi: 10.1038/s41598-017-13365-5 29018279; PubMed Central PMCID: PMC5635019.

35. Lee CH, Lee SD, Ou HC, Lai SC, Cheng YJ. Eicosapentaenoic acid protects against palmitic acid-induced endothelial dysfunction via activation of the AMPK/eNOS pathway. Int J Mol Sci. 2014;15(6):10334–49. Epub 2014/06/12. doi: 10.3390/ijms150610334 24918290; PubMed Central PMCID: PMC4100154.

36. Mozaffarian D, Micha R, Wallace S. Effects on coronary heart disease of increasing polyunsaturated fat in place of saturated fat: a systematic review and meta-analysis of randomized controlled trials. PLoS Med. 2010;7(3):e1000252. Epub 2010/03/31. doi: 10.1371/journal.pmed.1000252 20351774; PubMed Central PMCID: PMC2843598.

37. Martinez-Gonzalez MA, Gea A, Ruiz-Canela M. The Mediterranean Diet and Cardiovascular Health. Circ Res. 2019;124(5):779–98. Epub 2019/03/01. doi: 10.1161/CIRCRESAHA.118.313348 30817261.

38. Schwingshackl L, Hoffmann G. Monounsaturated fatty acids, olive oil and health status: a systematic review and meta-analysis of cohort studies. Lipids Health Dis. 2014;13:154. Epub 2014/10/03. doi: 10.1186/1476-511X-13-154 25274026; PubMed Central PMCID: PMC4198773.

39. Artwohl M, Lindenmair A, Sexl V, Maier C, Rainer G, Freudenthaler A, et al. Different mechanisms of saturated versus polyunsaturated FFA-induced apoptosis in human endothelial cells. J Lipid Res. 2008;49(12):2627–40. Epub 2008/08/07. doi: 10.1194/jlr.M800393-JLR200 18682607.

40. Staiger K, Staiger H, Weigert C, Haas C, Haring HU, Kellerer M. Saturated, but not unsaturated, fatty acids induce apoptosis of human coronary artery endothelial cells via nuclear factor-kappaB activation. Diabetes. 2006;55(11):3121–6. doi: 10.2337/db06-0188 17065351.

41. Sargsyan E, Artemenko K, Manukyan L, Bergquist J, Bergsten P. Oleate protects beta-cells from the toxic effect of palmitate by activating pro-survival pathways of the ER stress response. Biochim Biophys Acta. 2016;1861(9 Pt A):1151–60. Epub 2016/06/28. doi: 10.1016/j.bbalip.2016.06.012 27344025.

42. Paillard F, Catheline D, Duff FL, Bouriel M, Deugnier Y, Pouchard M, et al. Plasma palmitoleic acid, a product of stearoyl-coA desaturase activity, is an independent marker of triglyceridemia and abdominal adiposity. Nutr Metab Cardiovasc Dis. 2008;18(6):436–40. Epub 2007/12/11. doi: 10.1016/j.numecd.2007.02.017 18068341.

43. Puri P, Wiest MM, Cheung O, Mirshahi F, Sargeant C, Min HK, et al. The plasma lipidomic signature of nonalcoholic steatohepatitis. Hepatology. 2009;50(6):1827–38. Epub 2009/11/26. doi: 10.1002/hep.23229 19937697; PubMed Central PMCID: PMC5031239.

44. Frigolet ME, Gutierrez-Aguilar R. The Role of the Novel Lipokine Palmitoleic Acid in Health and Disease. Adv Nutr. 2017;8(1):173S–81S. Epub 2017/01/18. doi: 10.3945/an.115.011130 28096141; PubMed Central PMCID: PMC5227969.

45. Bernstein AM, Roizen MF, Martinez L. Purified palmitoleic acid for the reduction of high-sensitivity C-reactive protein and serum lipids: a double-blinded, randomized, placebo controlled study. J Clin Lipidol. 2014;8(6):612–7. Epub 2014/12/17. doi: 10.1016/j.jacl.2014.08.001 25499944.

46. Cimen I, Kocaturk B, Koyuncu S, Tufanli O, Onat UI, Yildirim AD, et al. Prevention of atherosclerosis by bioactive palmitoleate through suppression of organelle stress and inflammasome activation. Sci Transl Med. 2016;8(358):358ra126. Epub 2016/09/30. doi: 10.1126/scitranslmed.aaf9087 27683551.

47. Gustavo Vazquez-Jimenez J, Chavez-Reyes J, Romero-Garcia T, Zarain-Herzberg A, Valdes-Flores J, Manuel Galindo-Rosales J, et al. Palmitic acid but not palmitoleic acid induces insulin resistance in a human endothelial cell line by decreasing SERCA pump expression. Cell Signal. 2016;28(1):53–9. Epub 2015/10/18. doi: 10.1016/j.cellsig.2015.10.001 26475209.

48. Li J, Wang Y, Wang Y, Wen X, Ma XN, Chen W, et al. Pharmacological activation of AMPK prevents Drp1-mediated mitochondrial fission and alleviates endoplasmic reticulum stress-associated endothelial dysfunction. J Mol Cell Cardiol. 2015;86:62–74. doi: 10.1016/j.yjmcc.2015.07.010 26196303.

49. Ye J, Ji Q, Liu J, Liu L, Huang Y, Shi Y, et al. Interleukin 22 Promotes Blood Pressure Elevation and Endothelial Dysfunction in Angiotensin II-Treated Mice. J Am Heart Assoc. 2017;6(10). Epub 2017/10/05. doi: 10.1161/JAHA.117.005875 28974499; PubMed Central PMCID: PMC5721831.

50. Bairwa SC, Parajuli N, Dyck JR. The role of AMPK in cardiomyocyte health and survival. Biochim Biophys Acta. 2016;1862(12):2199–210. Epub 2016/07/16. doi: 10.1016/j.bbadis.2016.07.001 27412473.

51. Wu Y, Song P, Xu J, Zhang M, Zou MH. Activation of protein phosphatase 2A by palmitate inhibits AMP-activated protein kinase. J Biol Chem. 2007;282(13):9777–88. Epub 2007/01/27. doi: 10.1074/jbc.M608310200 17255104.


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