Differential effects of saturated and unsaturated fatty acids on autophagy in pancreatic β-cells

in Journal of Molecular Endocrinology
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  • 1 Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, UK
  • 2 The Medical School, Newcastle University, Newcastle Upon Tyne, UK
  • 3 Living Systems Institute, University of Exeter, Exeter, UK

Correspondence should be addressed to S Dhayal or N G Morgan: s.dhayal2@exeter.ac.uk or n.g.morgan@exeter.ac.uk
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Long-chain saturated fatty acids are lipotoxic to pancreatic β-cells, whereas most unsaturates are better tolerated and some may even be cytoprotective. Fatty acids alter autophagy in β-cells and there is increasing evidence that such alterations can impact directly on the regulation of viability. Accordingly, we have compared the effects of palmitate (C16:0) and palmitoleate (C16:1) on autophagy in cultured β-cells and human islets. Treatment of BRIN-BD11 β-cells with palmitate led to enhanced autophagic activity, as judged by cleavage of microtubule-associated protein 1 light chain 3-I (LC3-I) and this correlated with a marked loss of cell viability in the cells. In addition, transfection of these cells with an mCherry-YFP-LC3 reporter construct revealed the accumulation of autophagosomes in palmitate-treated cells, indicating an impairment of autophagosome-lysosome fusion. This was also seen upon addition of the vacuolar ATPase inhibitor, bafilomycin A1. Exposure of BRIN-BD11 cells to palmitoleate (C16:1) did not lead directly to changes in autophagic activity or flux, but it antagonised the actions of palmitate. In parallel, palmitoleate also improved the viability of palmitate-treated BRIN-BD11 cells. Equivalent responses were observed in INS-1E cells and in isolated human islets. Taken together, these data suggest that palmitate may cause an impairment of autophagosome-lysosome fusion. These effects were not reproduced by palmitoleate which, instead, antagonised the responses mediated by palmitate suggesting that attenuation of β-cell stress may contribute to the improvement in cell viability caused by the mono-unsaturated fatty acid.

 

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  • Abdulkarim B, Hernangomez M, Igoillo-Esteve M, Cunha DA, Marselli L, Marchetti P, Ladriere L & Cnop M 2017 Guanabenz sensitizes pancreatic beta cells to lipotoxic endoplasmic reticulum stress and apoptosis. Endocrinology 16591670. (https://doi.org/10.1210/en.2016-1773)

    • Search Google Scholar
    • Export Citation
  • Assali EA, Shlomo D, Zeng J, Taddeo EP, Trudeau KM, Erion KA, Colby AH, Grinstaff MW, Liesa M, Las G, et al. 2019 Nanoparticle-mediated lysosomal reacidification restores mitochondrial turnover and function in beta cells under lipotoxicity. FASEB Journal 41544165. (https://doi.org/10.1096/fj.201801292R)

    • Search Google Scholar
    • Export Citation
  • Bachar E, Ariav Y, Ketzinel-Gilad M, Cerasi E, Kaiser N & Leibowitz G 2009 Glucose amplifies fatty acid-induced endoplasmic reticulum stress in pancreatic beta-cells via activation of mTORC1. PLoS ONE e4954. (https://doi.org/10.1371/journal.pone.0004954)

    • Search Google Scholar
    • Export Citation
  • Bellini L, Campana M, Rouch C, Chacinska M, Bugliani M, Meneyrol K, Hainault I, Lenoir V, Denom J, Veret J, et al. 2018 Protective role of the ELOVL2/docosahexaenoic acid axis in glucolipotoxicity-induced apoptosis in rodent beta cells and human islets. Diabetologia 17801793. (https://doi.org/10.1007/s00125-018-4629-8)

    • Search Google Scholar
    • Export Citation
  • Bugliani M, Mossuto S, Grano F, Suleiman M, Marselli L, Boggi U, De Simone P,, Eizirik DL, Cnop M, Marchetti P, et al. 2019 Modulation of autophagy influences the function and survival of human pancreatic beta cells under endoplasmic reticulum stress conditions and in type 2 diabetes. Frontiers in Endocrinology 52. (https://doi.org/10.3389/fendo.2019.00052)

    • Search Google Scholar
    • Export Citation
  • Chen YY, Sun LQ, Wang BA, Zou XM, Mu YM & Lu JM 2013 Palmitate induces autophagy in pancreatic beta-cells via endoplasmic reticulum stress and its downstream JNK pathway. International Journal of Molecular Medicine 14011406. (https://doi.org/10.3892/ijmm.2013.1530)

    • Search Google Scholar
    • Export Citation
  • Chen E, Tsai TH, Li L, Saha P, Chan L & Chang BH 2017 PLIN2 is a key regulator of the unfolded protein response and endoplasmic reticulum stress resolution in pancreatic beta cells. Scientific Reports 40855. (https://doi.org/10.1038/srep40855)

    • Search Google Scholar
    • Export Citation
  • Choi SE, Lee SM, Lee YJ, Li LJ, Lee SJ, Lee JH, Kim Y, Jun HS, Lee KW & Kang Y 2009 Protective role of autophagy in palmitate-induced INS-1 beta-cell death. Endocrinology 126134. (https://doi.org/10.1210/en.2008-0483)

    • Search Google Scholar
    • Export Citation
  • Ciregia F, Bugliani M, Ronci M, Giusti L, Boldrini C, Mazzoni MR, Mossuto S, Grano F, Cnop M, Marselli L, et al. 2017 Palmitate-induced lipotoxicity alters 410 acetylation of multiple proteins in clonal beta cells and human pancreatic islets. Scientific Reports 13445. (https://doi.org/10.1038/s41598-017-13908-w)

    • Search Google Scholar
    • Export Citation
  • Demirtas L, Guclu A, Erdur FM, Akbas EM, Ozcicek A, Onk D & Turkmen K 2016 Apoptosis, autophagy and endoplasmic reticulum stress in diabetes mellitus. Indian Journal of Medical Research 515524. (https://doi.org/10.4103/0971-5916.200887)

    • Search Google Scholar
    • Export Citation
  • Dhayal S & Morgan NG 2011 Structure-activity relationships influencing lipid-induced changes in eIF2alpha phosphorylation and cell viability in BRIN-BD11 cells. FEBS Letters 22432248. (https://doi.org/10.1016/j.febslet.2011.05.045)

    • Search Google Scholar
    • Export Citation
  • Dhayal S, Welters HJ & Morgan NG 2008 Structural requirements for the cytoprotective actions of mono-unsaturated fatty acids in the pancreatic beta-cell line, BRIN-BD11. British Journal of Pharmacology 17181727. (https://doi.org/10.1038/bjp.2008.43)

    • Search Google Scholar
    • Export Citation
  • Diakogiannaki E, Dhayal S, Childs CE, Calder PC, Welters HJ & Morgan NG 2007 Mechanisms involved in the cytotoxic and cytoprotective actions of saturated versus monounsaturated long-chain fatty acids in pancreatic {beta}-cells. Journal of Endocrinology 283291. (https://doi.org/10.1677/JOE-07-0082)

    • Search Google Scholar
    • Export Citation
  • Diakogiannaki E, Welters HJ & Morgan NG 2008 Differential regulation of the endoplasmic reticulum stress response in pancreatic beta-cells exposed to long-chain saturated and monounsaturated fatty acids. Journal of Endocrinology 553563. (https://doi.org/10.1677/JOE-08-0041)

    • Search Google Scholar
    • Export Citation
  • Eskelinen EL 2019 Autophagy: supporting cellular and organismal homeostasis by self-eating. International Journal of Biochemistry and Cell Biology 110. (https://doi.org/10.1016/j.biocel.2019.03.010)

    • Search Google Scholar
    • Export Citation
  • Green CD & Olson LK 2011 Modulation of palmitate-induced endoplasmic reticulum stress and apoptosis in pancreatic beta-cells by stearoyl-CoA desaturase and Elovl6. American Journal of Physiology: Endocrinology and Metabolism E640E649. (https://doi.org/10.1152/ajpendo.00544.2010)

    • Search Google Scholar
    • Export Citation
  • Hong YJ, Ahn HJ, Shin J, Lee JH, Kim JH, Park HW & Lee SK 2018 Unsaturated fatty acids protect trophoblast cells from saturated fatty acid-induced autophagy defects. Journal of Reproductive Immunology 5663. (https://doi.org/10.1016/j.jri.2017.12.001)

    • Search Google Scholar
    • Export Citation
  • Hu M, Yang S, Yang L, Cheng Y & Zhang H 2016 Interleukin-22 alleviated palmitate-induced endoplasmic reticulum stress in INS-1 cells through activation of autophagy. PLoS ONE e0146818. (https://doi.org/10.1371/journal.pone.0146818)

    • Search Google Scholar
    • Export Citation
  • Janikiewicz J, Hanzelka K, Kozinski K, Kolczynska K & Dobrzyn A 2015 Islet beta-cell failure in type 2 diabetes – within the network of toxic lipids. Biochemical and Biophysical Research Communications 491496. (https://doi.org/10.1016/j.bbrc.2015.03.153)

    • Search Google Scholar
    • Export Citation
  • Las G, Serada SB, Wikstrom JD, Twig G & Shirihai OS 2011 Fatty acids suppress autophagic turnover in beta-cells. Journal of Biological Chemistry 4253442544. (https://doi.org/10.1074/jbc.M111.242412)

    • Search Google Scholar
    • Export Citation
  • Liu Y, Wang N, Zhang S & Liang Q 2018 Autophagy protects bone marrow mesenchymal stem cells from palmitateinduced apoptosis through the ROSJNK/p38 MAPK signaling pathways. Molecular Medicine Reports 14851494. (https://doi.org/10.3892/mmr.2018.9100)

    • Search Google Scholar
    • Export Citation
  • Liu P, De La Vega MR, Dodson M, Yue F, Shi B, Fang D, Chapman E, Liu L & Zhang DD 2019a Spermidine confers liver protection by enhancing NRF2 signaling through a MAP1S-mediated non-canonical mechanism. Hepatology 372388. (https://doi.org/10.1002/hep.30616)

    • Search Google Scholar
    • Export Citation
  • Liu X, Zeng X, Chen X, Luo R, Li L, Wang C, Liu J, Cheng J, Lu Y & Chen Y 2019b Oleic acid protects insulin-secreting INS-1E cells against palmitic acid-induced lipotoxicity along with an amelioration of ER stress. Endocrine 512524. (https://doi.org/10.1007/s12020-019-01867-3)

    • Search Google Scholar
    • Export Citation
  • Martino L, Masini M, Novelli M, Beffy P, Bugliani M, Marselli L, Masiello P, Marchetti P & De Tata V 2012 Palmitate activates autophagy in INS-1E beta-cells and in isolated rat and human pancreatic islets. PLoS ONE e36188. (https://doi.org/10.1371/journal.pone.0036188)

    • Search Google Scholar
    • Export Citation
  • McClenaghan NH, Barnett CR, Ah-Sing E, Abdel-Wahab YH, O’Harte FP, Yoon TW, Swanston-Flatt SK & Flatt PR 1996 Characterization of a Novel Glucose-Responsive Insulin-Secreting Cell Line, BRIN-BD11, Produced by Electrofusio. Diabetes 45 1132. (https://doi.org/10.2337/diab.45.8.1132)

    • Search Google Scholar
    • Export Citation
  • Mehmeti I, Lortz S, Avezov E, Jorns A & Lenzen S 2017 ER-resident antioxidative GPx7 and GPx8 enzyme isoforms protect insulin-secreting INS-1E beta-cells against lipotoxicity by improving the ER antioxidative capacity. Free Radical Biology and Medicine 121130. (https://doi.org/10.1016/j.freeradbiomed.2017.07.021)

    • Search Google Scholar
    • Export Citation
  • Merglen A, Theander S, Rubi B, Chaffard G, Wollheim CB & Maechler P 2004 Glucose Sensitivity and Metabolism-Secretion Coupling Studied during Two-Year Continuous Culture in INS-1E Insulinoma Cells. Endocrinology 145 667. (https://doi.org/10.1210/en.2003-1099)

    • Search Google Scholar
    • Export Citation
  • Morgan NG & Dhayal S 2009 G-protein coupled receptors mediating long chain fatty acid signalling in the pancreatic beta-cell. Biochemical Pharmacology 14191427. (https://doi.org/10.1016/j.bcp.2009.07.020)

    • Search Google Scholar
    • Export Citation
  • Morgan NG & Dhayal S 2010 Unsaturated fatty acids as cytoprotective agents in the pancreatic beta-cell. Prostaglandins, Leukotrienes, and Essential Fatty Acids 231236. (https://doi.org/10.1016/j.plefa.2010.02.018)

    • Search Google Scholar
    • Export Citation
  • Nemcova-Furstova V, James RF & Kovar J 2011 Inhibitory effect of unsaturated fatty acids on saturated fatty acid-induced apoptosis in human pancreatic beta-cells: activation of caspases and ER stress induction. Cellular Physiology and Biochemistry 525538. (https://doi.org/10.1159/000329954)

    • Search Google Scholar
    • Export Citation
  • Nemecz M, Constantin A, Dumitrescu M, Alexandru N, Filippi A, Tanko G & Georgescu A 2018 The distinct effects of palmitic and oleic acid on pancreatic beta cell function: the elucidation of associated mechanisms and effector molecules. Frontiers in Pharmacology 1554. (https://doi.org/10.3389/fphar.2018.01554)

    • Search Google Scholar
    • Export Citation
  • Rostamirad A, Ebrahimi SSS, Sadeghi A, Taghikhani M & Meshkani R 2018 Palmitate-induced impairment of autophagy turnover leads to increased apoptosis and inflammation in peripheral blood mononuclear cells. Immunobiology 269278. (https://doi.org/10.1016/j.imbio.2017.10.041)

    • Search Google Scholar
    • Export Citation
  • Ruan JS, Lin JK, Kuo YY, Chen YW & Chen PC 2018 Chronic palmitic acid-induced lipotoxicity correlates with defective trafficking of ATP sensitive potassium channels in pancreatic beta cells. Journal of Nutritional Biochemistry 3748. (https://doi.org/10.1016/j.jnutbio.2018.05.005)

    • Search Google Scholar
    • Export Citation
  • Sargsyan E, Artemenko K, Manukyan L, Bergquist J & Bergsten P 2016 Oleate protects beta-cells from the toxic effect of palmitate by activating pro-survival pathways of the ER stress response. Biochimica and Biophysica Acta 11511160. (https://doi.org/10.1016/j.bbalip.2016.06.012)

    • Search Google Scholar
    • Export Citation
  • Sharma RB & Alonso LC 2014 Lipotoxicity in the pancreatic beta cell: not just survival and function, but proliferation as well? Current Diabetes Reports 492. (https://doi.org/10.1007/s11892-014-0492-2)

    • Search Google Scholar
    • Export Citation
  • Sharma S, Mells JE, Fu PP, Saxena NK & Anania FA 2011 GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy. PLoS ONE e25269. (https://doi.org/10.1371/journal.pone.0025269)

    • Search Google Scholar
    • Export Citation
  • Sramek J, Nemcova-Furstova V, Pavlikova N & Kovar J 2017 Effect of saturated stearic acid on MAP kinase and ER stress signaling pathways during apoptosis induction in human pancreatic beta-cells is inhibited by unsaturated oleic acid. International Journal of Molecular Sciences E2313. (https://doi.org/10.3390/ijms18112313)

    • Search Google Scholar
    • Export Citation
  • Tirupathi Pichiah PB, Suriyakalaa U, Kamalakkannan S, Kokilavani P, Kalaiselvi S, Sankarganesh D, Gowri J, Archunan G, Cha YS & Achiraman S 2011 Spermidine may decrease ER stress in pancreatic beta cells and may reduce apoptosis via activating AMPK dependent autophagy pathway. Medical Hypotheses 677679. (https://doi.org/10.1016/j.mehy.2011.07.014)

    • Search Google Scholar
    • Export Citation
  • Trudeau KM, Colby AH, Zeng J, Las G, Feng JH, Grinstaff MW & Shirihai OS 2016 Lysosome acidification by photoactivated nanoparticles restores autophagy under lipotoxicity. Journal of Cell Biology 2534. (https://doi.org/10.1083/jcb.201511042)

    • Search Google Scholar
    • Export Citation
  • Varshney R, Gupta S & Roy P 2017 Cytoprotective effect of kaempferol against palmitic acid-induced pancreatic beta-cell death through modulation of autophagy via AMPK/mTOR signaling pathway. Molecular and Cellular Endocrinology 120. (https://doi.org/10.1016/j.mce.2017.02.033)

    • Search Google Scholar
    • Export Citation
  • Wang Y, Xie T, Zhang D & Leung PS 2019 GPR120 protects lipotoxicity-induced pancreatic beta-cell dysfunction through regulation of PDX1 expression and inhibition of islet inflammation. Clinical Science 101116. (https://doi.org/10.1042/CS20180836)

    • Search Google Scholar
    • Export Citation
  • Welters HJ, Tadayyon M, Scarpello JH, Smith SA & Morgan NG 2004 Mono-unsaturated fatty acids protect against beta-cell apoptosis induced by saturated fatty acids, serum withdrawal or cytokine exposure. FEBS Letters 103108. (https://doi.org/10.1016/S0014-5793(04)00079-1)

    • Search Google Scholar
    • Export Citation
  • Wu J, Wu Q, Li JJ, Chen C, Sun S, Wang CH & Sun SR 2017 Autophagy mediates free fatty acid effects on MDA-MB-231 cell proliferation, migration and invasion. Oncology Letters 47154721. (https://doi.org/10.3892/ol.2017.6807)

    • Search Google Scholar
    • Export Citation
  • Xu K, Liu XF, Ke ZQ, Yao Q, Guo S & Liu C 2018 Resveratrol modulates apoptosis and autophagy induced by high glucose and palmitate in cardiac cells. Cellular Physiology and Biochemistry 20312040. (https://doi.org/10.1159/000489442)

    • Search Google Scholar
    • Export Citation
  • Zummo FP, Cullen KS, Honkanen-Scott M, Shaw JAM, Lovat PE & Arden C 2017 Glucagon-like peptide 1 protects pancreatic beta-cells from death by increasing autophagic flux and restoring lysosomal function. Diabetes 12721285. (https://doi.org/10.2337/db16-1009)

    • Search Google Scholar
    • Export Citation