The role of ER stress in lipid metabolism and lipotoxicity

Journal of Lipid Research

Volumn 57, Issue 8, 2016, Pages 1329-1338

  Han, Jaeseok ^a   Kaufman, Randal J ^b  

^a Soonchunhyang University   (South Korea)

^b BURNHAM INSTITUTE   (United States)

Author keywords

Cell Signaling; Diabetes; Endoplasmic Reticulum; Fatty Acid; Lipids

Indexed keywords

ACTIVATING TRANSCRIPTION FACTOR 4; FENOFIBRATE; GROWTH ARREST AND DNA DAMAGE INDUCIBLE PROTEIN 153; HIGH DENSITY LIPOPROTEIN; INITIATION FACTOR 2ALPHA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PLACEBO; PROTEIN KINASE R; RAPAMYCIN; REACTIVE OXYGEN METABOLITE; STEROL REGULATORY ELEMENT BINDING PROTEIN; TAUROURSODEOXYCHOLIC ACID; TRIACYLGLYCEROL;

APOPTOSIS; AUTOPHAGY; ENDOPLASMIC RETICULUM ASSOCIATED DEGRADATION; ENDOPLASMIC RETICULUM STRESS; FATTY ACID OXIDATION; FATTY LIVER; HEART MUSCLE ISCHEMIA; HUMAN; INSULIN DEPENDENT DIABETES MELLITUS; INSULIN RESISTANCE; LIPID HOMEOSTASIS; LIPID METABOLISM; LIPID STORAGE; LIPOGENESIS; LIPOTOXICITY; METABOLIC BALANCE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OXIDATIVE STRESS; PANCREAS ISLET BETA CELL; PRIORITY JOURNAL; PROTEIN FOLDING; REVIEW; UNFOLDED PROTEIN RESPONSE; ANIMAL; CARDIAC MUSCLE; ENDOPLASMIC RETICULUM; LIVER; METABOLISM; PATHOLOGY; SKELETAL MUSCLE;

ANIMALS; APOPTOSIS; ENDOPLASMIC RETICULUM; ENDOPLASMIC RETICULUM STRESS; HUMANS; LIPID METABOLISM; LIVER; MUSCLE, SKELETAL; MYOCARDIUM; UNFOLDED PROTEIN RESPONSE;

EID: 84982058671     PISSN: 00222275     EISSN: 15397262     Source Type: Journal    
DOI: 10.1194/jlr.R067595     Document Type: Review

References (129)

1. Clapham, D. E. 2007. Calcium signaling. Cell. 131: 1047-1058.
2. Moore, L., T. Chen, H. R. Knapp, Jr., and E. J. Landon. 1975. Energy-dependent calcium sequestration activity in rat liver microsomes. J. Biol. Chem. 250: 4562-4568.
3. Michalak, M., J. M. Robert Parker, and M. Opas. 2002. Ca2+ signaling and calcium binding chaperones of the endoplasmic reticulum. Cell Calcium. 32: 269-278.
4. Schröder, M., and R. J. Kaufman. 2005. The mammalian unfolded protein response. Annu. Rev. Biochem. 74: 739-789.
5. Wang, M., and R. J. Kaufman. 2016. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature. 529: 326-335.
6. Schuck, S., W. A. Prinz, K. S. Thorn, C. Voss, and P. Walter. 2009. Membrane expansion alleviates endoplasmic reticulum stress independently of the unfolded protein response. J. Cell Biol. 187: 525-536.
7. Fagone, P., and S. Jackowski. 2009. Membrane phospholipid synthesis and endoplasmic reticulum function. J. Lipid Res. 50(Suppl): S311-S316.
8. Unger, R. H., and P. E. Scherer. 2010. Gluttony, sloth and the metabolic syndrome: A roadmap to lipotoxicity. Trends Endocrinol. Metab. 21: 345-352.
9. Wang, S., and R. J. Kaufman. 2014. How does protein misfolding in the endoplasmic reticulum affect lipid metabolism in the liver? Curr. Opin. Lipidol. 25: 125-132.
10. Rutkowski, D. T., and R. J. Kaufman. 2004. A trip to the ER: coping with stress. Trends Cell Biol. 14: 20-28.
11. Shen, J., X. Chen, L. Hendershot, and R. Prywes. 2002. ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev. Cell. 3: 99-111.
12. Bertolotti, A., Y. Zhang, L. M. Hendershot, H. P. Harding, and D. Ron. 2000. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat. Cell Biol. 2: 326-332.
13. Ma, K., K. M. Vattem, and R. C. Wek. 2002. Dimerization and release of molecular chaperone inhibition facilitate activation of eukaryotic initiation factor-2 kinase in response to endoplasmic reticulum stress. J. Biol. Chem. 277: 18728-18735.
14. Harding, H. P., Y. Zhang, and D. Ron. 1999. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature. 397: 271-274.
15. Scheuner, D., B. Song, E. McEwen, C. Liu, R. Laybutt, P. Gillespie, T. Saunders, S. Bonner-Weir, and R. J. Kaufman. 2001. Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol. Cell. 7: 1165-1176.
16. Harding, H. P., I. Novoa, Y. Zhang, H. Zeng, R. Wek, M. Schapira, and D. Ron. 2000. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol. Cell. 6: 1099-1108.
17. Novoa, I., H. Zeng, H. P. Harding, and D. Ron. 2001. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J. Cell Biol. 153: 1011-1022.
18. Silva, R. M., V. Ries, T. F. Oo, O. Yarygina, V. Jackson-Lewis, E. J. Ryu, P. D. Lu, S. J. Marciniak, D. Ron, S. Przedborski, et al. 2005. CHOP/GADD153 is a mediator of apoptotic death in substantia nigra dopamine neurons in an in vivo neurotoxin model of parkinsonism. J. Neurochem. 95: 974-986.
19. Yamaguchi, H., and H. G. Wang. 2004. CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J. Biol. Chem. 279: 45495-45502.
20. Oyadomari, S., and M. Mori. 2004. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 11: 381-389.
21. Yoshida, H., T. Matsui, A. Yamamoto, T. Okada, and K. Mori. 2001. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 107: 881-891.
22. Casagrande, R., P. Stern, M. Diehn, C. Shamu, M. Osario, M. Zuniga, P. O. Brown, and H. Ploegh. 2000. Degradation of proteins from the ER of S. cerevisiae requires an intact unfolded protein response pathway. Mol. Cell. 5: 729-735.
23. Lee, A. H., N. N. Iwakoshi, and L. H. Glimcher. 2003. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol. Cell. Biol. 23: 7448-7459.
24. Acosta-Alvear, D., Y. Zhou, A. Blais, M. Tsikitis, N. H. Lents, C. Arias, C. J. Lennon, Y. Kluger, and B. D. Dynlacht. 2007. XBP1 controls diverse cell type-And condition-specific transcriptional regulatory networks. Mol. Cell. 27: 53-66.
25. Hassler, J. R., D. L. Scheuner, S. Wang, J. Han, V. K. Kodali, P. Li, J. Nguyen, J. S. George, C. Davis, S. P. Wu, et al. 2015. The IRE1alpha/XBP1s pathway is essential for the glucose response and protection of cells. PLoS Biol. 13: e1002277.
26. Haze, K., H. Yoshida, H. Yanagi, T. Yura, and K. Mori. 1999. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol. Biol. Cell. 10: 3787-3799.
27. Wu, J., D. T. Rutkowski, M. Dubois, J. Swathirajan, T. Saunders, J. Wang, B. Song, G. D. Yau, and R. J. Kaufman. 2007. ATF6alpha optimizes long-Term endoplasmic reticulum function to protect cells from chronic stress. Dev. Cell. 13: 351-364.
28. Kammoun, H. L., H. Chabanon, I. Hainault, S. Luquet, C. Magnan, T. Koike, P. Ferre, and F. Foufelle. 2009. GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice. J. Clin. Invest. 119: 1201-1215.
29. Song, B., D. Scheuner, D. Ron, S. Pennathur, and R. J. Kaufman. 2008. Chop deletion reduces oxidative stress, improves beta cell function, and promotes cell survival in multiple mouse models of diabetes. J. Clin. Invest. 118: 3378-3389.
30. Malhotra, J. D., H. Miao, K. Zhang, A. Wolfson, S. Pennathur, S. W. Pipe, and R. J. Kaufman. 2008. Antioxidants reduce endoplasmic reticulum stress and improve protein secretion. Proc. Natl. Acad. Sci. USA. 105: 18525-18530.
31. Han, J., B. Song, J. Kim, V. K. Kodali, A. Pottekat, M. Wang, J. Hassler, S. Wang, S. Pennathur, S. H. Back, et al. 2015. Antioxidants complement the requirement for protein chaperone function to maintain-cell function and glucose homeostasis. Diabetes. 64: 2892-2904.
32. Malhotra, J. D., and R. J. Kaufman. 2007. Endoplasmic reticulum stress and oxidative stress: A vicious cycle or a double-edged sword? Antioxid. Redox Signal. 9: 2277-2293.
33. Lauressergues, E., E. Bert, P. Duriez, D. Hum, Z. Majd, B. Staels, and D. Cussac. 2012. Does endoplasmic reticulum stress participate in APD-induced hepatic metabolic dysregulation? Neuropharmacology. 62: 784-796.
34. Oyadomari, S., H. P. Harding, Y. Zhang, M. Oyadomari, and D. Ron. 2008. Dephosphorylation of translation initiation factor 2alpha enhances glucose tolerance and attenuates hepatosteatosis in mice. Cell Metab. 7: 520-532.
35. Li, H., Q. Meng, F. Xiao, S. Chen, Y. Du, J. Yu, C. Wang, and F. Guo. 2011. ATF4 deficiency protects mice from high-carbohydrate-diet-induced liver steatosis. Biochem. J. 438: 283-289.
36. Xiao, G., T. Zhang, S. Yu, S. Lee, V. Calabuig-Navarro, J. Yamauchi, S. Ringquist, and H. H. Dong. 2013. ATF4 protein deficiency protects against high fructose-induced hypertriglyceridemia in mice. J. Biol. Chem. 288: 25350-25361.
37. Rutkowski, D. T., J. Wu, S. H. Back, M. U. Callaghan, S. P. Ferris, J. Iqbal, R. Clark, H. Miao, J. R. Hassler, J. Fornek, et al. 2008. UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators. Dev. Cell. 15: 829-840.
38. Wang, Y., L. Zhang, X. Wu, E. C. Gurley, E. Kennedy, P. B. Hylemon, W. M. Pandak, A. J. Sanyal, and H. Zhou. 2013. The role of CCAAT enhancer-binding protein homologous protein in human immunodeficiency virus protease-inhibitor-induced hepatic lipotoxicity in mice. Hepatology. 57: 1005-1016.
39. Ron, D., and J. F. Habener. 1992. CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription. Genes Dev. 6: 439-453.
40. Batchvarova, N., X. Z. Wang, and D. Ron. 1995. Inhibition of adipogenesis by the stress-induced protein CHOP (Gadd153). EMBO J. 14: 4654-4661.
41. Han, J., R. Murthy, B. Wood, B. Song, S. Wang, B. Sun, H. Malhi, and R. J. Kaufman. 2013. ER stress signalling through eIF2alpha and CHOP, but not IRE1alpha, attenuates adipogenesis in mice. Diabetologia. 56: 911-924.
42. Zhang, K., S. Wang, J. Malhotra, J. R. Hassler, S. H. Back, G. Wang, L. Chang, W. Xu, H. Miao, R. Leonardi, et al. 2011. The unfolded protein response transducer IRE1alpha prevents ER stress-induced hepatic steatosis. EMBO J. 30: 1357-1375.
43. Lee, A. H., E. F. Scapa, D. E. Cohen, and L. H. Glimcher. 2008. Regulation of hepatic lipogenesis by the transcription factor XBP1. Science. 320: 1492-1496.
44. Wang, S., Z. Chen, V. Lam, J. Han, J. Hassler, B. N. Finck, N. O. Davidson, and R. J. Kaufman. 2012. IRE1alpha-XBP1s induces PDI expression to increase MTP activity for hepatic VLDL assembly and lipid homeostasis. Cell Metab. 16: 473-486.
45. Wang, S., S. Park, V. K. Kodali, J. Han, T. Yip, Z. Chen, N. O. Davidson, and R. J. Kaufman. 2015. Identification of protein disulfide isomerase 1 as a key isomerase for disulfide bond formation in apolipoprotein B100. Mol. Biol. Cell. 26: 594-604.
46. So, J. S., K. Y. Hur, M. Tarrio, V. Ruda, M. Frank-Kamenetsky, K. Fitzgerald, V. Koteliansky, A. H. Lichtman, T. Iwawaki, L. H. Glimcher, et al. 2012. Silencing of lipid metabolism genes through IRE1alpha-mediated mRNA decay lowers plasma lipids in mice. Cell Metab. 16: 487-499.
47. Hollien, J., J. H. Lin, H. Li, N. Stevens, P. Walter, and J. S. Weissman. 2009. Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J. Cell Biol. 186: 323-331.
48. Han, D., A. G. Lerner, L. Vande Walle, J. P. Upton, W. Xu, A. Hagen, B. J. Backes, S. A. Oakes, and F. R. Papa. 2009. IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell. 138: 562-575.
49. Martinon, F., and L. H. Glimcher. 2011. Regulation of innate immunity by signaling pathways emerging from the endoplasmic reticulum. Curr. Opin. Immunol. 23: 35-40.
50. Martinon, F., X. Chen, A. H. Lee, and L. H. Glimcher. 2010. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat. Immunol. 11: 411-418.
51. Qiu, Q., Z. Zheng, L. Chang, Y. S. Zhao, C. Tan, A. Dandekar, Z. Zhang, Z. Lin, M. Gui, X. Li, et al. 2013. Toll-like receptormediated IRE1alpha activation as a therapeutic target for inflammatory arthritis. EMBO J. 32: 2477-2490.
52. Zeng, L., M. Lu, K. Mori, S. Luo, A. S. Lee, Y. Zhu, and J. Y. Shyy. 2004. ATF6 modulates SREBP2-mediated lipogenesis. EMBO J. 23: 950-958.
53. Yamamoto, K., K. Takahara, S. Oyadomari, T. Okada, T. Sato, A. Harada, and K. Mori. 2010. Induction of liver steatosis and lipid droplet formation in ATF6alpha-knockout mice burdened with pharmacological endoplasmic reticulum stress. Mol. Biol. Cell. 21: 2975-2986.
54. Usui, M., S. Yamaguchi, Y. Tanji, R. Tominaga, Y. Ishigaki, M. Fukumoto, H. Katagiri, K. Mori, Y. Oka, and H. Ishihara. 2012. Atf6-null mice are glucose intolerant due to pancreatic-cell failure on a high-fat diet but partially resistant to diet-induced insulin resistance. Metabolism. 61: 1118-1128.
55. Howarth, D. L., C. Lindtner, A. M. Vacaru, R. Sachidanandam, O. Tsedensodnom, T. Vasilkova, C. Buettner, and K. C. Sadler. 2014. Activating transcription factor 6 is necessary and sufficient for alcoholic fatty liver disease in zebrafish. PLoS Genet. 10: e1004335.
56. Cunha, D. A., P. Hekerman, L. Ladriere, A. Bazarra-Castro, F. Ortis, M. C. Wakeham, F. Moore, J. Rasschaert, A. K. Cardozo, E. Bellomo, et al. 2008. Initiation and execution of lipotoxic ER stress in pancreatic beta-cells. J. Cell Sci. 121: 2308-2318.
57. Bollheimer, L. C., R. H. Skelly, M. W. Chester, J. D. McGarry, and C. J. Rhodes. 1998. Chronic exposure to free fatty acid reduces pancreatic beta cell insulin content by increasing basal insulin secretion that is not compensated for by a corresponding increase in proinsulin biosynthesis translation. J. Clin. Invest. 101: 1094-1101.
58. Zhou, Y. P., and V. E. Grill. 1994. Long-Term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle. J. Clin. Invest. 93: 870-876.
59. Lee, Y., H. Hirose, M. Ohneda, J. H. Johnson, J. D. McGarry, and R. H. Unger. 1994. Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships. Proc. Natl. Acad. Sci. USA. 91: 10878-10882.
60. Lee, Y., H. Hirose, Y. T. Zhou, V. Esser, J. D. McGarry, and R. H. Unger. 1997. Increased lipogenic capacity of the islets of obese rats: A role in the pathogenesis of NIDDM. Diabetes. 46: 408-413.
61. Shimabukuro, M., M. Ohneda, Y. Lee, and R. H. Unger. 1997. Role of nitric oxide in obesity-induced beta cell disease. J. Clin. Invest. 100: 290-295.
62. Kharroubi, I., L. Ladriere, A. K. Cardozo, Z. Dogusan, M. Cnop, and D. L. Eizirik. 2004. Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms: role of nuclear factor-kappaB and endoplasmic reticulum stress. Endocrinology. 145: 5087-5096.
63. Cnop, M., L. Ladriere, P. Hekerman, F. Ortis, A. K. Cardozo, Z. Dogusan, D. Flamez, M. Boyce, J. Yuan, and D. L. Eizirik. 2007. Selective inhibition of eukaryotic translation initiation factor 2 alpha dephosphorylation potentiates fatty acid-induced endoplasmic reticulum stress and causes pancreatic beta-cell dysfunction and apoptosis. J. Biol. Chem. 282: 3989-3997.
64. Karaskov, E., C. Scott, L. Zhang, T. Teodoro, M. Ravazzola, and A. Volchuk. 2006. Chronic palmitate but not oleate exposure induces endoplasmic reticulum stress, which may contribute to INS-1 pancreatic beta-cell apoptosis. Endocrinology. 147: 3398-3407.
65. Laybutt, D. R., A. M. Preston, M. C. Akerfeldt, J. G. Kench, A. K. Busch, A. V. Biankin, and T. J. Biden. 2007. Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia. 50: 752-763.
66. Tran, K., Y. Li, H. Duan, D. Arora, H. Y. Lim, and W. Wang. 2014. Identification of small molecules that protect pancreatic beta cells against endoplasmic reticulum stress-induced cell death. ACS Chem. Biol. 9: 2796-2806.
67. Choi, S. E., Y. J. Lee, H. J. Jang, K. W. Lee, Y. S. Kim, H. S. Jun, S. S. Kang, J. Chun, and Y. Kang. 2008. A chemical chaperone 4-PBA ameliorates palmitate-induced inhibition of glucosestimulated insulin secretion (GSIS). Arch. Biochem. Biophys. 475: 109-114.
68. Chen, Y. Y., L. Q. Sun, B. A. Wang, X. M. Zou, Y. M. Mu, and J. M. Lu. 2013. Palmitate induces autophagy in pancreatic beta-cells via endoplasmic reticulum stress and its downstream JNK pathway. Int. J. Mol. Med. 32: 1401-1406.
69. Baldwin, A. C., C. D. Green, L. K. Olson, M. A. Moxley, and J. A. Corbett. 2012. A role for aberrant protein palmitoylation in FFAinduced ER stress and beta-cell death. Am. J. Physiol. Endocrinol. Metab. 302: E1390-E1398.
70. Boslem, E., G. MacIntosh, A. M. Preston, C. Bartley, A. K. Busch, M. Fuller, D. R. Laybutt, P. J. Meikle, and T. J. Biden. 2011. A lipidomic screen of palmitate-Treated MIN6 beta-cells links sphingolipid metabolites with endoplasmic reticulum (ER) stress and impaired protein trafficking. Biochem. J. 435: 267-276.
71. Véret, J., N. Coant, I. A. Gorshkova, P. Giussani, M. Fradet, E. Riccitelli, A. Skobeleva, J. Goya, N. Kassis, V. Natarajan, et al. 2013. Role of palmitate-induced sphingoid base-1-phosphate biosynthesis in INS-1 beta-cell survival. Biochim. Biophys. Acta. 1831: 251-262.
72. Boslem, E., J. M. Weir, G. MacIntosh, N. Sue, J. Cantley, P. J. Meikle, and T. J. Biden. 2013. Alteration of endoplasmic reticulum lipid rafts contributes to lipotoxicity in pancreatic beta-cells. J. Biol. Chem. 288: 26569-26582.
73. Gjoni, E., L. Brioschi, A. Cinque, N. Coant, M. N. Islam, C. K. Ng, C. Verderio, C. Magnan, L. Riboni, P. Viani, et al. 2014. Glucolipotoxicity impairs ceramide flow from the endoplasmic reticulum to the Golgi apparatus in INS-1 beta-cells. PLoS One. 9: e110875.
74. Moffitt, J. H., B. A. Fielding, R. Evershed, R. Berstan, J. M. Currie, and A. Clark. 2005. Adverse physicochemical properties of tripalmitin in beta cells lead to morphological changes and lipotoxicity in vitro. Diabetologia. 48: 1819-1829.
75. Ariyama, H., N. Kono, S. Matsuda, T. Inoue, and H. Arai. 2010. Decrease in membrane phospholipid unsaturation induces unfolded protein response. J. Biol. Chem. 285: 22027-22035.
76. Volmer, R., K. van der Ploeg, and D. Ron. 2013. Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains. Proc. Natl. Acad. Sci. USA. 110: 4628-4633.
77. Kuznetsov, G., M. A. Brostrom, and C. O. Brostrom. 1992. Demonstration of a calcium requirement for secretory protein processing and export. Differential effects of calcium and dithiothreitol. J. Biol. Chem. 267: 3932-3939.
78. Lodish, H. F., and N. Kong. 1990. Perturbation of cellular calcium blocks exit of secretory proteins from the rough endoplasmic reticulum. J. Biol. Chem. 265: 10893-10899.
79. Borradaile, N. M., X. Han, J. D. Harp, S. E. Gale, D. S. Ory, and J. E. Schaffer. 2006. Disruption of endoplasmic reticulum structure and integrity in lipotoxic cell death. J. Lipid Res. 47: 2726-2737.
80. Choi, S. E., S. M. Lee, Y. J. Lee, L. J. Li, S. J. Lee, J. H. Lee, Y. Kim, H. S. Jun, K. W. Lee, and Y. Kang. 2009. Protective role of autophagy in palmitate-induced INS-1 beta-cell death. Endocrinology. 150: 126-134.
81. Cnop, M., B. Abdulkarim, G. Bottu, D. A. Cunha, M. Igoillo-Esteve, M. Masini, J. V. Turatsinze, T. Griebel, O. Villate, I. Santin, et al. 2014. RNA sequencing identifies dysregulation of the human pancreatic islet transcriptome by the saturated fatty acid palmitate. Diabetes. 63: 1978-1993.
82. Chu, K. Y., L. O'Reilly, G. Ramm, and T. J. Biden. 2015. High-fat diet increases autophagic flux in pancreatic beta cells in vivo and ex vivo in mice. Diabetologia. 58: 2074-2078.
83. Hu, M., S. Yang, L. Yang, Y. Cheng, and H. Zhang. 2016. Interleukin-22 alleviated palmitate-induced endoplasmic reticulum stress in INS-1 cells through activation of autophagy. PLoS One. 11: e0146818.
84. Prause, M., D. P. Christensen, N. Billestrup, and T. Mandrup-Poulsen. 2014. JNK1 protects against glucolipotoxicity-mediated-cell apoptosis. PLoS One. 9: e87067.
85. Simon-Szabó, L., M. Kokas, J. Mandl, G. Kéri, and M. Csala. 2014. Metformin attenuates palmitate-induced endoplasmic reticulum stress, serine phosphorylation of IRS-1 and apoptosis in rat insulinoma cells. PLoS One. 9: e97868.
86. Pétremand, J., J. Puyal, J. Y. Chatton, J. Duprez, F. Allagnat, M. Frias, R. W. James, G. Waeber, J. C. Jonas, and C. Widmann. 2012. HDLs protect pancreatic beta-cells against ER stress by restoring protein folding and trafficking. Diabetes. 61: 1100-1111.
87. Puyal, J., J. Petremand, G. Dubuis, C. Rummel, and C. Widmann. 2013. HDLs protect the MIN6 insulinoma cell line against tunicamycin-induced apoptosis without inhibiting ER stress and without restoring ER functionality. Mol. Cell. Endocrinol. 381: 291-301.
88. Hong, D., L. F. Li, H. C. Gao, X. Wang, C. C. Li, Y. Luo, Y. P. Bai, and G. G. Zhang. 2015. High-density lipoprotein prevents endoplasmic reticulum stress-induced downregulation of liver LOX-1 expression. PLoS One. 10: e0124285.
89. Engin, F., A. Yermalovich, T. Nguyen, S. Hummasti, W. Fu, D. L. Eizirik, D. Mathis, and G. S. Hotamisligil. 2013. Restoration of the unfolded protein response in pancreatic beta cells protects mice against type 1 diabetes. Sci. Transl. Med. 5: 211ra156. [Erratum. 2013. Sci. Transl. Med. 5: 214er11.]
90. Engin, F., and G. S. Hotamisligil. 2010. Restoring endoplasmic reticulum function by chemical chaperones: An emerging therapeutic approach for metabolic diseases. Diabetes Obes. Metab. 12(Suppl 2): 108-115.
91. Cao, J., D. L. Dai, L. Yao, H. H. Yu, B. Ning, Q. Zhang, J. Chen, W. H. Cheng, W. Shen, and Z. X. Yang. 2012. Saturated fatty acid induction of endoplasmic reticulum stress and apoptosis in human liver cells via the PERK/ATF4/CHOP signaling pathway. Mol. Cell. Biochem. 364: 115-129.
92. Gu, X., K. Li, D. R. Laybutt, M. L. He, H. L. Zhao, J. C. Chan, and G. Xu. 2010. Bip overexpression, but not CHOP inhibition, attenuates fatty-Acid-induced endoplasmic reticulum stress and apoptosis in HepG2 liver cells. Life Sci. 87: 724-732.
93. Pan, Q. R., Y. L. Ren, W. X. Liu, Y. J. Hu, J. S. Zheng, Y. Xu, and G. Wang. 2015. Resveratrol prevents hepatic steatosis and endoplasmic reticulum stress and regulates the expression of genes involved in lipid metabolism, insulin resistance, and inflammation in rats. Nutr. Res. 35: 576-584.
94. Ao, N., J. Yang, X. Wang, and J. Du. 2016. Glucagon-like peptide-1 preserves non-Alcoholic fatty liver disease through inhibition of the endoplasmic reticulum stress-Associated pathway. Hepatol. Res. 46: 343-353.
95. Pierre, N., L. Deldicque, C. Barbe, D. Naslain, P. D. Cani, and M. Francaux. 2013. Toll-like receptor 4 knockout mice are protected against endoplasmic reticulum stress induced by a high-fat diet. PLoS One. 8: e65061.
96. Miyamoto, Y., A. S. Mauer, S. Kumar, J. L. Mott, and H. Malhi. 2014. Mmu-miR-615-3p regulates lipoapoptosis by inhibiting C/EBP homologous protein. PLoS One. 9: e109637.
97. Listenberger, L. L., D. S. Ory, and J. E. Schaffer. 2001. Palmitateinduced apoptosis can occur through a ceramide-independent pathway. J. Biol. Chem. 276: 14890-14895.
98. Egnatchik, R. A., A. K. Leamy, D. A. Jacobson, M. Shiota, and J. D. Young. 2014. ER calcium release promotes mitochondrial dysfunction and hepatic cell lipotoxicity in response to palmitate overload. Mol. Metab. 3: 544-553.
99. Rong, X., C. J. Albert, C. Hong, M. A. Duerr, B. T. Chamberlain, E. J. Tarling, A. Ito, J. Gao, B. Wang, P. A. Edwards, et al. 2013. LXRs regulate ER stress and inflammation through dynamic modulation of membrane phospholipid composition. Cell Metab. 18: 685-697.
100. Leamy, A. K., R. A. Egnatchik, M. Shiota, P. T. Ivanova, D. S. Myers, H. A. Brown, and J. D. Young. 2014. Enhanced synthesis of saturated phospholipids is associated with ER stress and lipotoxicity in palmitate treated hepatic cells. J. Lipid Res. 55: 1478-1488.
101. Flowers, M. T., M. P. Keller, Y. Choi, H. Lan, C. Kendziorski, J. M. Ntambi, and A. D. Attie. 2008. Liver gene expression analysis reveals endoplasmic reticulum stress and metabolic dysfunction in SCD1-deficient mice fed a very low-fat diet. Physiol. Genomics. 33: 361-372.
102. Fu, S., L. Yang, P. Li, O. Hofmann, L. Dicker, W. Hide, X. Lin, S. M. Watkins, A. R. Ivanov, and G. S. Hotamisligil. 2011. Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature. 473: 528-531.
103. Damiano, F., S. Alemanno, G. V. Gnoni, and L. Siculella. 2010. Translational control of the sterol-regulatory transcription factor SREBP-1 mRNA in response to serum starvation or ER stress is mediated by an internal ribosome entry site. Biochem. J. 429: 603-612.
104. Damiano, F., A. Rochira, R. Tocci, S. Alemanno, A. Gnoni, and L. Siculella. 2013. hnRNP A1 mediates the activation of the IRESdependent SREBP-1a mRNA translation in response to endoplasmic reticulum stress. Biochem. J. 449: 543-553.
105. Fang, D. L., Y. Wan, W. Shen, J. Cao, Z. X. Sun, H. H. Yu, Q. Zhang, W. H. Cheng, J. Chen, and B. Ning. 2013. Endoplasmic reticulum stress leads to lipid accumulation through upregulation of SREBP-1c in normal hepatic and hepatoma cells. Mol. Cell. Biochem. 381: 127-137.
106. Jo, H., S. S. Choe, K. C. Shin, H. Jang, J. H. Lee, J. K. Seong, S. H. Back, and J. B. Kim. 2013. Endoplasmic reticulum stress induces hepatic steatosis via increased expression of the hepatic very lowdensity lipoprotein receptor. Hepatology. 57: 1366-1377.
107. Su, Q., J. Tsai, E. Xu, W. Qiu, E. Bereczki, M. Santha, and K. Adeli. 2009. Apolipoprotein B100 acts as a molecular link between lipidinduced endoplasmic reticulum stress and hepatic insulin resistance. Hepatology. 50: 77-84.
108. Su, Q., C. Baker, P. Christian, M. Naples, X. Tong, K. Zhang, M. Santha, and K. Adeli. 2014. Hepatic mitochondrial and ER stress induced by defective PPARalpha signaling in the pathogenesis of hepatic steatosis. Am. J. Physiol. Endocrinol. Metab. 306: E1264-E1273.
109. Chan, S. M., R. Q. Sun, X. Y. Zeng, Z. H. Choong, H. Wang, M. J. Watt, and J. M. Ye. 2013. Activation of PPARalpha ameliorates hepatic insulin resistance and steatosis in high fructose-fed mice despite increased endoplasmic reticulum stress. Diabetes. 62: 2095-2105.
110. Xiong, X., X. Wang, Y. Lu, E. Wang, Z. Zhang, J. Yang, H. Zhang, and X. Li. 2014. Hepatic steatosis exacerbated by endoplasmic reticulum stress-mediated downregulation of FXR in aging mice. J. Hepatol. 60: 847-854.
111. Watanabe, M., S. M. Houten, L. Wang, A. Moschetta, D. J. Mangelsdorf, R. A. Heyman, D. D. Moore, and J. Auwerx. 2004. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J. Clin. Invest. 113: 1408-1418.
112. González-Rodríguez, A., R. Mayoral, N. Agra, M. P. Valdecantos, V. Pardo, M. E. Miquilena-Colina, J. Vargas-Castrillón, O. Lo Iacono, M. Corazzari, G. M. Fimia, et al. 2014. Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD. Cell Death Dis. 5: e1179.
113. Peter, A., C. Weigert, H. Staiger, F. Machicao, F. Schick, J. Machann, N. Stefan, C. Thamer, H. U. Haring, and E. Schleicher. 2009. Individual stearoyl-CoA desaturase 1 expression modulates endoplasmic reticulum stress and inflammation in human myotubes and is associated with skeletal muscle lipid storage and insulin sensitivity in vivo. Diabetes. 58: 1757-1765.
114. Deldicque, L., P. D. Cani, A. Philp, J. M. Raymackers, P. J. Meakin, M. L. Ashford, N. M. Delzenne, M. Francaux, and K. Baar. 2010. The unfolded protein response is activated in skeletal muscle by high-fat feeding: potential role in the downregulation of protein synthesis. Am. J. Physiol. Endocrinol. Metab. 299: E695-E705.
115. Kars, M., L. Yang, M. F. Gregor, B. S. Mohammed, T. A. Pietka, B. N. Finck, B. W. Patterson, J. D. Horton, B. Mittendorfer, G. S. Hotamisligil, et al. 2010. Tauroursodeoxycholic acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women. Diabetes. 59: 1899-1905.
116. Zhang, H., Y. Wang, J. Li, J. Yu, J. Pu, L. Li, H. Zhang, S. Zhang, G. Peng, F. Yang, et al. 2011. Proteome of skeletal muscle lipid droplet reveals association with mitochondria and apolipoprotein a-I. J. Proteome Res. 10: 4757-4768.
117. Salvadó, L., T. Coll, A. M. Gómez-Foix, E. Salmerón, E. Barroso, X. Palomer, and M. Vázquez-Carrera. 2013. Oleate prevents saturated-fatty-Acid-induced ER stress, inflammation and insulin resistance in skeletal muscle cells through an AMPK-dependent mechanism. Diabetologia. 56: 1372-1382.
118. Salvadó, L., E. Barroso, A. M. Gómez-Foix, X. Palomer, L. Michalik, W. Wahli, and M. Vázquez-Carrera. 2014. PPARbeta/delta prevents endoplasmic reticulum stress-Associated inflammation and insulin resistance in skeletal muscle cells through an AMPK-dependent mechanism. Diabetologia. 57: 2126-2135.
119. Deldicque, L., K. Van Proeyen, M. Francaux, and P. Hespel. 2011. The unfolded protein response in human skeletal muscle is not involved in the onset of glucose tolerance impairment induced by a fat-rich diet. Eur. J. Appl. Physiol. 111: 1553-1558.
120. Hage Hassan, R., I. Hainault, J. T. Vilquin, C. Samama, F. Lasnier, P. Ferre, F. Foufelle, and E. Hajduch. 2012. Endoplasmic reticulum stress does not mediate palmitateinduced insulin resistance in mouse and human muscle cells. Diabetologia. 55: 204-214.
121. Rieusset, J., M. A. Chauvin, A. Durand, A. Bravard, F. Laugerette, M. C. Michalski, and H. Vidal. 2012. Reduction of endoplasmic reticulum stress using chemical chaperones or Grp78 overexpression does not protect muscle cells from palmitate-induced insulin resistance. Biochem. Biophys. Res. Commun. 417: 439-445.
122. Nielsen, L. B., M. Perko, H. Arendrup, and C. B. Andersen. 2002. Microsomal triglyceride transfer protein gene expression and triglyceride accumulation in hypoxic human hearts. Arterioscler. Thromb. Vasc. Biol. 22: 1489-1494.
123. Marfella, R., C. Di Filippo, M. Portoghese, M. Barbieri, F. Ferraraccio, M. Siniscalchi, F. Cacciapuoti, F. Rossi, M. D'Amico, and G. Paolisso. 2009. Myocardial lipid accumulation in patients with pressure-overloaded heart and metabolic syndrome. J. Lipid Res. 50: 2314-2323.
124. Okada, K., T. Minamino, Y. Tsukamoto, Y. Liao, O. Tsukamoto, S. Takashima, A. Hirata, M. Fujita, Y. Nagamachi, T. Nakatani, et al. 2004. Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis. Circulation. 110: 705-712.
125. Azfer, A., J. Niu, L. M. Rogers, F. M. Adamski, and P. E. Kolattukudy. 2006. Activation of endoplasmic reticulum stress response during the development of ischemic heart disease. Am. J. Physiol. Heart Circ. Physiol. 291: H1411-H1420.
126. Perman, J. C., P. Bostrom, M. Lindbom, U. Lidberg, M. StAhlman, D. Hagg, H. Lindskog, M. Scharin Tang, E. Omerovic, L. Mattsson Hulten, et al. 2011. The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction. J. Clin. Invest. 121: 2625-2640.
127. Drevinge, C., L. O. Karlsson, M. Stahlman, T. Larsson, J. Perman Sundelin, L. Grip, L. Andersson, J. Boren, and M. C. Levin. 2013. Cholesteryl esters accumulate in the heart in a porcine model of ischemia and reperfusion. PLoS One. 8: e61942.
128. Palomer, X., E. Capdevila-Busquets, G. Botteri, L. Salvado, E. Barroso, M. M. Davidson, L. Michalik, W. Wahli, and M. Vazquez-Carrera. 2014. PPARbeta/delta attenuates palmitate-induced endoplasmic reticulum stress and induces autophagic markers in human cardiac cells. Int. J. Cardiol. 174: 110-118.
129. Bosma, M., D. H. Dapito, Z. Drosatos-Tampakaki, N. Huiping-Son, L. S. Huang, S. Kersten, K. Drosatos, and I. J. Goldberg. 2014. Sequestration of fatty acids in triglycerides prevents endoplasmic reticulum stress in an in vitro model of cardiomyocyte lipotoxicity. Biochim. Biophys. Acta. 1841: 1648-1655.