Journal of Food and Nutrition Research
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Journal of Food and Nutrition Research. 2018, 6(8), 518-524
DOI: 10.12691/jfnr-6-8-6
Open AccessArticle

Defensive Effect of Quercetin against Tumor Necrosis Factor α-induced Endoplasmic Reticulum Stress and Hepatic Insulin Resistance in HepG2 Cells

Jeongjin Park1, Woojin Jun1, Jeongmin Lee2, and Ok-Kyung Kim1,

1Division of Food and Nutrition, Chonnam National University, Gwangju, South Korea

2Department of Medical Nutrition, Kyung Hee University, Yongin, South Korea

Pub. Date: September 05, 2018

Cite this paper:
Jeongjin Park, Woojin Jun, Jeongmin Lee and Ok-Kyung Kim. Defensive Effect of Quercetin against Tumor Necrosis Factor α-induced Endoplasmic Reticulum Stress and Hepatic Insulin Resistance in HepG2 Cells. Journal of Food and Nutrition Research. 2018; 6(8):518-524. doi: 10.12691/jfnr-6-8-6


In order to examine the hypothesis that the treatment of TNF-α can impose inflammation and endoplasmic reticulum (ER) stress in hepatic cells, and that quercetin has a defensive effect against TNF-α-induced ER stress and insulin resistance, we evaluated the effect of quercetin (3 µg/mL and 5 µg/mL) in the TNF-α-induced HepG2 cells. The TNF-α-stimulated control group caused a marked increase in the activation of inflammation and ER stress response. Quercetin, however, caused the interruption of TNF-α-induced inflammation and ER stress. In addition, the treatment of quercetin resulted in significant decreases in serine phosphorylation of IRS-1, phosphorylation of JNK, and the expression of gluconeogenic genes compared with the TNF-α-stimulated control group. In conclusion, we suggest that quercetin can protect hepatic insulin resistance by exerting a protective effect against the ER stress and inflammation induced by TNF-α.

quercetin TNF-α ER stress insulin resistance inflammation

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[1]  Treede, I., Braun, A., Jeliaskova, P., Giese, T., et al., “TNF-alpha-induced up-regulation of pro-inflammatory cytokines is reduced by phosphatidylcholine in intestinal epithelial cells.” BMC Gastroenterol, 9. 53. 2009.
[2]  Schuerwegh, A.J., Dombrecht, E.J., Stevens, W.J., Van Offel, J.F., et al., “Influence of pro-inflammatory (IL-1 alpha, IL-6, TNF-alpha, IFN-gamma) and anti-inflammatory (IL-4) cytokines on chondrocyte function.” Osteoarthritis Cartilage, 11. 681-687. 2003.
[3]  Torre-Amione, G., Kapadia, S., Lee, J., Durand, J.B.,et al., “Tumor necrosis factor-alpha and tumor necrosis factor receptors in the failing human heart. “ Circulation, 93. 704-711. 1996.
[4]  Cheung, A.T., Wang, J., Ree, D., Kolls, J.K., Bryer-Ash, M., “Tumor necrosis factor-alpha induces hepatic insulin resistance in obese Zucker (fa/fa) rats via interaction of leukocyte antigen-related tyrosine phosphatase with focal adhesion kinase.” Diabetes, 49. 810-819. 2000.
[5]  Gupta, D., Varma, S., Khandelwal, R.L., “Long-term effects of tumor necrosis factor-alpha treatment on insulin signaling pathway in HepG2 cells and HepG2 cells overexpressing constitutively active Akt/PKB.” J. Cell Biochem, 100. 593-607. 2007.
[6]  Denis, R.G., Arruda, A.P., Romanatto, T., Milanski, M., et al., “TNF-α transiently induces endoplasmic reticulum stress and an incomplete unfolded protein response in the hypothalamus.” Neuroscience, 170. 1035-1044. 2010.
[7]  Xue, X., Piao, J.H., Nakajima, A., Sakon-Komazawa, S., et al., “Tumor necrosis factor alpha (TNFalpha) induces the unfolded protein response (UPR) in a reactive oxygen species (ROS)-dependent fashion, and the UPR counteracts ROS accumulation by TNFalpha.” J. Biol. Chem, 280. 33917-33925. 2005.
[8]  Lang, C.H., Dobrescu, C., Bagby, G.J., “Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output.” Endocrinology, 130. 43-52. 1992.
[9]  Ozcan, U., Cao, Q., Yilmaz, E., Lee, A.H., et al., “Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes.” Science, 306. 457-461. 2004.
[10]  Cnop, M., Foufelle, F., Velloso, L.A., “Endoplasmic reticulum stress, obesity and diabetes.” Trends Mol. Med, 18. 59-68. 2012.
[11]  Hotamisligil, G.S., “Inflammation and endoplasmic reticulum stress in obesity and diabetes.” Int. J. Obes, 32. S52-54. 2008.
[12]  Hotamisligil, G.S., Shargill, N.S., Spiegelman, B.M., “Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.” Science, 259. 87-91. 1993.
[13]  Cottam, D.R., Mattar, S.G., Barinas-Mitchell, E., Eid, G., et al., “The chronic inflammatory hypothesis for the morbidity associated with morbid obesity: implications and effects of weight loss.” Obes. Surg, 14. 589-600. 2004.
[14]  Björntorp, P., ““Portal” adipose tissue as a generator of risk factors for cardiovascular disease and diabetes.” Arteriosclerosis, 10. 493-496. 1990.
[15]  Schröder, M., “Endoplasmic reticulum stress responses.” Cell Mol. Life Sci, 65. 862-894. 2008.
[16]  Shen, X., Zhang, K., Kaufman, R.J., “The unfolded protein response--a stress signaling pathway of the endoplasmic reticulum.” J. Chem. Neuroanat, 28. 79-92. 2004.
[17]  Urano, F., Wang, X., Bertolotti, A., Zhang, Y., et al., “Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1.” Science, 287. 664-666. 2000.
[18]  Hirosumi, J., Tuncman, G., Chang, L., Görgün, C.Z., et al., “A central role for JNK in obesity and insulin resistance.” Nature, 420. 333-336. 2002.
[19]  Oyadomari, S., Harding, H.P., Zhang, Y., Oyadomari, M., Ron, D., “Dephosphorylation of translation initiation factor 2alpha enhances glucose tolerance and attenuates hepatosteatosis in mice.” Cell Metab, 7. 520-532. 2008.
[20]  Pedersen, T.A., Bereshchenko, O., Garcia-Silva, S., Ermakova, O., et al., “Distinct C/EBPalpha motifs regulate lipogenic and gluconeogenic gene expression in vivo.” EMBO J, 26. 1081-1093. 2007.
[21]  Choudhury, M., Qadri, I., Rahman, S.M., Schroeder-Gloeckler, J., et al., “C/EBPβ is AMP kinase sensitive and up-regulates PEPCK in response to ER stress in hepatoma cells.” Mol Cell Endocrinol, 331. 102-128. 2011.
[22]  Scalbert, A., Williamson, G., “Dietary intake and bioavailability of polyphenols.” J. Nutr, 130. 2073S-2085S. 2000.
[23]  Formica, J.V., Regelson, W., “Review of the biology of Quercetin and related bioflavonoids.” Food Chem. Toxicol, 33. 1061-1080. 1995.
[24]  Boots, A.W., Wilms, L.C., Swennen, E.L., Kleinjans, J.C., et al., “In vitro and ex vivo anti-inflammatory activity of quercetin in healthy volunteers.” Nutrition, 24. 703-710. 2008.
[25]  Ohnishi, E., Bannai, H., “Quercetin potentiates TNF-induced antiviral activity.” Antiviral Res, 22. 327-331. 1993.
[26]  Ruiz, P.A., Braune, A., Hölzlwimmer, G., Quintanilla-Fend, L., Haller, D., “Quercetin inhibits TNF-induced NF-kappaB transcription factor recruitment to proinflammatory gene promoters in murine intestinal epithelial cells.” J. Nutr, 137. 1208-1215. 2007.
[27]  Cho, S.Y., Park, S.J., Kwon, M.J., Jeong, T.S., et al., “Quercetin suppresses proinflammatory cytokines production through MAP kinases and NF-kappaB pathway in lipopolysaccharide-stimulated macrophage.” Mol. Cell Biochem, 243. 153-160. 2003.
[28]  Schwabe, R.F., Brenner, D.A., “Mechanisms of Liver Injury. I. TNF-alpha-induced liver injury: role of IKK, JNK, and ROS pathways.” Am. J. Physiol. Gastrointest. Liver Physiol, 290. G583-589. 2006.
[29]  Liu, H., Lo, C.R., Czaja, M.J., “NF-kappaB inhibition sensitizes hepatocytes to TNF-induced apoptosis through a sustained activation of JNK and c-Jun.” Hepatology, 35. 772-778. 2002.
[30]  Baker, R.G., Hayden, M.S., Ghosh, S., “NF-κB, inflammation, and metabolic disease.” Cell Metab, 13. 11-22. 2011.
[31]  Jiao, P., Chen, Q., Shah, S., Du, J., et al., “Obesity-related upregulation of monocyte chemotactic factors in adipocytes: involvement of nuclear factor-kappaB and c-Jun NH2-terminal kinase pathways.” Diabetes, 58. 104-115. 2009.
[32]  Cai, D., Yuan, M., Frantz, D.F., Melendez, P.A., et al., “Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB.” Nat. Med, 11. 183-190. 2005.
[33]  Shepherd, P.R., Withers, D.J., Siddle, K., “Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling.” Biochem. J, 333. 471-490. 1998.
[34]  Nakae, J., Kitamura, T., Silver, D.L., Accili, D., “The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression.” J. Clin. Invest, 108. 1359-1367. 2001.
[35]  Puigserver, P., Rhee, J., Donovan, J., Walkey, C.J., et al., “Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction.” Nature, 423. 550-555. 2003.
[36]  Oakes, N.D., Cooney, G.J., Camilleri, S., Chisholm, D.J., Kraegen, E.W., “Mechanisms of liver and muscle insulin resistance induced by chronic high-fat feeding.” Diabetes, 46. 1768-1774. 1997.
[37]  Kahn, S.E., Hull, R.L., Utzschneider, K.M., “Mechanisms linking obesity to insulin resistance and type 2 diabetes.” Nature, 444. 840-846. 2006.
[38]  Arkan, M.C., Hevener, A.L., Greten, F.R., Maeda, S.,et al., “IKK-beta links inflammation to obesity-induced insulin resistance.” Nat. Med, 11. 191-198. 2005.
[39]  Ozawa, K., Miyazaki, M., Matsuhisa, M., Takano, K., et al., “The endoplasmic reticulum chaperone improves insulin resistance in type 2 diabetes.” Diabetes, 54. 657-663. 2005.
[40]  Harding, H.P., Zhang, Y., Bertolotti, A., Zeng, H., Ron, D., “Perk is essential for translational regulation and cell survival during the unfolded protein response.” Mol. Cell, 5. 897-904. 2000.
[41]  DuRose, J.B., Scheuner, D., Kaufman, R.J., Rothblum, L.I., Niwa, M., “Phosphorylation of eukaryotic translation initiation factor 2alpha coordinates rRNA transcription and translation inhibition during endoplasmic reticulum stress.” Mol. Cell Biol, 29. 4295-4307. 2009.
[42]  Hendershot, L.M., “The ER function BiP is a master regulator of ER function.” Mt. Sinai. J. Med, 71. 289-297. 2004.
[43]  Ye, J., Rawson, R.B., Komuro, R., Chen, X., et al., “ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs.” Mol. Cell, 6. 1355-1364. 2000.
[44]  Hotamisligil, G.S., Peraldi, P., Budavari, A., Ellis, R., et al., “IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance.” Science, 271. 665-668. 1996.
[45]  Diehl, A.M., Yang, S.Q., Yin, M., Lin, H.Z., et al., “Tumor necrosis factor-alpha modulates CCAAT/enhancer binding proteins-DNA binding activities and promotes hepatocyte-specific gene expression during liver regeneration.” Hepatology, 22. 252-261. 1995.
[46]  Vidyashankar, S., Sandeep Varma, R., Patki, P.S., “Quercetin ameliorate insulin resistance and up-regulates cellular antioxidants during oleic acid induced hepatic steatosis in HepG2 cells.” Toxicol. In Vitro, 27. 945-953. 2013.
[47]  Chuang, C.C., Martinez, K., Xie, G., Kennedy, A., et al., “Quercetin is equally or more effective than resveratrol in attenuating tumor necrosis factor-{alpha}-mediated inflammation and insulin resistance in primary human adipocytes.” Am. J. Clin. Nutr, 92. 1511-1521. 2010.
[48]  Rivera, L., Morón, R., Sánchez, M., Zarzuelo, A., Galisteo, M., “Quercetin ameliorates metabolic syndrome and improves the inflammatory status in obese Zucker rats.” Obesity, 16. 2081-2087. 2008.
[49]  Suganya, N., Bhakkiyalakshmi, E., Suriyanarayanan, S., Paulmurugan, R., Ramkumar, K.M., “Quercetin ameliorates tunicamycin-induced endoplasmic reticulum stress in endothelial cells.” Cell Prolif, 47. 231-240. 2014.
[50]  Natsume, Y., Ito, S., Satsu, H., Shimizu, M., “Protective effect of quercetin on ER stress caused by calcium dynamics dysregulation in intestinal epithelial cells.” Toxicology, 258. 164-175. 2009.
[51]  Yao, S., Sang, H., Song, G., Yang, N., et al., “Quercetin protects macrophages from oxidized low-density lipoprotein-induced apoptosis by inhibiting the endoplasmic reticulum stress-C/EBP homologous protein pathway.” Exp. Biol. Med, 237. 822-831. 2012.