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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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General Research Article

Influence of Resveratrol on Sphingolipid Metabolism in Hepatocellular Carcinoma Cells in Lipid Overload State

Author(s): Tomasz Charytoniuk*, Ewa Harasim-Symbor, Agnieszka Polak, Krzysztof Drygalski, Klaudia Berk, Adrian Chabowski and Karolina Konstantynowicz-Nowicka

Volume 19, Issue 1, 2019

Page: [121 - 129] Pages: 9

DOI: 10.2174/1871520619666181224161255

Price: $65

Abstract

Background: Obesity is characterized by increased long chain fatty acids (LCFA) uptake and impaired lipid metabolism in hepatocytes. Consequently, an enhanced intracellular lipid content, including sphingolipids, may lead to lipotoxicity. It is believed that resveratrol (RSV), one of the most extensively studied plant-derived polyphenols, and its interaction with sphingolipid metabolism may constitute one of the major therapeutic targets for cancer and metabolic diseases treatment.

Objective: The aim of this study was to ascertain, whether resveratrol may affect sphingolipid metabolic pathways, enzymes and transporters in a lipid overload state.

Methods: The experiments were conducted on hepatocellular carcinoma cells (HepG2) incubated with RSV and/or Palmitic Acid (PA) at the concentration of 0.5 mM and 50 µM, respectively for 16h. Intra- and extracellular sphingolipid concentrations were assessed by high-performance liquid chromatography and gas liquid chromatography. Moreover, the expression of caspase 3, selected fatty acid transporters and sphingolipid metabolism pathway proteins were estimated by Western Blot.

Results: RSV alone and together with PA significantly increased the intracellular concentration of ceramide, sphinganine and sphingosine as well as the expression of enzymes related to de novo ceramide synthesis pathway. Moreover, in our study, we observed augmented ceramide and sphingomyelin efflux into the incubation media in these groups. In addition, RSV substantially reduced intracellular triacylglycerols accumulation in lipid overload conditions.

Conclusion: The above-mentioned findings suggest that RSV, at least partially, demonstrates a potential protective effect on HepG2 cells in a lipid overload state.

Keywords: Resveratrol, ceramide, hepatocellular carcinoma, fatty acid transporters, metabolic disorders, sphingolipids.

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[1]
Frémont, L. Biological effects of resveratrol. Antioxid. Redox Signal., 2001, 3, 1041-1064.
[2]
Charytoniuk, T.; Drygalski, K.; Konstantynowicz-Nowicka, K.; Berk, K.; Chabowski, A. Alternative treatment methods attenuate the development of NAFLD: A review of resveratrol molecular mechanisms and clinical trials. Nutrition, 2017, 34, 108-117.
[3]
Heebøll, S.; Thomsen, K.L.; Pedersen, S.B.; Vilstrup, H.; George, J.; Grønbæk, H. Effects of resveratrol in experimental and clinical non-alcoholic fatty liver disease. World J. Hepatol., 2014, 6, 188-198.
[4]
Faghihzadeh, F.; Adibi, P.; Hekmatdoost, A. The effects of resveratrol supplementation on cardiovascular risk factors in patients with non-alcoholic fatty liver disease: A randomised, double-blind, placebo-controlled study. Br. J. Nutr., 2015, 114, 796-803.
[5]
Choi, Y-J.; Suh, H-R.; Yoon, Y.; Lee, K-J.; Kim, D.G.; Kim, S.; Lee, B-H. Protective effect of resveratrol derivatives on high-fat diet induced fatty liver by activating AMP-activated protein kinase. Arch. Pharm. Res., 2014, 37, 1169-1176.
[6]
Gault, C.R.; Obeid, L.M.; Hannun, Y.A. An overview of sphingolipid metabolism: From synthesis to breakdown. Adv. Exp. Med. Biol., 2010, 688, 1-23.
[7]
Delgado, A.; Casas, J.; Llebaria, A.; Abad, J.L.; Fabrias, G. Inhibitors of sphingolipid metabolism enzymes. Biochim. Biophys. Acta - Biomembr, 2006, 1758, 1957-1977.
[8]
Meikle, P.J.; Summers, S.A. Sphingolipids and phospholipids in insulin resistance and related metabolic disorders. Nat. Rev. Endocrinol., 2016, 13, 79-91.
[9]
Holland, W.L.; Summers, S.A. Sphingolipids, insulin resistance, and metabolic disease: New insights from in vivo manipulation of sphingolipid metabolism. Endocr. Rev., 2008, 29, 381-402.
[10]
Apostolopoulou, M.; Gordillo, R.; Koliaki, C.; Gancheva, S.; Jelenik, T.; De Filippo, E.; Herder, C.; Markgraf, D.; Jankowiak, F.; Esposito, I.; Schlensak, M.; Scherer, P.E.; Roden, M. Specific hepatic sphingolipids relate to insulin resistance, oxidative stress, and inflammation in nonalcoholic steato hepatitis. Diabetes Care, 2018, 41(6), 1235-1243.
[11]
Pagadala, M.; Kasumov, T.; McCullough, A.J.; Zein, N.N.; Kirwan, J.P. Role of ceramides in nonalcoholic fatty liver disease. Trends Endocrinol. Metab., 2012, 23(8), 365-371.
[12]
Lim, K.G.; Gray, A.I.; Anthony, N.G.; Mackay, S.P.; Pyne, S.; Pyne, N.J. Resveratrol and its oligomers: Modulation of sphingolipid metabolism and signaling in disease. Arch. Toxicol., 2014, 88, 2213-2232.
[13]
Konstantynowicz-Nowicka, K.; Harasim, E.; Baranowski, M.; Chabowski, A. New evidence for the role of ceramide in the development of hepatic insulin resistance. PLoS One, 2015, 10, e0116858.
[14]
Kimbrough, C.W.; Lakshmanan, J.; Matheson, P.J.; Woeste, M.; Gentile, A.; Benns, M.V.; Zhang, B.; Smith, J.W.; Harbrecht, B.G. Resveratrol decreases nitric oxide production by hepatocytes during inflammation. Surg. (United States), 2015, 158(4), 1095-1101.
[15]
Baranowski, M.; Zabielski, P.; Blachnio, A.; Gorski, J. Effect of exercise duration on ceramide metabolism in the rat heart. Acta Physiol., 2008, 192, 519-529.
[16]
Folch, J.; Lees, M.; Stanley, G.H.S. A simple method for the isolation and purification of total lipids from animal tissues. J. Biol. Chem., 1957, 226, 497-509.
[17]
van der Vusse, G.J.; Roemen, T.H.M.; Reneman, R.S. Assessment of fatty acids in dog left ventricular myocardium. Biochim. Biophys. Acta (BBA). Lipids Lipid Metab., 1980, 617, 347-352.
[18]
Mikłosz, A.; Łukaszuk, B.; Chabowski, A.; Rogowski, F.; Kurek, K.; Zendzian-Piotrowska, M. Hyperthyroidism evokes myocardial ceramide accumulation. Cell. Physiol. Biochem., 2015, 35, 755-766.
[19]
Pan, Q-R.; Ren, Y-L.; Liu, W-X.; Hu, Y-J.; Zheng, J-S.; Xu, Y.; Wang, G. 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., 2015, 35, 576-584.
[20]
Kitatani, K.; Idkowiak-Baldys, J.; Hannun, Y.A. The sphingolipid salvage pathway in ceramide metabolism and signaling. Cell. Signal., 2008, 20, 1010-1018.
[21]
Lipina, C.; Hundal, H.S. Sphingolipids: Agents provocateurs in the pathogenesis of insulin resistance. Diabetologia, 2011, 54, 1596-1607.
[22]
Glatz, J.F.C.; Luiken, J.J.F.P.; Bonen, A. Membrane fatty acid transporters as regulators of lipid metabolism: Implications for metabolic disease. Physiol. Rev., 2010, 90, 367-417.
[23]
Ehehalt, R.; Füllekrug, J.; Pohl, J.; Ring, A.; Herrmann, T.; Stremmel, W. Translocation of long chain fatty acids across the plasma membrane - Lipid rafts and fatty acid transport proteins. Mol. Cell. Biochem., 2006, 284, 135-140.
[24]
Sharonov, A.; Bandichhor, R.; Burgess, K.; Petrescu, A.D.; Schroeder, F.; Kier, A.B.; Hochstrasser, R.M. Lipid diffusion from single molecules of a labeled protein undergoing dynamic association with giant unilamellar vesicles and supported bilayers. Langmuir, 2008, 24, 844-850.
[25]
Watt, M.J.; Barnett, A.C.; Bruce, C.R.; Schenk, S.; Horowitz, J.F.; Hoy, A.J. Regulation of plasma ceramide levels with fatty acid oversupply: Evidence that the liver detects and secretes de novo synthesised ceramide. Diabetologia, 2012, 55, 2741-2746.
[26]
Perry, D.K.; Carton, J.; Shah, A.K.; Meredith, F.; Uhlinger, D.J.; Hannun, Y.A. Serine palmitoyltransferase regulates de novo ceramide generation during etoposide-induced apoptosis. J. Biol. Chem., 2000, 275, 9078-9084.
[27]
Ahn, E.H.; Schroeder, J.J. Sphingoid bases and ceramide induce apoptosis in HT-29 and HCT-116 human colon cancer cells. Exp. Biol. Med., (Maywood), 2002, 227, 345-353.
[28]
Scarlatti, F.; Sala, G.; Somenzi, G.; Signorelli, P.; Sacchi, N.; Ghidoni, R. Resveratrol induces growth inhibition and apoptosis in metastatic breast cancer cells via de novo ceramide signaling. FASEB J., 2003, 17, 2339-2341.
[29]
Lavieu, G.; Scarlatti, F.; Sala, G.; Carpentier, S.; Levade, T.; Ghidoni, R.; Botti, J.; Codogno, P. Regulation of autophagy by sphingosine kinase 1 and its role in cell survival during nutrient starvation. J. Biol. Chem., 2006, 281, 8518-8527.
[30]
Brizuela, L.; Dayon, A.; Doumerc, N.; Ader, I.; Golzio, M.; Izard, J.C.; Hara, Y.; Malavaud, B.; Cuvillier, O. The sphingosine kinase-1 survival pathway is a molecular target for the tumor-suppressive tea and wine polyphenols in prostate cancer. FASEB J., 2010, 24, 3882-3894.
[31]
Park, K.; Elias, P.M.; Hupe, M.; Borkowski, A.W.; Gallo, R.L.; Shin, K-O.; Lee, Y-M.; Holleran, W.M.; Uchida, Y. Resveratrol stimulates sphingosine-1-phosphate signaling of cathelicidin production. J. Invest. Dermatol., 2013, 133, 1942-1949.
[32]
Vethakanraj, H.S.; Babu, T.A.; Sudarsanan, G.B.; Duraisamy, P.K.; Kumar, A.S. Targeting ceramide metabolic pathway induces apoptosis in human breast cancer cell lines. Biochem. Biophys. Res. Commun., 2015, 464, 833-839.
[33]
Cheng, Y.; Tauschel, H.D.; Nilsson, A.; Duan, R.D. Ursodeoxycholic acid increases the activities of alkaline sphingomyelinase and caspase-3 in the rat colon. Scand. J. Gastroenterol., 1999, 34, 915-920.
[34]
Momchilova, A.; Petkova, D.; Staneva, G.; Markovska, T.; Pankov, R.; Skrobanska, R.; Nikolova-Karakashian, M.; Koumanov, K. Resveratrol alters the lipid composition, metabolism and peroxide level in senescent rat hepatocytes. Chem. Biol. Interact., 2014, 207, 74-80.
[35]
Xuan, L.; Shi, J.; Yao, C.; Bai, J.; Qu, F.; Zhang, J.; Hou, Q. Vam3, a resveratrol dimer, inhibits cigarette smoke-induced cell apoptosis in lungs by improving mitochondrial function. Acta Pharmacol. Sin., 2014, 35, 779-791.
[36]
Quazi, F.; Molday, R.S. Lipid transport by mammalian ABC proteins. Essays Biochem., 2011, 50, 265-290.
[37]
Berrougui, H.; Grenier, G.; Loued, S.; Drouin, G.; Khalil, A. A new insight into resveratrol as an atheroprotective compound: Inhibition of lipid peroxidation and enhancement of cholesterol efflux. Atherosclerosis, 2009, 207, 420-427.

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