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Current Bioactive Compounds

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ISSN (Print): 1573-4072
ISSN (Online): 1875-6646

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Research Article

Effects of Polymethoxylated Flavone Metabolites on ApoB100 Secretion and MTP Activity in Huh7.5 Cells

Author(s): Danielle R. Gonçalves, Thais B. Cesar*, John A. Manthey and Paulo I. Costa

Volume 18, Issue 6, 2022

Published on: 24 February, 2022

Article ID: e301221199681 Pages: 10

DOI: 10.2174/1573407218666211230140952

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Abstract

Background: Citrus polymethoxylated flavones (PMFs) reduce the synthesis of liver lipoproteins in animal and in vitro cell assays, but few studies have evaluated the direct effects of their metabolites on this highly regulated process.

Objective: The aim of the study was to investigate the effects of representative metabolites of PMF on the secretion of liver lipoproteins using the mammalian cell Huh7.5.

Methods: In this study, the influences of three PMFs and five previously isolated PMF metabolites on hepatic apoB-100 secretion and microsomal transfer protein (MTP) activity were evaluated. Tangeretin (TAN), nobiletin (NOB) and 3,5,6,7,8,3′,4′-heptamethoxyflavone (HMF), their glucuronides (TAN-Gluc, NOB-Gluc and HMF-Gluc) and oxidatively demethylated metabolites (TAN-OH, NOB-OH, HMF-OH), were incubated with Huh7.5 cells to measure their inhibitory effects on lipid synthesis.

Results: The results showed that TAN, HMF and TAN-OH reduced the secretion of apoB-100 in a dose-dependent manner, while NOB and the other tested metabolites showed no inhibition. MTP activity in the Huh7.5 cells was significantly reduced in the presence of low concentrations of TAN and high concentrations of NOB-OH. This study also showed that PMFs and PMF metabolites produced a wide range of effects on apoB-100 secretion and MTP activity.

Conclusion: The results suggest that while PMFs and their metabolites control dyslipidemia in vivo, the inhibition of MTP activity cannot be the only pathway influenced by these compounds.

Keywords: Hepatic lipids, tangeretin, nobiletin, heptamethoxyflavone, glucuronide PMF metabolites, demethylated PMF metabolites.

Graphical Abstract

[1]
Mahmoud, A.M.; Hernández Bautista, R.J.; Sandhu, M.A.; Hussein, O.E. Beneficial effects of citrus flavonoids on cardiovascular and metabolic health. Oxid. Med. Cell. Longev., 2019, 2019, 5484138.
[http://dx.doi.org/10.1155/2019/5484138] [PMID: 30962863]
[2]
Mulvihill, E.E.; Burke, A.C.; Huff, M.W. Citrus flavonoids as regulators of lipoprotein metabolism and atherosclerosis. Annu. Rev. Nutr., 2016, 36, 275-299.
[http://dx.doi.org/10.1146/annurev-nutr-071715-050718] [PMID: 27146015]
[3]
Testai, L.; Calderone, V. Nutraceutical value of citrus flavanones and their implications in cardiovascular disease. Nutrients, 2017, 9(5), 502.
[http://dx.doi.org/10.3390/nu9050502] [PMID: 28509871]
[4]
Pla-Pagà, L.; Companys, J.; Calderón-Pérez, L.; Llauradó, E.; Solà, R.; Valls, R.M.; Pedret, A. Effects of hesperidin consumption on cardiovascular risk biomarkers: A systematic review of animal studies and human randomized clinical trials. Nutr. Rev., 2019, 77(12), 845-864.
[http://dx.doi.org/10.1093/nutrit/nuz036] [PMID: 31271436]
[5]
Ramasamy, I. Recent advances in physiological lipoprotein metabolism. Clin. Chem. Lab. Med., 2014, 52(12), 1695-1727.
[http://dx.doi.org/10.1515/cclm-2013-0358] [PMID: 23940067]
[6]
Abd alamir, M.; Goyfman, M.; Chaus, A.; Dabbous, F.; Tamura, L.; Sandfort, V. The correlation of dyslipidemia with the extent of coronary artery disease in the multiethnic study of atherosclerosis. J Lipids, 2018, 2018, 1-9.
[http://dx.doi.org/10.1155/2018/5607349]
[7]
Li, S.; Lo, C.Y.; Ho, C.T. Hydroxylated polymethoxyflavones and methylated flavonoids in sweet orange (Citrus sinensis) peel. J. Agric. Food Chem., 2006, 54(12), 4176-4185.
[http://dx.doi.org/10.1021/jf060234n] [PMID: 16756344]
[8]
Tung, Y.C.; Chang, W.T.; Li, S.; Wu, J.C.; Badmeav, V.; Ho, C.T.; Pan, M.H. Citrus peel extracts attenuated obesity and modulated gut microbiota in mice with high-fat diet-induced obesity. Food Funct., 2018, 9(6), 3363-3373.
[http://dx.doi.org/10.1039/C7FO02066J] [PMID: 29855643]
[9]
Kou, M.C.; Fu, S.H.; Yen, J.H.; Weng, C.Y.; Li, S.; Ho, C.T.; Wu, M.J. Effects of citrus flavonoids, 5-hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone and 3,5,6,7,8,3′,4′-heptamethoxyflavone, on the activities of macrophage scavenger receptors and the hepatic LDL receptor. Food Funct., 2013, 4(4), 602-609.
[http://dx.doi.org/10.1039/c3fo30301b] [PMID: 23370792]
[10]
Kurowska, E.M.; Manthey, J.A. Hypolipidemic effects and absorption of citrus polymethoxylated flavones in hamsters with diet-induced hypercholesterolemia. J. Agric. Food Chem., 2004, 52(10), 2879-2886.
[http://dx.doi.org/10.1021/jf035354z] [PMID: 15137829]
[11]
Whitman, S.C.; Kurowska, E.M.; Manthey, J.A.; Daugherty, A. Nobiletin, a citrus flavonoid isolated from tangerines, selectively inhibits class A scavenger receptor-mediated metabolism of acetylated LDL by mouse macrophages. Atherosclerosis, 2005, 178(1), 25-32.
[http://dx.doi.org/10.1016/j.atherosclerosis.2004.07.034] [PMID: 15585197]
[12]
Lei, L.; Li, Y.M.; Wang, X.; Liu, Y.; Ma, K.Y.; Wang, L. Plasma triacylglycerol-lowering activity of citrus polymethoxylated flavones is mediated by modulating the genes involved in lipid metabolism in hamsters. Eur. J. Lipid Sci. Technol., 2016, 118, 147-156.
[http://dx.doi.org/10.1002/ejlt.201500060]
[13]
Morin, B.; Nichols, L.A.; Zalasky, K.M.; Davis, J.W.; Manthey, J.A.; Holland, L.J. The citrus flavonoids hesperetin and nobiletin differentially regulate low density lipoprotein receptor gene transcription in HepG2 liver cells. J. Nutr., 2008, 138(7), 1274-1281.
[http://dx.doi.org/10.1093/jn/138.7.1274] [PMID: 18567747]
[14]
Mulvihill, E.E.; Assini, J.M.; Lee, J.K.; Allister, E.M.; Sutherland, B.G.; Koppes, J.B.; Sawyez, C.G.; Edwards, J.Y.; Telford, D.E.; Charbonneau, A.; St-Pierre, P.; Marette, A.; Huff, M.W. Nobiletin attenuates VLDL overproduction, dyslipidemia, and atherosclerosis in mice with diet-induced insulin resistance. Diabetes, 2011, 60(5), 1446-1457.
[http://dx.doi.org/10.2337/db10-0589] [PMID: 21471511]
[15]
Silberberg, M.; Morand, C.; Mathevon, T.; Besson, C.; Manach, C.; Scalbert, A.; Remesy, C. The bioavailability of polyphenols is highly governed by the capacity of the intestine and of the liver to secrete conjugated metabolites. Eur. J. Nutr., 2006, 45(2), 88-96.
[http://dx.doi.org/10.1007/s00394-005-0568-5] [PMID: 15981077]
[16]
Brand, W.; Boersma, M.G.; Bik, H.; Hoek-van den Hil, E.F.; Vervoort, J.; Barron, D.; Meinl, W.; Glatt, H.; Williamson, G.; van Bladeren, P.J.; Rietjens, I.M. Phase II metabolism of hesperetin by individual UDP-glucuronosyltransferases and sulfotransferases and rat and human tissue samples. Drug Metab. Dispos., 2010, 38(4), 617-625.
[http://dx.doi.org/10.1124/dmd.109.031047] [PMID: 20056724]
[17]
Zeka, K.; Ruparelia, K.; Arroo, R.R.J.; Budriesi, R.; Micucci, M. Flavonoids and their metabolites: Prevention in cardiovascular diseases and diabetes. Diseases, 2017, 5(3), 19.
[http://dx.doi.org/10.3390/diseases5030019] [PMID: 32962323]
[18]
Manthey, J.A.; Cesar, T.B.; Jackson, E.; Mertens-Talcott, S. Pharmacokinetic study of nobiletin and tangeretin in rat serum by high-performance liquid chromatography-electrospray ionization-mass spectrometry. J. Agric. Food Chem., 2011, 59(1), 145-151.
[http://dx.doi.org/10.1021/jf1033224] [PMID: 21133365]
[19]
Hung, W.L.; Chang, W.S.; Lu, W.C.; Wei, G.J.; Wang, Y.; Ho, C.T.; Hwang, L.S. Pharmacokinetics, bioavailability, tissue distribution and excretion of tangeretin in rat. J. Food Drug Anal., 2018, 26(2), 849-857.
[http://dx.doi.org/10.1016/j.jfda.2017.08.003] [PMID: 29567257]
[20]
Lo, Y.H.; Pan, M.H.; Li, S.; Yen, J.H.; Kou, M.C.; Ho, C.T.; Wu, M.J. Nobiletin metabolite, 3′,4′-dihydroxy-5,6,7,8-tetramethoxyflavone, inhibits LDL oxidation and down-regulates scavenger receptor expression and activity in THP-1 cells. Biochim. Biophys. Acta, 2010, 1801(2), 114-126.
[http://dx.doi.org/10.1016/j.bbalip.2009.10.002] [PMID: 19833227]
[21]
Gonçalves, D.R.; Manthey, J.A.; da Costa, P.I.; Rodrigues, M.C.M.; Cesar, T.B. Analysis of fluorescence spectra of citrus polymethoxylated flavones and their incorporation into mammalian cells. J. Agric. Food Chem., 2018, 66(28), 7531-7541.
[http://dx.doi.org/10.1021/acs.jafc.8b02052] [PMID: 29984997]
[22]
Ferrari, M.; Fornasiero, M.C.; Isetta, A.M. MTT colorimetric assay for testing macrophage cytotoxic activity in vitro. J. Immunol. Methods, 1990, 131(2), 165-172.
[http://dx.doi.org/10.1016/0022-1759(90)90187-Z] [PMID: 2391427]
[23]
Nahmias, Y.; Goldwasser, J.; Casali, M.; van Poll, D.; Wakita, T.; Chung, R.T.; Yarmush, M.L. Apolipoprotein B-dependent hepatitis C virus secretion is inhibited by the grapefruit flavonoid naringenin. Hepatology, 2008, 47(5), 1437-1445.
[http://dx.doi.org/10.1002/hep.22197] [PMID: 18393287]
[24]
Bradford, M.M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem., 1976, 72, 248-254.
[http://dx.doi.org/10.1016/0003-2697(76)90527-3] [PMID: 942051]
[25]
Al Rahim, M.; Nakajima, A.; Saigusa, D.; Tetsu, N.; Maruyama, Y.; Shibuya, M.; Yamakoshi, H.; Tomioka, Y.; Iwabuchi, Y.; Ohizumi, Y.; Yamakuni, T. 4′-Demethylnobiletin, a bioactive metabolite of nobiletin enhancing PKA/ERK/CREB signaling, rescues learning impairment associated with NMDA receptor antagonism via stimulation of the ERK cascade. Biochemistry, 2009, 48(32), 7713-7721.
[http://dx.doi.org/10.1021/bi901088w] [PMID: 19601643]
[26]
Su, J.D.; Yen, J.H.; Li, S.; Weng, C.Y.; Lin, M.H.; Ho, C.T.; Wu, M.J. 3′,4′-didemethylnobiletin induces phase II detoxification gene expression and modulates PI3K/Akt signaling in PC12 cells. Free Radic. Biol. Med., 2012, 52(1), 126-141.
[http://dx.doi.org/10.1016/j.freeradbiomed.2011.10.002] [PMID: 22064360]
[27]
Cheng, Z.; Surichan, S.; Ruparelia, K.; Arroo, R.; Boarder, M.R. Tangeretin and its metabolite 4′-hydroxytetramethoxyflavone attenuate EGF-stimulated cell cycle progression in hepatocytes; role of inhibition at the level of mTOR/p70S6K. Br. J. Pharmacol., 2011, 162(8), 1781-1791.
[http://dx.doi.org/10.1111/j.1476-5381.2010.01185.x] [PMID: 21198542]
[28]
Wu, X.; Song, M.; Wang, M.; Zheng, J.; Gao, Z.; Xu, F.; Zhang, G.; Xiao, H. Chemopreventive effects of nobiletin and its colonic metabolites on colon carcinogenesis. Mol. Nutr. Food Res., 2015, 59(12), 2383-2394.
[http://dx.doi.org/10.1002/mnfr.201500378] [PMID: 26445322]
[29]
Mulvihill, E.E.; Allister, E.M.; Sutherland, B.G.; Telford, D.E.; Sawyez, C.G.; Edwards, J.Y.; Markle, J.M.; Hegele, R.A.; Huff, M.W. Naringenin prevents dyslipidemia, apolipoprotein B overproduction, and hyperinsulinemia in LDL receptor-null mice with diet-induced insulin resistance. Diabetes, 2009, 58(10), 2198-2210.
[http://dx.doi.org/10.2337/db09-0634] [PMID: 19592617]
[30]
Wilcox, L.J.; Borradaile, N.M.; de Dreu, L.E.; Huff, M.W. Secretion of hepatocyte apoB is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of ACAT2 and MTP. J. Lipid Res., 2001, 42(5), 725-734.
[http://dx.doi.org/10.1016/S0022-2275(20)31634-5] [PMID: 11352979]
[31]
Kurowska, E.M.; Manthey, J.A.; Casaschi, A.; Theriault, A.G. Modulation of HepG2 cell net apolipoprotein B secretion by the citrus polymethoxyflavone, tangeretin. Lipids, 2004, 39(2), 143-151.
[http://dx.doi.org/10.1007/s11745-004-1212-8] [PMID: 15134141]
[32]
Lin, Y.; Vermeer, M.A.; Bos, W.; van Buren, L.; Schuurbiers, E.; Miret-Catalan, S.; Trautwein, E.A. Molecular structures of citrus flavonoids determine their effects on lipid metabolism in HepG2 cells by primarily suppressing apoB secretion. J. Agric. Food Chem., 2011, 59(9), 4496-4503.
[http://dx.doi.org/10.1021/jf1044475] [PMID: 21425871]
[33]
Walle, T. Methoxylated flavones, a superior cancer chemopreventive flavonoid subclass? Semin. Cancer Biol., 2007, 17(5), 354-362.
[http://dx.doi.org/10.1016/j.semcancer.2007.05.002] [PMID: 17574860]
[34]
Proteggente, A.R.; Basu-Modak, S.; Kuhnle, G.; Gordon, M.J.; Youdim, K.; Tyrrell, R.; Rice-Evans, C.A. Hesperetin glucuronide, a photoprotective agent arising from flavonoid metabolism in human skin fibroblasts. Photochem. Photobiol., 2003, 78(3), 256-261.
[http://dx.doi.org/10.1562/0031-8655(2003)078<0256:HGAPAA>2.0.CO;2] [PMID: 14556312]
[35]
Shah, A.; Rader, D.J.; Millar, J.S. The effect of PPAR-α agonism on apolipoprotein metabolism in humans. Atherosclerosis, 2010, 210(1), 35-40.
[http://dx.doi.org/10.1016/j.atherosclerosis.2009.11.010] [PMID: 20005515]
[36]
Allister, E.M.; Borradaile, N.M.; Edwards, J.Y.; Huff, M.W. Inhibition of microsomal triglyceride transfer protein expression and apolipoprotein B100 secretion by the citrus flavonoid naringenin and by insulin involves activation of the mitogen-activated protein kinase pathway in hepatocytes. Diabetes, 2005, 54(6), 1676-1683.
[http://dx.doi.org/10.2337/diabetes.54.6.1676] [PMID: 15919788]
[37]
Hussain, M.M.; Nijstad, N.; Franceschini, L. Regulation of microsomal triglyceride transfer protein. Clin. Lipidol., 2011, 6(3), 293-303.
[http://dx.doi.org/10.2217/clp.11.21] [PMID: 21808658]
[38]
Sato, R.; Miyamoto, W.; Inoue, J.; Terada, T.; Imanaka, T.; Maeda, M. Sterol regulatory element-binding protein negatively regulates microsomal triglyceride transfer protein gene transcription. J. Biol. Chem., 1999, 274(35), 24714-24720.
[http://dx.doi.org/10.1074/jbc.274.35.24714] [PMID: 10455139]
[39]
Améen, C.; Edvardsson, U.; Ljungberg, A.; Asp, L.; Åkerblad, P.; Tuneld, A.; Olofsson, S.O.; Lindén, D.; Oscarsson, J. Activation of peroxisome proliferator-activated receptor α increases the expression and activity of microsomal triglyceride transfer protein in the liver. J. Biol. Chem., 2005, 280(2), 1224-1229.
[http://dx.doi.org/10.1074/jbc.M412107200] [PMID: 15537571]
[40]
Kersten, S. Peroxisome proliferator activated receptors and lipoprotein metabolism. PPAR Res., 2008, 2008, 132960.
[http://dx.doi.org/10.1155/2008/132960] [PMID: 18288277]
[41]
Kraft, H.G.; Demosky, S.J., Jr; Schumacher, K.; Brewer, H.B., Jr; Hoeg, J.M. Regulation of LDL receptor, apoB, and apoE protein and mRNA in Hep G2 cells. DNA Cell Biol., 1992, 11(4), 291-300.
[http://dx.doi.org/10.1089/dna.1992.11.291] [PMID: 1605852]
[42]
Kim, Y.J.; Choi, M.S.; Woo, J.T.; Jeong, M.J.; Kim, S.R.; Jung, U.J. Long-term dietary supplementation with low-dose nobiletin ameliorates hepatic steatosis, insulin resistance, and inflammation without altering fat mass in diet-induced obesity. Mol. Nutr. Food Res., 2017, 61(8), 1-41.
[http://dx.doi.org/10.1002/mnfr.201600889] [PMID: 28116779]
[43]
Alam, M.A.; Kauter, K.; Brown, L. Naringin improves diet-induced cardiovascular dysfunction and obesity in high carbohydrate, high fat diet-fed rats. Nutrients, 2013, 5(3), 637-650.
[http://dx.doi.org/10.3390/nu5030637] [PMID: 23446977]
[44]
Assini, J.M.; Mulvihill, E.E.; Huff, M.W. Citrus flavonoids and lipid metabolism. Curr. Opin. Lipidol., 2013, 24(1), 34-40.
[http://dx.doi.org/10.1097/MOL.0b013e32835c07fd] [PMID: 23254473]
[45]
Ahmed, A.A.; Adam Essa, M.E.; Mollica, A.; Stefanucci, A.; Zengin, G.; Ahmed, H. Gum Arabic modifies anti-inflammatory cytokine in mice fed with high fat diet induced obesity. Bioactive Carbohydrates and Dietary Fibre, 2020, 25, 1-35.
[http://dx.doi.org/10.1016/j.bcdf.2020.100258]

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