Generic placeholder image

The Natural Products Journal

Editor-in-Chief

ISSN (Print): 2210-3155
ISSN (Online): 2210-3163

Letter Article

Naringenin Ameliorates Palmitic Acid-induced Fatty Acid Stress in Hepatocytes

Author(s): Subhajit Maity, Partha Chakrabarti and Abhay Sankar Chakraborti*

Volume 12, Issue 4, 2022

Published on: 07 January, 2022

Article ID: e070122190570 Pages: 7

DOI: 10.2174/2210315511666210121154928

Price: $65

Abstract

Type 2 diabetes is strongly associated with the development of insulin resistance in metabolically active tissues. Non-alcoholic fatty liver disease (NAFLD) is considered to be a manifestation of hepatic insulin resistance. Saturated fatty acids such as palmitic acid (PA) induce insulin resistance, which may be studied for therapeutic prevention by herbal agents. In the present study, the role of naringenin, a bioflavonoid, is examined in PA-induced cytotoxicity in human hepatocellular carcinoma (HepG2) cells. PA causes significant inflammation and apoptosis in these cells primarily by inhibiting phosphorylation of Akt at serine 473 residue. Apoptosis assay, mitochondrial transmembrane potential measurement and immunoblotting for protein expressions have been used for demonstrating PA-induced abnormalities. Naringenin treatment effectively inhibits the fatty acid-induced inflammation and cytotoxicity, along with improvement of insulin signalling. Naringenin has a potential to prevent the fatty acid-induced stresses in hepatocytes, and may be beneficial for improving hepatic insulin sensitivity and mitigating lipotoxicity.

Keywords: Naringenin, palmitic acid, insulin resistance, hepatocytes, inflammation, apoptosis.

Graphical Abstract

[1]
Zhang, Q.; Kong, X.; Yuan, H.; Guan, H.; Li, Y.; Niu, Y. Mangiferin improved palmitate-induced-insulin resistance by promoting free fatty acid metabolism in HepG2 and C2C12 Cells via PPARα: Mangiferin improved insulin resistance. J Diab Res, 2019, 10, 1-13.
[http://dx.doi.org/10.1155/2019/2052675]
[2]
Huang, T.D.; Behary, J.; Zekry, A. Non-alcoholic fatty liver disease: a review of epidemiology, risk factors, diagnosis and management. Intern. Med. J., 2020, 50(9), 1038-1047.
[http://dx.doi.org/10.1111/imj.14709] [PMID: 31760676]
[3]
Song, Z.; Song, M.; Lee, D.Y.W.; Liu, Y.; Deaciuc, I.V.; McClain, C.J. Silymarin prevents palmitate-induced lipotoxicity in HepG2 cells: Involvement of maintenance of Akt kinase activation. Basic Clin. Pharmacol. Toxicol., 2007, 101(4), 262-268.
[http://dx.doi.org/10.1111/j.1742-7843.2007.00116.x] [PMID: 17845508]
[4]
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, 2013, 27(2), 945-953.
[http://dx.doi.org/10.1016/j.tiv.2013.01.014] [PMID: 23348005]
[5]
Annadurai, T.; Muralidharan, A.R.; Joseph, T.; Hsu, M.J.; Thomas, P.A.; Geraldine, P. Antihyperglycemic and antioxidant effects of a flavanone, naringenin, in streptozotocin-nicotinamide-induced experimental diabetic rats. J. Physiol. Biochem., 2012, 68(3), 307-318.
[http://dx.doi.org/10.1007/s13105-011-0142-y] [PMID: 22234849]
[6]
Maity, S.; Chakraborti, A.S. Formulation, physico-chemical characterization and antidiabetic potential of naringenin-loaded poly D, L lactide-co-glycolide (N-PLGA) nanoparticles. Eur. Polym. J., 2020, 134, 109818-109828.
[http://dx.doi.org/10.1016/j.eurpolymj.2020.109818]
[7]
Maity, S.; Chakraborty, S.; Chakraborti, A.S. Critical insight into the interaction of naringenin with human haemoglobin: A combined spectroscopic and computational modelling approaches. J. Mol. Struct., 2017, 112, 9256-9262.
[http://dx.doi.org/10.1016/j.molstruc.2016.09.085]
[8]
Maity, S.; Mukhopadhyay, P.; Kundu, P.P.; Chakraborti, A.S. Alginate coated chitosan core-shell nanoparticles for efficient oral delivery of naringenin in diabetic animals-An in vitro and in vivo approach. Carbohydr. Polym., 2017, 170, 124-132.
[http://dx.doi.org/10.1016/j.carbpol.2017.04.066] [PMID: 28521977]
[9]
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]
[10]
Allister, E.M.; Mulvihill, E.E.; Barrett, P.H.; Edwards, J.Y.; Carter, L.P.; Huff, M.W. Inhibition of apoB secretion from HepG2 cells by insulin is amplified by naringenin, independent of the insulin receptor. J. Lipid Res., 2008, 49(10), 2218-2229.
[http://dx.doi.org/10.1194/jlr.M800297-JLR200] [PMID: 18587069]
[11]
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.
[PMID: 11352979]
[12]
Borradaile, N.M.; de Dreu, L.E.; Huff, M.W. Inhibition of net HepG2 cell apolipoprotein B secretion by the citrus flavonoid naringenin involves activation of phosphatidylinositol 3-kinase, independent of insulin receptor substrate-1 phosphorylation. Diabetes, 2003, 52(10), 2554-2561.
[http://dx.doi.org/10.2337/diabetes.52.10.2554] [PMID: 14514640]
[13]
Wang, H.; Chan, P.K.; Pan, S.Y.; Kwon, K.H.; Ye, Y.; Chu, J.H.; Fong, W.F.; Tsui, W.M.; Yu, Z.L. ERp57 is up-regulated in free fatty acids-induced steatotic L-02 cells and human nonalcoholic fatty livers. J. Cell. Biochem., 2010, 110(6), 1447-1456.
[http://dx.doi.org/10.1002/jcb.22696] [PMID: 20506389]
[14]
Lee, Y.A.; Cho, E.J.; Yokozawa, T. Effects of proanthocyanidin preparations on hyperlipidemia and other biomarkers in mouse model of type 2 diabetes. J. Agric. Food Chem., 2008, 56(17), 7781-7789.
[http://dx.doi.org/10.1021/jf800639m] [PMID: 18690694]
[15]
Baldwin, A.S., Jr The NF-κ B and I κ B proteins: New discoveries and insights. Annu. Rev. Immunol., 1996, 14, 649-683.
[http://dx.doi.org/10.1146/annurev.immunol.14.1.649] [PMID: 8717528]
[16]
Cossarizza, A.; Baccarani-Contri, M.; Kalashnikova, G.; Franceschi, C. A new method for the cytofluorimetric analysis of mitochondrial membrane potential using the J-aggregate forming lipophilic cation 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolcarbocyanine iodide (JC-1). Biochem. Biophys. Res. Commun., 1993, 197(1), 40-45.
[http://dx.doi.org/10.1006/bbrc.1993.2438] [PMID: 8250945]
[17]
Virkamäki, A.; Ueki, K.; Kahn, C.R. Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J. Clin. Invest., 1999, 103(7), 931-943.
[http://dx.doi.org/10.1172/JCI6609] [PMID: 10194465]
[18]
Gonzalez, E.; McGraw, T.E. Insulin-modulated Akt subcellular localization determines Akt isoform-specific signaling. Proc. Natl. Acad. Sci. USA, 2009, 106(17), 7004-7009.
[http://dx.doi.org/10.1073/pnas.0901933106] [PMID: 19372382]
[19]
Li, M.; Zhang, Y.; Cao, Y.; Zhang, D.; Liu, L.; Guo, Y.; Wang, C. Icariin ameliorates palmitate-induced insulin resistance through reducing thioredoxin-interacting protein (TXNIP) and suppressing ER stress in C2C12 myotubes. Front. Pharmacol., 2018, 9, 1180.
[http://dx.doi.org/10.3389/fphar.2018.01180] [PMID: 30459603]
[20]
Vlavcheski, F.; Tsiani, E. Attenuation of free fatty acid-induced muscle insulin resistance by Rosemary extract. Nutrients, 2018, 10(11), 1-16.
[http://dx.doi.org/10.3390/nu10111623] [PMID: 30400151]
[21]
Wilcox, L.J.; Borradaile, N.M.; Huff, M.W. Antiatherogenic properties of naringenin, a citrus flavonoid. Cardiovasc. Drug Rev., 1999, 17, 160-178.
[http://dx.doi.org/10.1111/j.1527-3466.1999.tb00011.x]
[22]
Anhê, G.F.; Okamoto, M.M.; Kinote, A.; Sollon, C.; Lellis-Santos, C.; Anhê, F.F.; Lima, G.A.; Hirabara, S.M.; Velloso, L.A.; Bordin, S.; Machado, U.F. Quercetin decreases inflammatory response and increases insulin action in skeletal muscle of ob/ob mice and in L6 myotubes. Eur. J. Pharmacol., 2012, 689(1-3), 285-293.
[http://dx.doi.org/10.1016/j.ejphar.2012.06.007] [PMID: 22713545]
[23]
Li, H.B.; Yang, Y.R.Y.; Mo, Z.J.; Ding, Y.; Jiang, W.J. Silibinin improves palmitate-induced insulin resistance in C2C12 myotubes by attenuating IRS-1/PI3K/Akt pathway inhibition. Braz. J. Med. Biol. Res., 2015, 48(5), 440-446.
[http://dx.doi.org/10.1590/1414-431x20144238] [PMID: 25760026]
[24]
Boden, G.; She, P.; Mozzoli, M.; Cheung, P.; Gumireddy, K.; Reddy, P.; Xiang, X.; Luo, Z.; Ruderman, N. Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-kappaB pathway in rat liver. Diabetes, 2005, 54(12), 3458-3465.
[http://dx.doi.org/10.2337/diabetes.54.12.3458] [PMID: 16306362]
[25]
Baldwin, A.S. The transcription factor NF-kB and human disease. J. Clin. Invest., 2001, 107, 3-6.
[http://dx.doi.org/10.1172/JCI11891] [PMID: 11134170]
[26]
Hotamisligil, G.S. Role of endoplasmic reticulum stress and c-Jun NH2-terminal kinase pathways in inflammation and origin of obesity and diabetes. Diabetes, 2005, 54(Suppl. 2), S73-S78.
[http://dx.doi.org/10.2337/diabetes.54.suppl_2.S73] [PMID: 16306344]
[27]
Choi, Y.J.; Choi, S.E.; Ha, E.S.; Kang, Y.; Han, S.J.; Kim, D.J.; Lee, K.W.; Kim, H.J. Involvement of visfatin in palmitate-induced upregulation of inflammatory cytokines in hepatocytes. Metabolism, 2011, 60(12), 1781-1789.
[http://dx.doi.org/10.1016/j.metabol.2011.05.003] [PMID: 21664630]
[28]
Yan, C.; Sun, W.; Wang, X.; Long, J.; Liu, X.; Feng, Z.; Liu, J. Punicalagin attenuates palmitate-induced lipotoxicity in HepG2 cells by activating the Keap1-Nrf2 antioxidant defense system. Mol. Nutr. Food Res., 2016, 60(5), 1139-1149.
[http://dx.doi.org/10.1002/mnfr.201500490] [PMID: 26989875]
[29]
Yan, W.; Wang, Y.; Xiao, Y.; Wen, J.; Wu, J.; Du, L.; Cai, W. Palmitate induces TRB3 expression and promotes apoptosis in human liver cells. Cell. Physiol. Biochem., 2014, 33(3), 823-834.
[http://dx.doi.org/10.1159/000358655] [PMID: 24685558]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy