Hesperidin and Myricetin Attenuated Non-Alcoholic Fatty Liver Disease (NAFLD) in HepG2 Cells
doi.org/10.26538/tjnpr/v4i10.14
Keywords:
Fenofibrate, SREBPs, PPARs, Palmitic acid, Oleic acid, FlavonoidsAbstract
Flavonoids are natural compounds that might have beneficial effects on non-alcoholic fatty liver disease (NAFLD). This study determined the efficacy of flavonoids in an NAFLD cell model. HepG2 cells were treated for 24 h with either 1 mM oleic acid (OA) or palmitic acid (PA) and 10 M of one of eleven flavonoids (4 flavones, 2 flavanones, and 5 flavonols) or fenofibrate. Cell morphology was examined by oil-red-O staining. Metabolic gene expression (PPAR α/γ, SREBP 1a/1c, ACC, ACOX, and FAS) was analyzed by RT/qPCR. All flavonoids and fenofibrate reduced intracellular lipid content. Hesperidin, myricetin, and all tested flavanones and flavonols prevented fatty acid-induced increases in metabolic gene expression but fenofibrate and some flavones did not suppress OA-induced FAS expression. Hesperidin and myricetin suppressed metabolic gene expression by more than fenofibrate indicating that they may provide potential pharmacological treatment options for regression of NAFLD status.
References
Bellentani S, Scaglioni F, Marino M, Bedogni G. Epidemiology of non-alcoholic fatty liver disease. Dig Dis. 2010; 28(1):155–161.
Van De Wier B, Koek GH, Bast A, Haenen GRMM. The potential of flavonoids in the treatment of non-alcoholic fatty liver disease. Crit Rev Food Sci Nutr. 2017; 57(4):834–855.
Oliveira AF, Cunha DA, Ladriere L, Igoillo-Esteve M, Bugliani M, Marchetti P, Cnop, M. In vitro use of free fatty acids bound to albumin: A comparison of protocols. Biotech. 2015; 58(5):228–233.
Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metab. 2016; 65(8):1038–1048.
Fernández-Miranda C, Perez-Carreras M, Colina F, LopezAlonso G, Vargas C, Solis-Herruzo JA. A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease. Dig Liv Dis. 2008; 40(3):200–205.
Kostapanos MS, Kei A, Elisaf MS. Current role of fenofibrate in the prevention and management of nonalcoholic fatty liver disease. World J Hepatol. 2013; 5(9):470-478.
Semwal DK, Semwal RB, Combrinck S, Viljoen A. Myricetin: A dietary molecule with diverse biological activities. Nutrients. 2016; 8(2):90.
Hajialyani M, Hosein Farzaei M, Echeverría J, Nabavi SM, Uriarte E, Sobarzo-Sánchez E. Hesperidin as a neuroprotective agent: a review of animal and clinical evidence. Mol. 2019; 24(3):648.
Vargas-Mendoza N, Madrigal-Santillán E, MoralesGonzález Á, Esquivel-Soto J, Esquivel-Chirino C, González-Rubio M, Gayosso-de-Lucio JA, MoralesGonzález JA. Hepatoprotective effect of silymarin. World J Hepatol. 2014; 6(3):144-149.
Leamy AK, Egnatchik RA, Young JD. Molecular mechanisms and the role of saturated fatty acids in the progression of non-alcoholic fatty liver disease. Prog Lipid Res. 2013; 52(1):165–174.
Sukkasem N, Chatuphonprasert W, Jarukamjorn K. Cytochrome P450 expression-associated multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD) in HepG2 cells. Trop J Pharm Res. 2020; 19(4):707–714.
Chatuphonprasert W, Kondo S, Jarukamjorn K, Kawasaki Y, Sakuma T, Nemoto N. Potent modification of inducible CYP1A1 expression by flavonoids. Biol Pharm Bull. 2010; 33(10):1698–1703.
Chatuphonprasert W, Nawaratt N, Jarukamjorn K. Reused palm oil from frying pork or potato induced expression of cytochrome P450s and the SLCO1B1 transporter in HepG2 cells. J Food Biochem. 2020; 44:e13178.
Karasawa T, Takahashi A, Saito R, Sekiya M, Igarashi M, Iwasaki H, et al. Sterol regulatory element–binding protein- 1 determines plasma remnant lipoproteins and accelerates atherosclerosis in low-density lipoprotein receptor–deficient mice. Arterioscler Thromb Vasc Biol. 2011; 31(8):1788– 1795.
Illesca P, Valenzuela R, Espinosa A, Echeverría F, SotoAlarcon S, Ortiz M, Videla LA. Hydroxytyrosol supplementation ameliorates the metabolic disturbances in white adipose tissue from mice fed a high-fat diet through recovery of transcription factors Nrf2, SREBP-1c, PPAR-γ
and NF-κB. Biomed Pharmacother. 2019; 109:2472–2481.
Feng X, Yu W, Li X, Zhou F, Zhang W, Shen Q, Li J, Zhang C, Shen P. Apigenin, a modulator of PPARγ, attenuates HFD-induced NAFLD by regulating hepatocyte lipid metabolism and oxidative stress via Nrf2 activation. Biochem Pharmacol. 2017; 136:136–149.
Huang CS, Lii CK, Lin AH, Yeh YW, Yao HT, Li CC, Wang TS, Chen HW. Protection by chrysin, apigenin, and luteolin against oxidative stress is mediated by the Nrf2- dependent up-regulation of heme oxygenase 1 and glutamate cysteine ligase in rat primary hepatocytes. Arch
Toxicol. 2013; 87(1):167–178.
Zhang R, Chu K, Zhao N, Wu J, Ma L, Zhu C, Chen X, Wei G, Liao M. Corilagin alleviates nonalcoholic fatty liver disease in high-fat diet-induced C57BL/6 mice by ameliorating oxidative stress and restoring autophagic flux. Front Pharmacol. 2019; 10:1693.
Xia SF, Le GW, Wang P, Qiu YY, Jiang YY, Tang X. Regressive effect of myricetin on hepatic steatosis in mice fed a high-fat diet. Nutrients. 2016; 8(12):799.
Agrawal YO, Sharma PK, Shrivastava B, Ojha S, Upadhya HM, Arya DS, Goyal SN. Hesperidin produces cardioprotective activity via PPAR-γ pathway in ischemic heart disease model in diabetic rats. PLoS One. 2014; 9(11):e111212.
Mosqueda-Solís A, Sánchez J, Reynés B, Palou M, Portillo MP, Palou A, Picó C. Hesperidin and capsaicin, but not the combination, prevent hepatic steatosis and other metabolic syndrome-related alterations in western diet-fed rats. Sci Rep. 2018; 8(1):1–14.
Moslehi A and Hamidi-zad Z. Role of SREBPs in liver diseases: a mini-review. J Clin Transl Hepatol. 2018; 6(3):332.
Sadler NC, Webb-Robertson BJM, Clauss TR, Pounds JG, Corley R, Wright AT. High-fat diets alter the modulatory effects of xenobiotics on cytochrome P450 activities. Chem Res Toxicol. 2018; 31(5):308–318.
Palomer X, Pizarro-Delgado J, Barroso E, Vázquez-Carrera M. Palmitic and Oleic Acid: The Yin and Yang of Fatty Acids in Type 2 Diabetes Mellitus. Trends Endocrinol Metab. 2018; 29(3):178–190.
Choi YS, Lee JK, Jung JT, Jung YC, Jung JH, Jung MO, Choi YI, Jin SK, Choi JS. Comparison of meat quality and fatty acid composition of longissimus muscles from purebred pigs and three-way crossbred LYD pigs. Korean J Food Sci Anim Resour. 2016; 36(5):689.
Fattore E and Fanelli R. Palm oil and palmitic acid: a review on cardiovascular effects and carcinogenicity. Int J Food Sci Nutr. 2013; 64(5):648–659.
Kanuri G, Landmann M, Priebs J, Spruss A, Löscher M, Ziegenhardt D, Röhl C, Degen C, Bergheim I. Moderate alcohol consumption diminishes the development of nonalcoholic fatty liver disease (NAFLD) in ob/ob mice. Eur J Nutr. 2016; 55(3):1153–1164.
Zeng X, Zhu M, Liu X, Chen X, Yuan Y, Li L, Jingping Liu J, Lu Y, Cheng J, Chen Y. Oleic acid ameliorates palmitic acid induced hepatocellular lipotoxicity by inhibition of ER stress and pyroptosis. Nutr Metab (Lond). 2020; 17(1):11.
Rafiei H, Omidian K, Bandy B. Dietary polyphenols protect against oleic acid-induced steatosis in an in vitro model of nafld by modulating lipid metabolism and improving mitochondrial function. Nutrients. 2019; 11(3):541.
Chen X, Li L, Liu X, Luo R, Liao G, Li L, Liu J, Cheng J, Lu Y, Chen Y. Oleic acid protects saturated fatty acid mediated lipotoxicity in hepatocytes and rat of nonalcoholic steatohepatitis. Life Sci. 2018; 203:291–304.
Michalopoulos GK and Khan Z. Liver regeneration, growth factors, and amphiregulin. Gastroenterol. 2005; 128(2):503.
Kholodenko IV and Yarygin KN. Cellular mechanisms of liver regeneration and cell-based therapies of liver diseases. Biomed Res Int. 2017; 2017: 8910821.
Kountouras J, Boura P, Lygidakis NJ. Liver regeneration after hepatectomy. Hepatogastroenterology. 2001; 48(38):556–562.
Liu Q, Pan R, Ding L, Zhang F, Hu L, Ding B, Zhu L, Xia Y, Dou X. Rutin exhibits hepatoprotective effects in a mouse model of non-alcoholic fatty liver disease by reducing hepatic lipid levels and mitigating lipid-induced oxidative injuries. Int Immunopharmacol. 2017; 49:132–
Morin B, Nichols LA, Zalasky KM, Davis JW, Manthey JA, Holland LJ. 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.
Avior Y, Bomze D, Ramon O, Nahmias Y. Flavonoids as dietary regulators of nuclear receptor activity. Food Funct. 2013; 4(6):831–844.
Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JMA, Shimomura I, Shan B, Brown MS, Goldstein JL, Mangelsdorf DJ. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ. Genes Dev. 2000; 14(22):2819–2830.
Published
How to Cite
Issue
Section
License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
