Volume 6, Issue 3 (July 2020)                   RABMS 2020, 6(3): 167-185 | Back to browse issues page

XML Persian Abstract Print

Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:

Karimi N, Ghadimi D, Fathi M. The Inhibitory Effect of Biochanin A on Hepatic Cholesterol Biosynthesis in High Glucose-Induced Steatosis in HepG2 Cells. RABMS. 2020; 6 (3) :167-185
URL: http://ijrabms.umsu.ac.ir/article-1-118-en.html
Biochemistry Department, School of Medicine, Zanjan University of Medical Sciences , d.ghadimi@zums.ac.ir
Abstract:   (915 Views)
Background & Aims:  Non-alcoholic fatty liver disease (NAFLD) results from fat accumulation in the liver (liver fat >5% of liver weight). The excess of lipids in hepatic steatosis primarily consists of triacylglycerol and cholesterol esters. De novo hepatic lipogenesis from excessive dietary carbohydrate intake is the most consistent underlying pathogenic agent of NAFLD. Hypercholesterolemia that mostly associates with NAFLD has been recognized as the most important risk factor for the development of coronary heart disease (CHD). In other words, reducing the hepatic cholesterol synthesis in NAFLD patients prevents risk of developing atherosclerosis and CHD. HMGCR is the rate-controlling enzyme pathway, responsible for cholesterol biosynthesis. De novo cholesterol synthesis by inducing the expression of HMGCR; activates the SREBP2. PPARα activation significantly lowers hepatic SREBP2 and HMGR mRNA levels. The aim of this study was to investigate the effect of Fenofibrate and Biochanin A, as PPARα agonists, on mRNA levels of SREBP2 and HMGR in HepG2 cells exposed to high glucose concentration.
Materials & Methods: HepG2 cells were used in this study. The induction of steatosis was performed by high glucose concentration. Cytotoxicity of Glucose, Fenofibrate, and Biochanin A were assessed in separate experiments for HepG2 cells. Some biochemical parameters such as intracellular total cholesterol, HMGCR, ALT, and AST activity were measured. SREBP2 and HMGR mRNA levels were examined by real-time RT-PCR.
Results: Results of our study indicated an inhibitory effect of Fenofibrate and Biochanin A on the mRNA levels of SREBP2 and HMGR in HepG2 cells which were treated by high glucose concentration. Additionally, a decreased level of intracellular total cholesterol concentration was accompanied by decreased HMGCR activity.
Conclusion: Based on the findings of the present study, it can be concluded that Biochanin A could be a useful agent in the prevention of de novo hepatic cholesterol synthesis and development of hypercholesterolemia; which is the main cause of CHD
Full-Text [PDF 947 kb]   (738 Downloads)    
Type of Study: orginal article | Subject: Special

1. Malaguarnera M, Di Rosa M, Nicoletti F, Malaguarnera L. Molecular mechanisms involved in NAFLD progression. J Mol Med (Berl) 2009;87(7):679-95. [DOI:10.1007/s00109-009-0464-1]
2. Jung CH, Lee B, Choi DH, Jung SH, Kim BY, Kim CH, et al. Association of grade of non-alcoholic fatty liver disease and glycated albumin to glycated hemoglobin ratio in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 2017;125:53-61. [DOI:10.1016/j.diabres.2016.12.017]
3. Polyzos SA, Bugianesi E, Kountouras J, Mantzoros CS. Nonalcoholic fatty liver disease: Updates on associations with the metabolic syndrome and lipid profile and effects of treatment with PPAR-gamma agonists. Metabolism 2017;66:64-8. [DOI:10.1016/j.metabol.2016.08.001]
4. Katsagoni CN, Georgoulis M, Papatheodoridis GV, Panagiotakos DB, Kontogianni MD. Effects of lifestyle interventions on clinical characteristics of patients with non-alcoholic fatty liver disease: A meta-analysis. Metabolism 2017;68:119-32. [DOI:10.1016/j.metabol.2016.12.006]
5. Tolman KG, Dalpiaz AS. Treatment of non-alcoholic fatty liver disease. Ther Clin Risk Manag 2007;3(6):1153-63. [PubMed]
6. Antonucci L, Porcu C, Iannucci G, Balsano C, Barbaro B. Non-Alcoholic Fatty Liver Disease and Nutritional Implications: Special Focus on Copper. Nutrients 2017;9(10):1137. [DOI:10.3390/nu9101137]
7. Abd El-Kader SM, El-Den Ashmawy EM. Non-alcoholic fatty liver disease: The diagnosis and management. World J Hepatol 2015;7(6):846-58. [DOI:10.4254/wjh.v7.i6.846]
8. Sanders FW, Griffin JL. De novo lipogenesis in the liver in health and disease: more than just a shunting yard for glucose. Biol Rev Camb Philos Soc 2016;91(2):452-68. [DOI:10.1111/brv.12178]
9. Izdebska M, Herbet M, Gawronska-Grzywacz M, Piatkowska-Chmiel I, Korga A, Sysa M, et al. Resveratrol Limits Lipogenesis and Enhance Mitochondrial Activity in HepG2 Cells. J Pharm Pharm Sci 2018;21(1):504-15. [DOI:10.18433/jpps29994]
10. Wallace M, Metallo CM. Tracing insights into de novo lipogenesis in liver and adipose tissues. Semin Cell Dev Biol 2020. [DOI:10.1016/j.semcdb.2020.02.012]
11. Rui L. Energy metabolism in the liver. Compr Physiol 2014;4(1):177-97. [DOI:10.1002/cphy.c130024]
12. Shi L, Tu BP. Acetyl-CoA and the regulation of metabolism: mechanisms and consequences. Curr Opin Cell Biol 2015;33:125-31. [DOI:10.1016/j.ceb.2015.02.003]
13. Chen L, Duan Y, Wei H, Ning H, Bi C, Zhao Y, et al. Acetyl-CoA carboxylase (ACC) as a therapeutic target for metabolic syndrome and recent developments in ACC1/2 inhibitors. Expert Opin Investig Drugs 2019;28(10):917-30. [DOI:10.1080/13543784.2019.1657825]
14. DeBose-Boyd RA. Feedback regulation of cholesterol synthesis: sterol-accelerated ubiquitination and degradation of HMG CoA reductase. Cell Res 2008;18(6):609-21. [DOI:10.1038/cr.2008.61]
15. Du T, Sun X, Yu X. Non-HDL cholesterol and LDL cholesterol in the dyslipidemic classification in patients with nonalcoholic fatty liver disease. Lipids Health Dis 2017;16(1):229. [DOI:10.1186/s12944-017-0621-4]
16. Ghadimi D, Goodarzi MT, Ziamajidi N , Moradkhani S. The effect of aqueous extract of Origanum Vulgare leaves on adiponectin and c-Cbl associated protein levels in adipose tissue of Streptozotocin - Nicotinamide induced diabetic rats. Pharmacophore. 2017;8(6S):9-19. [ResearchGate]
17. Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017;38(32):2459-72. [DOI:10.1093/eurheartj/ehx144]
18. Wu N, Sarna LK, Hwang SY, Zhu Q, Wang P, Siow YL, et al. Activation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase during high fat diet feeding. Biochim Biophys Acta 2013;1832(10):1560-8. [DOI:10.1016/j.bbadis.2013.04.024]
19. Jung JH, Kim HS. The inhibitory effect of black soybean on hepatic cholesterol accumulation in high cholesterol and high fat diet-induced non-alcoholic fatty liver disease. Food Chem Toxicol 2013;60:404-12. [DOI:10.1016/j.fct.2013.07.048]
20. Konig B, Koch A, Spielmann J, Hilgenfeld C, Stangl GI, Eder K. Activation of PPARalpha lowers synthesis and concentration of cholesterol by reduction of nuclear SREBP-2. Biochem Pharmacol 2007;73(4):574-85. [DOI:10.1016/j.bcp.2006.10.027]
21. Kondo K, Sugioka T, Tsukada K, Aizawa M, Takizawa M, Shimizu K, et al. Fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, improves hepatic microcirculatory patency and oxygen availability in a high-fat-diet-induced fatty liver in mice. Adv Exp Med Biol 2010;662:77-82. [DOI:10.1007/978-1-4419-1241-1_10]
22. Ghadimi D, Goodarzi M T , Ziamajidi N , S M. The influence of biochanin a consumption on c-CBL-associated protein level in adipose tissue of streptozotocine-nicotinamide induced diabetic rats. International Journal of medical research and health sciences 2016;5(7):195-201. [address]
23. Ghadimi D, Goodarzi MT, Ziamajidi N, Moradkhani S. The effect of Biochanin A on the expression of Adiponectin in adipose tissue of Streptozotocin-Nicotinamide induced diabetic rats. International Journal of medical research and health sciences 2016;5(7):223-30. [ResearchGate]
24. Do MT, Kim HG, Choi JH, Khanal T, Park BH, Tran TP, et al. Phillyrin attenuates high glucose-induced lipid accumulation in human HepG2 hepatocytes through the activation of LKB1/AMP-activated protein kinase-dependent signalling. Food Chem 2013;136(2):415-25. [DOI:10.1016/j.foodchem.2012.09.012]
25. Samson SL, Garber AJ. Metabolic syndrome. Endocrinol Metab Clin North Am 2014;43(1):1-23. [DOI:10.1016/j.ecl.2013.09.009]
26. Ansarimoghaddam A, Adineh HA, Zareban I, Iranpour S, HosseinZadeh A, Kh F. Prevalence of metabolic syndrome in Middle-East countries: Meta-analysis of cross-sectional studies. Diabetes Metab Syndr 2018;12(2):195-201. [DOI:10.1016/j.dsx.2017.11.004]
27. Sherling DH, Perumareddi P, Hennekens CH. Metabolic Syndrome. J Cardiovasc Pharmacol Ther 2017;22(4):365-7. [DOI:10.1177/1074248416686187]
28. Brown AE, Walker M. Genetics of Insulin Resistance and the Metabolic Syndrome. Curr Cardiol Rep 2016;18(8):75. [DOI:10.1007/s11886-016-0755-4]
29. Sankar P, Zachariah B, Vickneshwaran V, Jacob SE, Sridhar MG. Amelioration of oxidative stress and insulin resistance by soy isoflavones (from Glycine max) in ovariectomized Wistar rats fed with high fat diet: the molecular mechanisms. Exp Gerontol 2015;63:67-75. [DOI:10.1016/j.exger.2015.02.001]
30. Urbano F, Di Pino A, Scicali R, Filippello A, Di Mauro S, Scamporrino A, et al. Impaired glucagon suppression and reduced insulin sensitivity in subjects with prediabetes undergoing atorvastatin therapy. Eur J Endocrinol 2019;181(6):579-90. [DOI:10.1530/EJE-19-0173]
31. van Raalte DH, Li M, Pritchard PH, Wasan KM. Peroxisome proliferator-activated receptor (PPAR)-alpha: a pharmacological target with a promising future. Pharm Res 2004;21(9):1531-8. [DOI:10.1023/B:PHAM.0000041444.06122.8d]
32. Zhang L, Li C, Wang F, Zhou S, Shangguan M, Xue L, et al. Treatment with PPARalpha Agonist Clofibrate Inhibits the Transcription and Activation of SREBPs and Reduces Triglyceride and Cholesterol Levels in Liver of Broiler Chickens. PPAR Res 2015;2015:347245. [DOI:10.1155/2015/347245]

Add your comments about this article : Your username or Email:

Send email to the article author

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

© 2022 CC BY-NC 4.0 | Journal of Research in Applied and Basic Medical Sciences

Designed & Developed by : Yektaweb