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Exp Clin Endocrinol Diabetes 2019; 127(09): 615-622
DOI: 10.1055/a-0650-4082
Article
© Georg Thieme Verlag KG Stuttgart · New York

Morin Exerts Anti-Diabetic Effects in Human HepG2 Cells Via Down-Regulation of miR-29a

Toktam Razavi
1   Department of Cellular and Molecular Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran
,
Shideh Montasser Kouhsari
1   Department of Cellular and Molecular Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran
,
Khalil Abnous
2   Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
› Author Affiliations
Further Information

Publication History

received 26 April 2018
revised 04 June 2018

accepted 27 June 2018

Publication Date:
08 October 2018 (online)

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Abstract

Diabetes mellitus is a complex metabolic disease around the world that is characterized by hyperglycemia resulting from impaired insulin secretion, insulin action, or both. MicroRNA-29a is an important regulator of insulin signaling and gluconeogenesis pathways through IRS2, PI3K and PEPCK expressions which up regulates in Diabetes. Morin is a substantial bioflavonoid which has insulin mimetic effect, and interacting with nucleic acids and proteins. In this study HepG2 cells, were exposed to high glucose to induce diabetic condition. We have determined whether high glucose stimulation might promotes miR-29a expression level in HepG2 cells and subsequently evaluated the Morin treatment effects on this state. In HepG2 cells, high glucose increases miR-29a expression level and decreases its target genes, IRS2 and PI3K expression, and increases associated downstream gene in gluconeogenic pathway, PEPCK. Morin treatment down regulates miR-29a expression level and improves insulin signaling and glucose metabolism. To confirm the inhibitory effects of Morin on miR-29a, we have transfected cells with mimic and inhibitor-miR-29a. This study for the first time identifies that Morin improves diabetic condition through down regulation of the miR-29a level, and suggest that this new inhibitor of miR-29a may be a useful biomedicine to treat diabetes.

Key words

morin - miR-29a - diabetes - hyperglycemia - insulin signaling
 

  • References

  • 1 Mellor DD, Sathyapalan T, Kilpatrick ES. et al. Diabetes and chocolate: friend or foe?. J Agric Food Chem 2015; 63: 9910-9918
    CrossrefPubMedGoogle Scholar
  • 2 Spínola V, Castilho PC. Evaluation of Asteraceae herbal extracts in the management of diabetes and obesity. Contribution of caffeoylquinic acids on the inhibition of digestive enzymes activity and formation of advanced glycation end-products (in vitro). Phytochemistry 2017; 143: 29-35
    CrossrefPubMedGoogle Scholar
  • 3 Kooti W, Farokhipour M, Asadzadeh Z. et al. The role of medicinal plants in the treatment of diabetes: a systematic review. Electron physician 2016; 8: 1832-1842
    CrossrefPubMedGoogle Scholar
  • 4 Vanitha P, Uma C, Suganya N. et al. Modulatory effects of morin on hyperglycemia by attenuating the hepatic key enzymes of carbohydrate metabolism and β-cell function in streptozotocininduced diabetic rats. Environ Toxicol Pharmacol 2014; 37: 326-335
    CrossrefPubMedGoogle Scholar
  • 5 Vinayagam R, Xu B. Antidiabetic properties of dietary flavonoids: a cellular mechanism review. Nutr Metab (Lond) 2015; 12: 60
    CrossrefPubMedGoogle Scholar
  • 6 Ovalle-Magallanes B, Medina-Campos ON, Pedraza-Chaverri J. et al. Hypoglycemic and antihyperglycemic effects of phytopreparations and limonoids from Swietenia humilis. Phytochemistry 2015; 110: 111-119
    CrossrefPubMedGoogle Scholar
  • 7 Paoli P, Cirri P, Caselli A. et al. The insulin-mimetic effect of Morin: A promising molecule in diabetes treatment. Biochim Biophys Acta - Gen Subj 2013; 1830: 3102-3111
    CrossrefPubMedGoogle Scholar
  • 8 Torel J, Cillard J, Cillard P. Antioxidant activity of flavonoids and reactivity with peroxy radical. Phytochemistry 1986; 25: 383-385
    CrossrefPubMedGoogle Scholar
  • 9 Abuohashish HM, Al-Rejaie SS, Al-Hosaini KA. et al. Alleviating effects of morin against experimentally-induced diabetic osteopenia. Diabetol Metab Syndr 2013; 5: 5
    CrossrefPubMedGoogle Scholar
  • 10 Ola MS, Aleisa AM, Al-Rejaie SS. et al. Flavonoid, morin inhibits oxidative stress, inflammation and enhances neurotrophic support in the brain of streptozotocin-induced diabetic rats. Neurol Sci 2014; 35: 1003-1008
    CrossrefPubMedGoogle Scholar
  • 11 Subash S, Subramanian P. Morin a flavonoid exerts antioxidant potential in chronic hyperammonemic rats: a biochemical and histopathological study. Mol Cell Biochem 2009; 327: 153-161
    CrossrefPubMedGoogle Scholar
  • 12 Taguchi K, Hida M, Hasegawa M. et al. Dietary polyphenol morin rescues endothelial dysfunction in a diabetic mouse model by activating the Akt/eNOS pathway. Mol Nutr Food Res 2016; 60: 580-588
    CrossrefPubMedGoogle Scholar
  • 13 Lançon A, Michaille J-J, Latruffe N. Effects of dietary phytophenols on the expression of microRNAs involved in mammalian cell homeostasis. J Sci Food Agric 2013; 93: 3155-3164
    CrossrefPubMedGoogle Scholar
  • 14 Ha T-Y. MicroRNAs in Human Diseases: From Cancer to Cardiovascular Disease. Immune Netw 2011; 11: 135
    CrossrefPubMedGoogle Scholar
  • 15 Feng J, Xing W, Xie L. Regulatory Roles of MicroRNAs in Diabetes. Int J Mol Sci 2016; 17: 1729
    CrossrefPubMedGoogle Scholar
  • 16 He Y, Ding Y, Liang B. et al. A Systematic Study of Dysregulated MicroRNA in Type 2 Diabetes Mellitus. Int J Mol Sci 2017; 18: 456
    CrossrefPubMedGoogle Scholar
  • 17 TANG X, TANG G, OZCAN S. Role of microRNAs in diabetes. Biochim Biophys Acta - Gene Regul Mech 2008; 1779: 697-701
    CrossrefPubMedGoogle Scholar
  • 18 Zhang F, Xu X, Zhang Y. et al. Gene Expression Profile Analysis of Type 2 Diabetic Mouse Liver. PLoS One 2013; 8: e57766
    CrossrefPubMedGoogle Scholar
  • 19 Ślusarz A, Pulakat L. The two faces of miR-29. J Cardiovasc Med 2015; 16: 480-490
    CrossrefPubMedGoogle Scholar
  • 20 Dooley J, Garcia-Perez JE, Sreenivasan J. et al. The microRNA-29 Family Dictates the Balance Between Homeostatic and Pathological Glucose Handling in Diabetes and Obesity. Diabetes 2016; 65: 53-61
    CrossrefPubMedGoogle Scholar
  • 21 Pandey AK, Verma G, Vig S. et al. miR-29a levels are elevated in the db/db mice liver and its overexpression leads to attenuation of insulin action on PEPCK gene expression in HepG2 cells. Mol Cell Endocrinol 2011; 332: 125-133
    CrossrefPubMedGoogle Scholar
  • 22 Lavin DP, White MF, Brazil DP. IRS proteins and diabetic complications. Diabetologia 2016; 59: 2280-2291
    CrossrefPubMedGoogle Scholar
  • 23 Brady MJ. IRS2 takes center stage in the development of type 2 diabetes. J Clin Invest 2004; 114: 886-888
    CrossrefPubMedGoogle Scholar
  • 24 Guo S. Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models into disease mechanisms. J Endocrinol 2014; 220: T1-T23
    PubMedGoogle Scholar
  • 25 Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 2001; 414: 799-806
    CrossrefPubMedGoogle Scholar
  • 26 Foretz M, Hébrard S, Leclerc J. et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest 2010; 120: 2355-2369
    CrossrefPubMedGoogle Scholar
  • 27 Witkos TM, Koscianska E, Krzyzosiak WJ. Practical Aspects of microRNA Target Prediction. Curr Mol Med 2011; 11: 93-109
    CrossrefPubMedGoogle Scholar
  • 28 Ling Q, Xie H, Li J. et al. Donor Graft MicroRNAs: A Newly Identified Player in the Development of New-onset Diabetes After Liver Transplantation. Am J Transplant 2017; 17: 255-264
    CrossrefPubMedGoogle Scholar
  • 29 Shao J, Qiao L, Janssen RC. et al. Chronic Hyperglycemia Enhances PEPCK Gene Expression and Hepatocellular Glucose Production Via Elevated Liver Activating Protein/Liver Inhibitory Protein Ratio. Diabetes 2005; 54: 976-984
    CrossrefPubMedGoogle Scholar
  • 30 He A, Zhu L, Gupta N. et al. Overexpression of Micro Ribonucleic Acid 29, Highly Up-Regulated in Diabetic Rats, Leads to Insulin Resistance in 3T3-L1 Adipocytes. Mol Endocrinol 2007; 21: 2785-2794
    CrossrefPubMedGoogle Scholar
  • 31 Chakraborty C, Agoramoorthy G, Hsu MJ. Exploring the Evolutionary Relationship of Insulin Receptor Substrate Family Using Computational Biology. PLoS One 2011; 6: e16580
    CrossrefPubMedGoogle Scholar
  • 32 Mardilovich K, Pankratz SL, Shaw LM. Expression and function of the insulin receptor substrate proteins in cancer. Cell Commun Signal 2009; 7: 14
    CrossrefPubMedGoogle Scholar
  • 33 Nordlie RC, Foster JD, Lange AJ. Regulation of glucose production by the liver. Annu Rev Nutr 1999; 19: 379-406
    CrossrefPubMedGoogle Scholar
  • 34 Massart J, Sjögren RJO, Lundell LS. et al. Altered miR-29 Expression in Type 2 Diabetes Influences Glucose and Lipid Metabolism in Skeletal Muscle. Diabetes 2017; 66: 1807-1818
    CrossrefPubMedGoogle Scholar
  • 35 Kurtz CL, Peck BCE, Fannin EE. et al. MicroRNA-29 Fine-tunes the Expression of Key FOXA2-Activated Lipid Metabolism Genes and Is Dysregulated in Animal Models of Insulin Resistance and Diabetes. Diabetes 2014; 63: 3141-3148
    CrossrefPubMedGoogle Scholar
  • 36 Fröjdö S, Vidal H, Pirola L. Alterations of insulin signaling in type 2 diabetes: A review of the current evidence from humans. Biochim Biophys Acta - Mol Basis Dis 2009; 1792: 83-92
    CrossrefPubMedGoogle Scholar
  • 37 Han J-W. Impaired PI3K/Akt signal pathway and hepatocellular injury in high-fat fed rats. World J Gastroenterol 2010; 16: 6111
    CrossrefPubMedGoogle Scholar
  • 38 Xu H, Zhou Y, Liu Y. et al. Metformin improves hepatic IRS2/PI3K/Akt signaling in insulin-resistant rats of NASH and cirrhosis. J Endocrinol 2016; 229: 133-144
    CrossrefPubMedGoogle Scholar
  • 39 AlSharari S, Al-Rejaie S, Abuohashish H. et al. Ameliorative Potential of Morin in Streptozotocin-Induced Neuropathic Pain in Rats. Trop J Pharm Res 2014; 13: 1429
    CrossrefPubMedGoogle Scholar
  • 40 Zeng L, Zhang G, Liao Y. et al. Inhibitory mechanism of morin on α-glucosidase and its anti-glycation properties. Food Funct 2016; 7: 3953-3963
    CrossrefPubMedGoogle Scholar
  • 41 Kanakis CD, Nafisi S, Rajabi M. et al. Structural analysis of DNA and RNA interactions with antioxidant flavonoids. Spectroscopy 2009; 23: 29-43
    CrossrefPubMedGoogle Scholar
  • 42 Baselga-Escudero L, Blade C, Ribas-Latre A. et al. Resveratrol and EGCG bind directly and distinctively to miR-33a and miR-122 and modulate divergently their levels in hepatic cells. Nucleic Acids Res 2014; 42: 882-892
    CrossrefPubMedGoogle Scholar
  • 43 Milenkovic D, Jude B, Morand C. miRNA as molecular target of polyphenols underlying their biological effects. Free Radic Biol Med 2013; 64: 40-51
    CrossrefPubMedGoogle Scholar
  • 44 Blade C, Baselga-Escudero L, Arola-Arnal A. microRNAs as New Targets of Dietary Polyphenols. Curr Pharm Biotechnol 2014; 15: 343-351
    CrossrefPubMedGoogle Scholar
  • 45 Chakraborty C, Doss CGP, Bandyopadhyay S et al. Influence of miRNA in insulin signaling pathway and insulin resistance: micro-molecules with a major role in type-2 diabetes. Wiley Interdiscip Rev RNA; 2014
    PubMed