Browse > Article
http://dx.doi.org/10.4142/jvs.2021.22.e92

The effects of naringenin and naringin on the glucose uptake and AMPK phosphorylation in high glucose treated HepG2 cells  

Dayarathne, Lakshi A. (College of Veterinary Medicine, Jeju National University)
Ranaweera, Sachithra S. (College of Veterinary Medicine, Jeju National University)
Natraj, Premkumar (College of Veterinary Medicine, Jeju National University)
Rajan, Priyanka (College of Veterinary Medicine, Jeju National University)
Lee, Young Jae (College of Veterinary Medicine, Jeju National University)
Han, Chang-Hoon (College of Veterinary Medicine, Jeju National University)
Publication Information
Journal of Veterinary Science / v.22, no.6, 2021 , pp. 92.1-92.12 More about this Journal
Abstract
Background: Naringin and its aglycone naringenin are citrus-derived flavonoids with several pharmacological effects. On the other hand, the mechanism for the anti-diabetic effects of naringenin and naringin are controversial and remain to be clarified further. Objective: This study examined the relationship between glucose uptake and AMP-activated protein kinase (AMPK) phosphorylation by naringenin and naringin in high glucose-treated HepG2 cells. Methods: Glucose uptake was measured using the 2-NBDG fluorescent D-glucose analog. The phosphorylation levels of AMPK and GSK3β (Glycogen synthase kinase 3 beta) were observed by Western blotting. Molecular docking analysis was performed to evaluate the binding affinity of naringenin and naringin to the γ-subunit of AMPK. Results: The treatment with naringenin and naringin stimulated glucose uptake regardless of insulin stimulation in high glucose-treated HepG2 cells. Both flavonoids increased glucose uptake by promoting the phosphorylation of AMPK at Thr172 and increased the phosphorylation of GSK3β. Molecular docking analysis showed that both naringenin and naringin bind to the γ-subunit of AMPK with high binding affinities. In particular, naringin showed higher binding affinity than the true modulator, AMP with all three CBS domains (CBS1, 3, and 4) in the γ-subunit of AMPK. Therefore, both naringenin and naringin could be positive modulators of AMPK activation, which enhance glucose uptake regardless of insulin stimulation in high glucose-treated HepG2 cells. Conclusions: The increased phosphorylation of AMPK at Thr172 by naringenin and naringin might enhance glucose uptake regardless of insulin stimulation in high glucose treated HepG2 cells.
Keywords
Naringenin; naringin; glucose uptake; AMPK phosphorylation; molecular docking;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Olivares-Vicente M, Sanchez-Marzo N, Encinar JA, de la Luz Cadiz-Gurrea M, Lozano-Sanchez J, Segura-Carretero A, et al. The potential synergistic modulation of AMPK by Lippia citriodora compounds as a target in metabolic disorders. Nutrients. 2019;11(12):2961.   DOI
2 Krook A, Wallberg-Henriksson H, Zierath JR. Sending the signal: molecular mechanisms regulating glucose uptake. Med Sci Sports Exerc. 2004;36(7):1212-1217.   DOI
3 Suzuki T, Bridges D, Nakada D, Skiniotis G, Morrison SJ, Lin JD, et al. Inhibition of AMPK catabolic action by GSK3. Mol Cell. 2013;50(3):407-419.   DOI
4 Hardie DG, Hawley SA, Scott JW. AMP-activated protein kinase--development of the energy sensor concept. J Physiol. 2006;574(Pt 1):7-15.   DOI
5 Ishii K, Furuta T, Kasuya Y. Determination of naringin and naringenin in human plasma by high-performance liquid chromatography. J Chromatogr B Biomed Appl. 1996;683(2):225-229.   DOI
6 Zou C, Wang Y, Shen Z. 2-NBDG as a fluorescent indicator for direct glucose uptake measurement. J Biochem Biophys Methods. 2005;64(3):207-215.   DOI
7 Jung HA, Paudel P, Seong SH, Min BS, Choi JS. Structure-related protein tyrosine phosphatase 1B inhibition by naringenin derivatives. Bioorg Med Chem Lett. 2017;27(11):2274-2280.   DOI
8 Thorens B, Cheng ZQ, Brown D, Lodish HF. Liver glucose transporter: a basolateral protein in hepatocytes and intestine and kidney cells. Am J Physiol. 1990;259(6 Pt 1):C279-C285.   DOI
9 Ren Z, Xie Z, Cao D, Gong M, Yang L, Zhou Z, et al. C-Phycocyanin inhibits hepatic gluconeogenesis and increases glycogen synthesis via activating Akt and AMPK in insulin resistance hepatocytes. Food Funct. 2018;9(5):2829-2839.   DOI
10 Gowans GJ, Hawley SA, Ross FA, Hardie DG. AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation. Cell Metab. 2013;18(4):556-566.   DOI
11 Ribeiro IA, Ribeiro MH. Naringin and naringenin determination and control in grapefruit juice by a validated HPLC method. Food Control. 2008;19(4):432-438.   DOI
12 Rayasam GV, Tulasi VK, Sodhi R, Davis JA, Ray A. Glycogen synthase kinase 3: more than a namesake. Br J Pharmacol. 2009;156(6):885-898.   DOI
13 O'Neill HM. AMPK and exercise: glucose uptake and insulin sensitivity. Diabetes Metab J. 2013;37(1):1-21.   DOI
14 Mu J, Brozinick JT Jr, Valladares O, Bucan M, Birnbaum MJ. A role for AMP-activated protein kinase in contraction- and hypoxia-regulated glucose transport in skeletal muscle. Mol Cell. 2001;7(5):1085-1094.   DOI
15 Yuan HD, Kim DY, Quan HY, Kim SJ, Jung MS, Chung SH. Ginsenoside Rg2 induces orphan nuclear receptor SHP gene expression and inactivates GSK3β via AMP-activated protein kinase to inhibit hepatic glucose production in HepG2 cells. Chem Biol Interact. 2012;195(1):35-42.   DOI
16 Dayarathne LA, Ranaweera SS, Natraj P, Rajan P, Lee YJ, Han CH. Restoration of the adipogenic gene expression by naringenin and naringin in 3T3-L1 adipocytes. J Vet Sci. 2021;22(4):e55.   DOI
17 Tang HC, Chen CY. In silico design for adenosine monophosphate-activated protein kinase agonist from traditional chinese medicine for treatment of metabolic syndromes. Evid Based Complement Alternat Med. 2014;2014:928589.
18 Yong Y, Shin SY, Jung Y, Jung H, Ahn S, Chong Y, et al. Flavonoids activating adenosine monophosphate-activated protein kinase. J Korean Soc Appl Biol Chem. 2015;58(1):13-19.   DOI
19 Dhanya R, Arun KB, Nisha VM, Syama HP, Nisha P, Santhosh Kumar TR, et al. Preconditioning L6 muscle cells with naringin ameliorates oxidative stress and increases glucose uptake. PLoS One. 2015;10(7):e0132429.   DOI
20 Kramer B, Rarey M, Lengauer T. Evaluation of the FLEXX incremental construction algorithm for protein-ligand docking. Proteins. 1999;37(2):228-241.   DOI
21 Ahmed OM, Hassan MA, Abdel-Twab SM, Abdel Azeem MN. Navel orange peel hydroethanolic extract, naringin and naringenin have anti-diabetic potentials in type 2 diabetic rats. Biomed Pharmacother. 2017;94:197-205.   DOI
22 Rojas JM, Schwartz MW. Control of hepatic glucose metabolism by islet and brain. Diabetes Obes Metab. 2014;16 Suppl 1:33-40.   DOI
23 Yuan HD, Piao GC. An active part of Artemisia sacrorum Ledeb. suppresses gluconeogenesis through AMPK mediated GSK3β and CREB phosphorylation in human HepG2 cells. Biosci Biotechnol Biochem. 2011;75(6):1079-1084.   DOI
24 Kang OH, Shon MY, Kong R, Seo YS, Zhou T, Kim DY, et al. Anti-diabetic effect of black ginseng extract by augmentation of AMPK protein activity and upregulation of GLUT2 and GLUT4 expression in db/db mice. BMC Complement Altern Med. 2017;17(1):341.   DOI
25 Bung N, Surepalli S, Seshadri S, Patel S, Peddasomayajula S, Kummari LK, et al. 2-[2-(4-(trifluoromethyl) phenylamino)thiazol-4-yl]acetic acid (Activator-3) is a potent activator of AMPK. Sci Rep. 2018;8(1):9599.   DOI
26 Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Makela TP, et al. Complexes between the LKB1 tumor suppressor, STRAD α/β and MO25 α/β are upstream kinases in the AMP-activated protein kinase cascade. J Biol. 2003;2(4):28.   DOI
27 Momcilovic M, Hong SP, Carlson M. Mammalian TAK1 activates Snf1 protein kinase in yeast and phosphorylates AMP-activated protein kinase in vitro. J Biol Chem. 2006;281(35):25336-25343.   DOI
28 Morand C, Manach C, Crespy V, Remesy C. Respective bioavailability of quercetin aglycone and its glycosides in a rat model. Biofactors. 2000;12(1-4):169-174.   DOI
29 Kren V. Glycoside vs. Aglycon: the role of glycosidic residue in biological activity. Glycoscience. Berlin/Heidelberg: Springer-Verlag Berlin Heidelberg; 2008, 2589-2644.
30 Ameer B, Weintraub RA, Johnson JV, Yost RA, Rouseff RL. Flavanone absorption after naringin, hesperidin, and citrus administration. Clin Pharmacol Ther. 1996;60(1):34-40.   DOI
31 Yang LL, Xiao N, Liu J, Liu K, Liu B, Li P, et al. Differential regulation of baicalin and scutellarin on AMPK and Akt in promoting adipose cell glucose disposal. Biochim Biophys Acta Mol Basis Dis. 2017;1863(2):598-606.   DOI
32 Moore MC, Coate KC, Winnick JJ, An Z, Cherrington AD. Regulation of hepatic glucose uptake and storage in vivo. Adv Nutr. 2012;3(3):286-294.   DOI