HM-chromanone Isolated from L. Alleviates Insulin Resistance and Inhibits Gluconeogenesis by Regulating Palmitate-induced Activation of ROS/JNK in HepG2 Cells

Overview

Journal Toxicol Res (Camb)

Publisher Oxford University Press

Date 2023 Sep 4

PMID 37663815

Authors

Jae Eun Park

Ji Sook Han

Affiliations

Soon will be listed here.

Abstract

Oxidative stress is a major cause of hepatic insulin resistance. This study investigated whether )-5-hydroxy-7-methoxy-3-(2-hydroxybenzyl)-4-chromanone (HM-chromanone), a homoisoflavonoid compound isolated from L., alleviates insulin resistance and inhibits gluconeogenesis by reducing palmitate (PA)-induced reactive oxygen species (ROS)/c-Jun NH2-terminal kinase (JNK) activation in HepG2 cells. PA treatment (0.5 mM) for 16 h resulted in the highest production of ROS and induced insulin resistance in HepG2 cells. HM-chromanone, like N-acetyl-1-cysteine, significantly decreased PA-induced ROS production in the cells. HM-chromanone also significantly inhibited PA-induced JNK activation, showing a significant reduction in tumor necrosis factor and interleukin expression levels. Thus, HM-chromanone decreased the phosphorylation of Ser307 in insulin receptor substrate 1, while increasing phosphorylation of serine-threonine kinase (AKT), thereby restoring the insulin signaling pathway impaired by PA. HM-chromanone also significantly increased the phosphorylation of forkhead box protein O, thereby inhibiting the expression of gluconeogenic enzymes and reducing glucose production in PA-treated HepG2 cells. HM-chromanone also increased glycogen synthesis by phosphorylating glycogen synthase kinase-3β. Therefore, HM-chromanone may alleviate insulin resistance and inhibit gluconeogenesis by regulating PA-induced ROS/JNK activation in HepG2 cells.

References

Park J, Park J, Seo Y, Han J . A new chromanone isolated from Portulaca oleracea L. increases glucose uptake by stimulating GLUT4 translocation to the plasma membrane in 3T3-L1 adipocytes. Int J Biol Macromol. 2018; 123:26-34. DOI: 10.1016/j.ijbiomac.2018.10.206. View

Nakamura S, Takamura T, Matsuzawa-Nagata N, Takayama H, Misu H, Noda H . Palmitate induces insulin resistance in H4IIEC3 hepatocytes through reactive oxygen species produced by mitochondria. J Biol Chem. 2009; 284(22):14809-18. PMC: 2685662. DOI: 10.1074/jbc.M901488200. View

Dong Y, Gao G, Fan H, Li S, Li X, Liu W . Activation of the Liver X Receptor by Agonist TO901317 Improves Hepatic Insulin Resistance via Suppressing Reactive Oxygen Species and JNK Pathway. PLoS One. 2015; 10(4):e0124778. PMC: 4409387. DOI: 10.1371/journal.pone.0124778. View

Rice-Evans C, Miller N, Paganga G . Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med. 1996; 20(7):933-56. DOI: 10.1016/0891-5849(95)02227-9. View

Park J, Seo Y, Han J . HM-Chromanone Isolated from L. Protects INS-1 Pancreatic β Cells against Glucotoxicity-Induced Apoptosis. Nutrients. 2019; 11(2). PMC: 6412778. DOI: 10.3390/nu11020404. View

Ma C, Li G, Zhang J, Zheng Q, Fan X, Wang Z . An efficient combination of supercritical fluid extraction and high-speed counter-current chromatography to extract and purify homoisoflavonoids from Ophiopogon japonicus (Thunb.) Ker-Gawler. J Sep Sci. 2009; 32(11):1949-56. DOI: 10.1002/jssc.200800732. View

Daniele G, Eldor R, Merovci A, Clarke G, Xiong J, Tripathy D . Chronic reduction of plasma free fatty acid improves mitochondrial function and whole-body insulin sensitivity in obese and type 2 diabetic individuals. Diabetes. 2013; 63(8):2812-20. PMC: 4113069. DOI: 10.2337/db13-1130. View

Prasath G, Iyyam Pillai S, Subramanian S . Fisetin improves glucose homeostasis through the inhibition of gluconeogenic enzymes in hepatic tissues of streptozotocin induced diabetic rats. Eur J Pharmacol. 2014; 740:248-54. DOI: 10.1016/j.ejphar.2014.06.065. View

Machala M, Kubinova R, Horavova P, Suchy V . Chemoprotective potentials of homoisoflavonoids and chalcones of Dracaena cinnabari: modulations of drug-metabolizing enzymes and antioxidant activity. Phytother Res. 2001; 15(2):114-8. DOI: 10.1002/ptr.697. View

10.

Houstis N, Rosen E, Lander E . Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature. 2006; 440(7086):944-8. DOI: 10.1038/nature04634. View

11.

van de Werve G, Lange A, Newgard C, Mechin M, Li Y, Berteloot A . New lessons in the regulation of glucose metabolism taught by the glucose 6-phosphatase system. Eur J Biochem. 2000; 267(6):1533-49. DOI: 10.1046/j.1432-1327.2000.01160.x. View

12.

Barazzoni R, Zanetti M, Gortan Cappellari G, Semolic A, Boschelle M, Codarin E . Fatty acids acutely enhance insulin-induced oxidative stress and cause insulin resistance by increasing mitochondrial reactive oxygen species (ROS) generation and nuclear factor-κB inhibitor (IκB)-nuclear factor-κB (NFκB) activation in rat muscle,.... Diabetologia. 2011; 55(3):773-82. DOI: 10.1007/s00125-011-2396-x. View

13.

Chen B, Zhou H, Zhao W, Zhou W, Yuan Q, Yang G . Effects of aqueous extract of Portulaca oleracea L. on oxidative stress and liver, spleen leptin, PARα and FAS mRNA expression in high-fat diet induced mice. Mol Biol Rep. 2012; 39(8):7981-8. DOI: 10.1007/s11033-012-1644-6. View

14.

Calvo M . Three new homoisoflavanones from the bulbs of Ledebouria floribunda. Fitoterapia. 2009; 80(7):394-8. DOI: 10.1016/j.fitote.2009.05.010. View

15.

Finkel T, Holbrook N . Oxidants, oxidative stress and the biology of ageing. Nature. 2000; 408(6809):239-47. DOI: 10.1038/35041687. View

16.

Gao D, Nong S, Huang X, Lu Y, Zhao H, Lin Y . The effects of palmitate on hepatic insulin resistance are mediated by NADPH Oxidase 3-derived reactive oxygen species through JNK and p38MAPK pathways. J Biol Chem. 2010; 285(39):29965-73. PMC: 2943261. DOI: 10.1074/jbc.M110.128694. View

17.

Lou T, Zhang Z, Xi Z, Liu K, Li L, Liu B . Berberine inhibits inflammatory response and ameliorates insulin resistance in hepatocytes. Inflammation. 2010; 34(6):659-67. DOI: 10.1007/s10753-010-9276-2. View

18.

Kim M, Han J, Kim S, Kim H, Jeon D, Lee K . Polyhexamethylene guanidine phosphate induces IL-6 and TNF-α expression through JNK-dependent pathway in human lung epithelial cells. J Toxicol Sci. 2018; 43(8):485-492. DOI: 10.2131/jts.43.485. View

19.

Arner P . Insulin resistance in type 2 diabetes: role of fatty acids. Diabetes Metab Res Rev. 2002; 18 Suppl 2:S5-9. DOI: 10.1002/dmrr.254. View

20.

Martinez G, Mijares M, De Sanctis J . Effects of Flavonoids and Its Derivatives on Immune Cell Responses. Recent Pat Inflamm Allergy Drug Discov. 2019; 13(2):84-104. DOI: 10.2174/1872213X13666190426164124. View