Skip to main content
Top
Published in: BMC Complementary Medicine and Therapies 1/2023

Open Access 01-12-2023 | Insulins | Research

Artichoke (Cynara scolymus L.) water extract alleviates palmitate-induced insulin resistance in HepG2 hepatocytes via the activation of IRS1/PI3K/AKT/FoxO1 and GSK-3β signaling pathway

Authors: Aihua Deng, Yun Wang, Kerui Huang, Peng Xie, Ping Mo, Fengying Liu, Jun Chen, Kaiyi Chen, Yun Wang, Bing Xiao

Published in: BMC Complementary Medicine and Therapies | Issue 1/2023

Login to get access

Abstract

Background

Artichoke (Cynara scolymus L.) is a typical element of a traditional Mediterranean diet and has potential health advantages for insulin resistance (IR) and type 2 diabetes mellitus (T2DM). This study aims to evaluate the effect and underlying mechanism of artichoke water extract (AWE) on palmitate (PA)-induced IR in human hepatocellular carcinoma (HepG2) cells.

Methods

The effect of AWE on cell viability was determined using CCK8 assay. Cellular glucose uptake, glucose consumption, glucose production, and glycogen content were assessed after AWE treatment. The gene expression and protein levels were examined by real-time polymerase chain reaction (qRT-PCR) and western blotting.

Results

The results showed that AWE dose-dependently increased cell viability in IR HepG2 cells (P < 0.01). AWE treatment significantly promoted glucose uptake and consumption, decreased glucose production, and increased the cellular glycogen content in IR HepG2 cells (P < 0.01). Mechanistically, AWE elevated the phosphorylation and total protein levels of major insulin signaling molecules in IR HepG2 cells, which resulted in a decrease in the expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) and the inhibition of glycogen synthase (GS) phosphorylation in IR HepG2 cells. Furthermore, the protective effect of AWE on IR HepG2 cells might be ascribed to the inhibition of the endoplasmic reticulum (ER) stress.

Conclusion

We conclude that AWE may improve glucose metabolism by regulating IRS1/PI3K/AKT/FoxO1 and GSK-3β signaling associated with the inhibition of ER stress in IR HepG2 cells induced by PA.
Appendix
Available only for authorised users
Literature
1.
go back to reference DeFronzo RA, Ferrannini E, Groop L, Henry RR, Herman WH, Holst JJ, et al. Type 2 diabetes mellitus. Nat Rev Dis Primers. 2015;1(1):15019–40. DeFronzo RA, Ferrannini E, Groop L, Henry RR, Herman WH, Holst JJ, et al. Type 2 diabetes mellitus. Nat Rev Dis Primers. 2015;1(1):15019–40.
2.
go back to reference Li M, Chi X, Wang Y, Setrerrahmane S, Xie W, Xu H. Trends in insulin resistance: insights into mechanisms and therapeutic strategy. Signal Transduct Target Ther. 2022;7(1):216–40. Li M, Chi X, Wang Y, Setrerrahmane S, Xie W, Xu H. Trends in insulin resistance: insights into mechanisms and therapeutic strategy. Signal Transduct Target Ther. 2022;7(1):216–40.
4.
go back to reference Burgos-Moron E, Abad-Jimenez Z, Maranon AM, Iannantuoni F, Escribano-Lopez I, Lopez-Domenech S, et al. Relationship between oxidative stress, ER stress, and inflammation in type 2 diabetes: the battle continues. J Clin Med. 2019;8(9):1385–406.CrossRefPubMedPubMedCentral Burgos-Moron E, Abad-Jimenez Z, Maranon AM, Iannantuoni F, Escribano-Lopez I, Lopez-Domenech S, et al. Relationship between oxidative stress, ER stress, and inflammation in type 2 diabetes: the battle continues. J Clin Med. 2019;8(9):1385–406.CrossRefPubMedPubMedCentral
5.
go back to reference Achard CS, Laybutt DR. Lipid-induced endoplasmic reticulum stress in liver cells results in two distinct outcomes: adaptation with enhanced insulin signaling or insulin resistance. Endocrinology. 2012;153(5):2164–77.CrossRefPubMed Achard CS, Laybutt DR. Lipid-induced endoplasmic reticulum stress in liver cells results in two distinct outcomes: adaptation with enhanced insulin signaling or insulin resistance. Endocrinology. 2012;153(5):2164–77.CrossRefPubMed
6.
go back to reference Pardo V, Gonzalez-Rodriguez A, Muntane J, Kozma SC, Valverde AM. Role of hepatocyte S6K1 in palmitic acid-induced endoplasmic reticulum stress, lipotoxicity, insulin resistance and in oleic acid-induced protection. Food Chem Toxicol. 2015;80:298–309.CrossRefPubMed Pardo V, Gonzalez-Rodriguez A, Muntane J, Kozma SC, Valverde AM. Role of hepatocyte S6K1 in palmitic acid-induced endoplasmic reticulum stress, lipotoxicity, insulin resistance and in oleic acid-induced protection. Food Chem Toxicol. 2015;80:298–309.CrossRefPubMed
7.
go back to reference Hong SH, Hong Y, Lee M, Keum BR, Kim GH. Natural product skatole ameliorates lipotoxicity-induced multiple hepatic damage under hyperlipidemic conditions in hepatocytes. Nutrients. 2023;15(6):1490–06.CrossRefPubMedPubMedCentral Hong SH, Hong Y, Lee M, Keum BR, Kim GH. Natural product skatole ameliorates lipotoxicity-induced multiple hepatic damage under hyperlipidemic conditions in hepatocytes. Nutrients. 2023;15(6):1490–06.CrossRefPubMedPubMedCentral
9.
10.
go back to reference Gross DN, van den Heuvel AP, Birnbaum MJ. The role of FoxO in the regulation of metabolism. Oncogene. 2008;27(16):2320–36.CrossRefPubMed Gross DN, van den Heuvel AP, Birnbaum MJ. The role of FoxO in the regulation of metabolism. Oncogene. 2008;27(16):2320–36.CrossRefPubMed
11.
12.
go back to reference Wang L, Li J, Di LJ. Glycogen synthesis and beyond, a comprehensive review of GSK3 as a key regulator of metabolic pathways and a therapeutic target for treating metabolic diseases. Med Res Rev. 2022;42(2):946–82.CrossRefPubMed Wang L, Li J, Di LJ. Glycogen synthesis and beyond, a comprehensive review of GSK3 as a key regulator of metabolic pathways and a therapeutic target for treating metabolic diseases. Med Res Rev. 2022;42(2):946–82.CrossRefPubMed
13.
go back to reference Bellary S, Kyrou I, Brown JE, Bailey CJ. Type 2 diabetes mellitus in older adults: clinical considerations and management. Nat Rev Endocrinol. 2021;17(9):534–48.CrossRefPubMed Bellary S, Kyrou I, Brown JE, Bailey CJ. Type 2 diabetes mellitus in older adults: clinical considerations and management. Nat Rev Endocrinol. 2021;17(9):534–48.CrossRefPubMed
14.
go back to reference Ramos-Romero S, Torrella JR, Pages T, Viscor G, Torres JL. Edible microalgae and their bioactive compounds in the prevention and treatment of metabolic alterations. Nutrients. 2021;13(2):563–8.CrossRefPubMedPubMedCentral Ramos-Romero S, Torrella JR, Pages T, Viscor G, Torres JL. Edible microalgae and their bioactive compounds in the prevention and treatment of metabolic alterations. Nutrients. 2021;13(2):563–8.CrossRefPubMedPubMedCentral
15.
go back to reference Yang T, Zhou W, Xu W, Ran L, Yan Y, Lu L, Mi J, Zeng X, Cao Y. Modulation of gut microbiota and hypoglycemic/hypolipidemic activity of flavonoids from the fruits of Lycium barbarum on high-fat diet/streptozotocin-induced type 2 diabetic mice. Food Funct. 2022;13(21):11169–84.CrossRefPubMed Yang T, Zhou W, Xu W, Ran L, Yan Y, Lu L, Mi J, Zeng X, Cao Y. Modulation of gut microbiota and hypoglycemic/hypolipidemic activity of flavonoids from the fruits of Lycium barbarum on high-fat diet/streptozotocin-induced type 2 diabetic mice. Food Funct. 2022;13(21):11169–84.CrossRefPubMed
16.
go back to reference Zhang Y, Yan LS, Ding Y, Cheng BCY, Luo G, Kong J, et al. Edgeworthia gardneri (Wall.) Meisn. water extract ameliorates palmitate induced insulin resistance by regulating IRS1/GSK3beta/FoxO1 signaling pathway in human HepG2 hepatocytes. Front Pharmacol. 2019;10:1666–81. Zhang Y, Yan LS, Ding Y, Cheng BCY, Luo G, Kong J, et al. Edgeworthia gardneri (Wall.) Meisn. water extract ameliorates palmitate induced insulin resistance by regulating IRS1/GSK3beta/FoxO1 signaling pathway in human HepG2 hepatocytes. Front Pharmacol. 2019;10:1666–81.
17.
go back to reference Moradi S, Shokri-Mashhadi N, Saraf-Bank S, Mohammadi H, Zobeiri M, Clark CCT, Rouhani MH. The effects of Cynara scolymus L. supplementation on liver enzymes: A systematic review and meta-analysis. Int J Clin Pract. 2021;75(11):e14726.CrossRefPubMed Moradi S, Shokri-Mashhadi N, Saraf-Bank S, Mohammadi H, Zobeiri M, Clark CCT, Rouhani MH. The effects of Cynara scolymus L. supplementation on liver enzymes: A systematic review and meta-analysis. Int J Clin Pract. 2021;75(11):e14726.CrossRefPubMed
18.
go back to reference Nasef MA, Yousef MI, Ghareeb DA, Augustyniak M, Aboul-Soud MAM, El Wakil A. Hepatoprotective effects of a chemically-characterized extract from artichoke (Cynara scolymus L.) against AFB(1)-induced toxicity in rats. Drug Chem Toxicol. 2023;46(6):1070–82. Nasef MA, Yousef MI, Ghareeb DA, Augustyniak M, Aboul-Soud MAM, El Wakil A. Hepatoprotective effects of a chemically-characterized extract from artichoke (Cynara scolymus L.) against AFB(1)-induced toxicity in rats. Drug Chem Toxicol. 2023;46(6):1070–82.
19.
go back to reference Wegener T, Fintelmann V. Pharmacological properties and therapeutic profile of artichoke (Cynara scolymus L.). Wien Med Wochenschr. 1999;149(8–10):241–7.PubMed Wegener T, Fintelmann V. Pharmacological properties and therapeutic profile of artichoke (Cynara scolymus L.). Wien Med Wochenschr. 1999;149(8–10):241–7.PubMed
20.
go back to reference Ahmadi A, Heidarian E, Ghatreh-Samani K. Modulatory effects of artichoke (Cynara scolymus L.) leaf extract against oxidative stress and hepatic TNF-alpha gene expression in acute diazinon-induced liver injury in rats. J Basic Clin Physiol Pharmacol. 2019;30(5):1515–24. Ahmadi A, Heidarian E, Ghatreh-Samani K. Modulatory effects of artichoke (Cynara scolymus L.) leaf extract against oxidative stress and hepatic TNF-alpha gene expression in acute diazinon-induced liver injury in rats. J Basic Clin Physiol Pharmacol. 2019;30(5):1515–24.
21.
go back to reference Doostkam A, Fathalipour M, Anbardar MH, Purkhosrow A, Mirkhani H. Therapeutic Effects of Milk Thistle (Silybum marianum L.) and Artichoke (Cynara scolymus L.) on Nonalcoholic Fatty Liver Disease in Type 2 Diabetic Rats. Can J Gastroenterol Hepatol. 2022;2022:2868904.CrossRefPubMedPubMedCentral Doostkam A, Fathalipour M, Anbardar MH, Purkhosrow A, Mirkhani H. Therapeutic Effects of Milk Thistle (Silybum marianum L.) and Artichoke (Cynara scolymus L.) on Nonalcoholic Fatty Liver Disease in Type 2 Diabetic Rats. Can J Gastroenterol Hepatol. 2022;2022:2868904.CrossRefPubMedPubMedCentral
22.
go back to reference Deng A, Liu F, Tang X, Wang Y, Xie P, Yang Q, et al. Water extract from artichoke ameliorates high-fat diet-induced non-alcoholic fatty liver disease in rats. BMC Complement Med Ther. 2022;22(1):308–17.CrossRefPubMedPubMedCentral Deng A, Liu F, Tang X, Wang Y, Xie P, Yang Q, et al. Water extract from artichoke ameliorates high-fat diet-induced non-alcoholic fatty liver disease in rats. BMC Complement Med Ther. 2022;22(1):308–17.CrossRefPubMedPubMedCentral
23.
go back to reference Mo J, Zhou Y, Yang R, Zhang P, He B, Yang J, Li S, Shen Z, Chen P. Ginsenoside Rg1 ameliorates palmitic acid-induced insulin resistance in HepG2 cells in association with modulating Akt and JNK activity. Pharmacol Rep. 2019;71(6):1160–7.CrossRefPubMed Mo J, Zhou Y, Yang R, Zhang P, He B, Yang J, Li S, Shen Z, Chen P. Ginsenoside Rg1 ameliorates palmitic acid-induced insulin resistance in HepG2 cells in association with modulating Akt and JNK activity. Pharmacol Rep. 2019;71(6):1160–7.CrossRefPubMed
24.
go back to reference Ding Y, Xia S, Fang H, Niu B, Chen Q. Loureirin B attenuates insulin resistance in HepG2 cells by regulating gluconeogenesis signaling pathway. Eur J Pharmacol. 2021;910:174481.CrossRefPubMed Ding Y, Xia S, Fang H, Niu B, Chen Q. Loureirin B attenuates insulin resistance in HepG2 cells by regulating gluconeogenesis signaling pathway. Eur J Pharmacol. 2021;910:174481.CrossRefPubMed
25.
go back to reference Xiao B, Mao J, Sun B, Zhang W, Wang Y, Wang P, Ruan Z, Xi W, Li H, Zhou J, et al. Integrin beta3 Deficiency Results in Hypertriglyceridemia via Disrupting LPL (Lipoprotein Lipase) Secretion. Arterioscler Thromb Vasc Biol. 2020;40(5):1296–310.CrossRefPubMed Xiao B, Mao J, Sun B, Zhang W, Wang Y, Wang P, Ruan Z, Xi W, Li H, Zhou J, et al. Integrin beta3 Deficiency Results in Hypertriglyceridemia via Disrupting LPL (Lipoprotein Lipase) Secretion. Arterioscler Thromb Vasc Biol. 2020;40(5):1296–310.CrossRefPubMed
26.
go back to reference Ben Salem M, Affes H, Athmouni K, Ksouda K, Dhouibi R, Sahnoun Z, Hammami S, Zeghal KM. Chemicals Compositions, Antioxidant and Anti-Inflammatory Activity of Cynara scolymus Leaves Extracts, and Analysis of Major Bioactive Polyphenols by HPLC. Evid Based Complement Alternat Med. 2017;2017:4951937.CrossRefPubMedPubMedCentral Ben Salem M, Affes H, Athmouni K, Ksouda K, Dhouibi R, Sahnoun Z, Hammami S, Zeghal KM. Chemicals Compositions, Antioxidant and Anti-Inflammatory Activity of Cynara scolymus Leaves Extracts, and Analysis of Major Bioactive Polyphenols by HPLC. Evid Based Complement Alternat Med. 2017;2017:4951937.CrossRefPubMedPubMedCentral
27.
go back to reference Zhu X, Zhang H, Lo R. Phenolic compounds from the leaf extract of artichoke (Cynara scolymus L.) and their antimicrobial activities. J Agric Food Chem. 2004;52(24):7272–8.CrossRefPubMed Zhu X, Zhang H, Lo R. Phenolic compounds from the leaf extract of artichoke (Cynara scolymus L.) and their antimicrobial activities. J Agric Food Chem. 2004;52(24):7272–8.CrossRefPubMed
28.
go back to reference Zuniga LY, Aceves-de la Mora MCA, Gonzalez-Ortiz M, Ramos-Nunez JL, Martinez-Abundis E. Effect of Chlorogenic Acid Administration on Glycemic Control, Insulin Secretion, and Insulin Sensitivity in Patients with Impaired Glucose Tolerance. J Med Food. 2018;21(5):469–73.CrossRefPubMed Zuniga LY, Aceves-de la Mora MCA, Gonzalez-Ortiz M, Ramos-Nunez JL, Martinez-Abundis E. Effect of Chlorogenic Acid Administration on Glycemic Control, Insulin Secretion, and Insulin Sensitivity in Patients with Impaired Glucose Tolerance. J Med Food. 2018;21(5):469–73.CrossRefPubMed
29.
go back to reference Ma Y, Gao M, Liu D. Chlorogenic acid improves high fat diet-induced hepatic steatosis and insulin resistance in mice. Pharm Res. 2015;32(4):1200–9.CrossRefPubMed Ma Y, Gao M, Liu D. Chlorogenic acid improves high fat diet-induced hepatic steatosis and insulin resistance in mice. Pharm Res. 2015;32(4):1200–9.CrossRefPubMed
30.
go back to reference Yao J, Zhang Y, Zhao J, Wang XZ, Lin YP, Sun L, Lu QY, Fan GJ. Efficacy of flavonoids-containing supplements on insulin resistance and associated metabolic risk factors in overweight and obese subjects: a systematic review and meta-analysis of 25 randomized controlled trials. Front Endocrinol (Lausanne). 2022;13:917692.CrossRefPubMed Yao J, Zhang Y, Zhao J, Wang XZ, Lin YP, Sun L, Lu QY, Fan GJ. Efficacy of flavonoids-containing supplements on insulin resistance and associated metabolic risk factors in overweight and obese subjects: a systematic review and meta-analysis of 25 randomized controlled trials. Front Endocrinol (Lausanne). 2022;13:917692.CrossRefPubMed
31.
go back to reference Fatima S, Hu X, Gong RH, Huang C, Chen M, Wong HLX, Bian Z, Kwan HY. Palmitic acid is an intracellular signaling molecule involved in disease development. Cell Mol Life Sci. 2019;76(13):2547–57.CrossRefPubMed Fatima S, Hu X, Gong RH, Huang C, Chen M, Wong HLX, Bian Z, Kwan HY. Palmitic acid is an intracellular signaling molecule involved in disease development. Cell Mol Life Sci. 2019;76(13):2547–57.CrossRefPubMed
33.
go back to reference Foretz M, Guigas B, Viollet B. Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus. Nat Rev Endocrinol. 2019;15(10):569–89.CrossRefPubMed Foretz M, Guigas B, Viollet B. Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus. Nat Rev Endocrinol. 2019;15(10):569–89.CrossRefPubMed
34.
go back to reference Ishii M, Maeda A, Tani S, Akagawa M. Palmitate induces insulin resistance in human HepG2 hepatocytes by enhancing ubiquitination and proteasomal degradation of key insulin signaling molecules. Arch Biochem Biophys. 2015;566:26–35.CrossRefPubMed Ishii M, Maeda A, Tani S, Akagawa M. Palmitate induces insulin resistance in human HepG2 hepatocytes by enhancing ubiquitination and proteasomal degradation of key insulin signaling molecules. Arch Biochem Biophys. 2015;566:26–35.CrossRefPubMed
35.
go back to reference Szydlowski M, Jablonska E, Juszczynski P. FOXO1 transcription factor: a critical effector of the PI3K-AKT axis in B-cell development. Int Rev Immunol. 2014;33(2):146–57.CrossRefPubMed Szydlowski M, Jablonska E, Juszczynski P. FOXO1 transcription factor: a critical effector of the PI3K-AKT axis in B-cell development. Int Rev Immunol. 2014;33(2):146–57.CrossRefPubMed
36.
go back to reference Cho H, Wu M, Zhang L, Thompson R, Nath A, Chan C. Signaling dynamics of palmitate-induced ER stress responses mediated by ATF4 in HepG2 cells. BMC Syst Biol. 2013;7:9–21.CrossRefPubMedPubMedCentral Cho H, Wu M, Zhang L, Thompson R, Nath A, Chan C. Signaling dynamics of palmitate-induced ER stress responses mediated by ATF4 in HepG2 cells. BMC Syst Biol. 2013;7:9–21.CrossRefPubMedPubMedCentral
37.
go back to reference Celik C, Lee SYT, Yap WS, Thibault G. Endoplasmic reticulum stress and lipids in health and diseases. Prog Lipid Res. 2023;89:101198.CrossRefPubMed Celik C, Lee SYT, Yap WS, Thibault G. Endoplasmic reticulum stress and lipids in health and diseases. Prog Lipid Res. 2023;89:101198.CrossRefPubMed
Metadata
Title
Artichoke (Cynara scolymus L.) water extract alleviates palmitate-induced insulin resistance in HepG2 hepatocytes via the activation of IRS1/PI3K/AKT/FoxO1 and GSK-3β signaling pathway
Authors
Aihua Deng
Yun Wang
Kerui Huang
Peng Xie
Ping Mo
Fengying Liu
Jun Chen
Kaiyi Chen
Yun Wang
Bing Xiao
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2023
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-023-04275-3

Other articles of this Issue 1/2023

BMC Complementary Medicine and Therapies 1/2023 Go to the issue