Chlorogenic Acid Inhibits Ceramide Accumulation to Restrain Hepatic Glucagon Response

Overview

Journal Nutrients

Date 2023 Jul 29

PMID 37513589

Authors

Na Xiao

Tengfei Zhang

Mingli Han

Dan Tian

Jiawei Liu

Shan Li

Lele Yang

Guojun Pan

Affiliations

Soon will be listed here.

Abstract

Chlorogenic acid (CGA), a dietary natural phenolic acid, has been widely reported to regulate glucose and lipid metabolism. However, the protective effects and the underlying mechanisms of CGA on glucagon-induced hepatic glucose production remain largely uncharacterized. Herein, we investigated the efficacy of CGA on hepatic gluconeogenesis both in vivo and in vitro. The elevated levels of endogenous glucose production induced by infusion of glucagon or pyruvate were lowered in mice administered with CGA. Furthermore, chronic CGA treatment ameliorated the accumulation of glucose and ceramide in high-fat diet (HFD)-fed mice. CGA also attenuated HFD-fed-induced inflammation response. The protective effect of CGA on glucose production was further confirmed in primary mouse hepatocytes by inhibiting accumulation of ceramide and expression of p38 MAPK. Moreover, CGA administration in HFD-fed mice preserved the decreased phosphorylation of Akt in the liver, resulting in the inhibition of FoxO1 activation and, ultimately, hepatic gluconeogenesis. However, these protective effects were significantly attenuated by the addition of C2 ceramide. These results suggest that CGA inhibits ceramide accumulation to restrain hepatic glucagon response.

References

Wang Y, Yan S, Xiao B, Zuo S, Zhang Q, Chen G . Prostaglandin F Facilitates Hepatic Glucose Production Through CaMKIIγ/p38/FOXO1 Signaling Pathway in Fasting and Obesity. Diabetes. 2018; 67(9):1748-1760. DOI: 10.2337/db17-1521. View

Liang N, Kitts D . Chlorogenic Acid (CGA) Isomers Alleviate Interleukin 8 (IL-8) Production in Caco-2 Cells by Decreasing Phosphorylation of p38 and Increasing Cell Integrity. Int J Mol Sci. 2018; 19(12). PMC: 6320834. DOI: 10.3390/ijms19123873. View

Zhang W, Pan A, Zhang X, Ying A, Ma G, Liu B . Inactivation of NF-κB2 (p52) restrains hepatic glucagon response via preserving PDE4B induction. Nat Commun. 2019; 10(1):4303. PMC: 6754499. DOI: 10.1038/s41467-019-12351-x. View

Baker R, Hayden M, Ghosh S . NF-κB, inflammation, and metabolic disease. Cell Metab. 2011; 13(1):11-22. PMC: 3040418. DOI: 10.1016/j.cmet.2010.12.008. View

Matsuzaka T, Kuba M, Koyasu S, Yamamoto Y, Motomura K, Arulmozhiraja S . Hepatocyte ELOVL Fatty Acid Elongase 6 Determines Ceramide Acyl-Chain Length and Hepatic Insulin Sensitivity in Mice. Hepatology. 2019; 71(5):1609-1625. DOI: 10.1002/hep.30953. View

Laakso M . Biomarkers for type 2 diabetes. Mol Metab. 2019; 27S:S139-S146. PMC: 6768493. DOI: 10.1016/j.molmet.2019.06.016. View

Taylor S, Shahidzadeh Yazdi Z, Beitelshees A . Pharmacological treatment of hyperglycemia in type 2 diabetes. J Clin Invest. 2021; 131(2). PMC: 7810496. DOI: 10.1172/JCI142243. View

Norton L, Shannon C, Gastaldelli A, DeFronzo R . Insulin: The master regulator of glucose metabolism. Metabolism. 2022; 129:155142. DOI: 10.1016/j.metabol.2022.155142. View

Unger R, Cherrington A . Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J Clin Invest. 2012; 122(1):4-12. PMC: 3248306. DOI: 10.1172/JCI60016. View

10.

Shah S, Iqbal M, Karam J, Salifu M, McFarlane S . Oxidative stress, glucose metabolism, and the prevention of type 2 diabetes: pathophysiological insights. Antioxid Redox Signal. 2007; 9(7):911-29. DOI: 10.1089/ars.2007.1629. View

11.

Maceyka M, Spiegel S . Sphingolipid metabolites in inflammatory disease. Nature. 2014; 510(7503):58-67. PMC: 4320971. DOI: 10.1038/nature13475. View

12.

Perry R . Regulation of Hepatic Lipid and Glucose Metabolism by INSP3R1. Diabetes. 2022; 71(9):1834-1841. PMC: 9450566. DOI: 10.2337/dbi22-0003. View

13.

Bechmann L, Hannivoort R, Gerken G, Hotamisligil G, Trauner M, Canbay A . The interaction of hepatic lipid and glucose metabolism in liver diseases. J Hepatol. 2011; 56(4):952-64. DOI: 10.1016/j.jhep.2011.08.025. View

14.

Naveed M, Hejazi V, Abbas M, Kamboh A, Khan G, Shumzaid M . Chlorogenic acid (CGA): A pharmacological review and call for further research. Biomed Pharmacother. 2017; 97:67-74. DOI: 10.1016/j.biopha.2017.10.064. View

15.

Liu Q, Zhang F, Zhang W, Pan A, Yang Y, Liu J . Ginsenoside Rg1 Inhibits Glucagon-Induced Hepatic Gluconeogenesis through Akt-FoxO1 Interaction. Theranostics. 2017; 7(16):4001-4012. PMC: 5667421. DOI: 10.7150/thno.18788. View

16.

Bhandarkar N, Brown L, Panchal S . Chlorogenic acid attenuates high-carbohydrate, high-fat diet-induced cardiovascular, liver, and metabolic changes in rats. Nutr Res. 2019; 62:78-88. DOI: 10.1016/j.nutres.2018.11.002. View

17.

Turpin-Nolan S, Bruning J . The role of ceramides in metabolic disorders: when size and localization matters. Nat Rev Endocrinol. 2020; 16(4):224-233. DOI: 10.1038/s41574-020-0320-5. View

18.

Shi H, Shi A, Dong L, Lu X, Wang Y, Zhao J . Chlorogenic acid protects against liver fibrosis in vivo and in vitro through inhibition of oxidative stress. Clin Nutr. 2016; 35(6):1366-1373. DOI: 10.1016/j.clnu.2016.03.002. View

19.

Pan A, Sun X, Huang F, Liu J, Cai Y, Wu X . The mitochondrial β-oxidation enzyme HADHA restrains hepatic glucagon response by promoting β-hydroxybutyrate production. Nat Commun. 2022; 13(1):386. PMC: 8770464. DOI: 10.1038/s41467-022-28044-x. View

20.

Cao W, Collins Q, Becker T, Robidoux J, Lupo Jr E, Xiong Y . p38 Mitogen-activated protein kinase plays a stimulatory role in hepatic gluconeogenesis. J Biol Chem. 2005; 280(52):42731-7. DOI: 10.1074/jbc.M506223200. View