Journal of Yeungnam Medical Science

영남대 의대 학술지 편집위원회 (Yeungnam University College of Medicine, Yeungnam University Institute Medical Science)
권호 표지
DOI QR코드

DOI QR Code

DA-6034 ameliorates hepatic steatosis and inflammation in high fat diet-induced obese mice

  • Hong Min Kim (Astrogen Inc.) ;
  • Mi-Hye Kwon (The East Coast Research Institute of Life Science, Gangneung-Wonju National University) ;
  • Eun Soo Lee (Department of Internal Medicine, Yonsei University Wonju College of Medicine) ;
  • Kyung Bong Ha (Department of Clinical Research, Vaccine Center for Assisting Safety & Technology) ;
  • Choon Hee Chung (Department of Internal Medicine, Yonsei University Wonju College of Medicine)
  • 투고 : 2023.12.14
  • 심사 : 2024.02.09
  • 발행 : 2024.04.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Background: Nonalcoholic fatty liver disease (NAFLD) is characterized by an increase in hepatic triglyceride content and increased inflammatory macrophage infiltration through the C-C motif chemokine receptor (CCR) 5 pathway in the liver. DA-6034 (7-carboxymethyloxy-3',4',5-trimethoxy flavone), is a synthetic derivative of eupatilin that exhibits anti-inflammatory activity in inflammatory bowel disease. However, the effect of DA-6034 on the inflammatory response in NAFLD is not well elucidated. Therefore, we aimed to determine the effect of DA-6034 on hepatic steatosis and inflammation. Methods: Forty male C57BL/6J mice were divided into the following four groups: (1) regular diet (RD), (2) RD with DA-6034, (3) high fat diet (HFD), and (4) HFD with DA-6034. All mice were sacrificed 12 weeks after the start of the experiment. The effects of DA-6034 on macrophages were assessed using RAW 264.7 cells. Results: DA-6034 not only reduced hepatic triglyceride levels and lipid accumulation but also macrophage infiltration and proinflammatory cytokines in HFD-fed mice. According to fluorescence-activated cell sorter analysis, DA-6034 reduced the CD8+ T cell fraction in the liver of HFD-fed mice. DA-6034 also reduced CCR5 expression and the migration of liver macrophages in HFD-fed mice and inhibited CCR2 ligand and CCR4 ligand, which stimulated the migration of macrophages. Conclusion: Overall, DA-6034 attenuates hepatic steatosis and inflammation in obesity by regulating CCR5 expression in macrophages.

키워드

과제정보

This research was supported by the Basic Science Research Program through the National Research Program of the National Research Foundation of Korea (NRF) funded by the Korea government (MSIT) (NRF-2021R1A2B5B01002354) and Ministry of Education (NRF-2019R1I1A1A01042030).

참고문헌

  1. Tiniakos DG, Vos MB, Brunt EM. Nonalcoholic fatty liver disease: pathology and pathogenesis. Annu Rev Pathol 2010;5:145-71. https://doi.org/10.1146/annurev-pathol-121808-102132
  2. Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science 2011;332:1519-23. https://doi.org/10.1126/science.1204265
  3. Koyama Y, Brenner DA. Liver inflammation and fibrosis. J Clin Invest 2017;127:55-64. https://doi.org/10.1172/JCI88881
  4. Liu T, Zhang L, Joo D, Sun SC. NF-κB signaling in inflammation. Signal Transduct Target Ther 2017;2:17023.
  5. Baker RG, Hayden MS, Ghosh S. NF-κB, inflammation, and metabolic disease. Cell Metab 2011;13:11-22. https://doi.org/10.1016/j.cmet.2010.12.008
  6. Tak PP, Firestein GS. NF-kappaB: a key role in inflammatory diseases. J Clin Invest 2001;107:7-11. https://doi.org/10.1172/JCI11830
  7. Lee BC, Lee J. Cellular and molecular players in adipose tissue inflammation in the development of obesity-induced insulin resistance. Biochim Biophys Acta 2014;1842:446-62. https://doi.org/10.1016/j.bbadis.2013.05.017
  8. Monteiro R, Azevedo I. Chronic inflammation in obesity and the metabolic syndrome. Mediators Inflamm 2010;2010:289645.
  9. Fei X, Chen C, Kai S, Fu X, Man W, Ding B, et al. Eupatilin attenuates the inflammatory response induced by intracerebral hemorrhage through the TLR4/MyD88 pathway. Int Immunopharmacol 2019;76:105837.
  10. Du L, Chen J, Xing YQ. Eupatilin prevents H2O2-induced oxidative stress and apoptosis in human retinal pigment epithelial cells. Biomed Pharmacother 2017;85:136-40. https://doi.org/10.1016/j.biopha.2016.11.108
  11. Zhong WF, Wang XH, Pan B, Li F, Kuang L, Su ZX. Eupatilin induces human renal cancer cell apoptosis via ROS-mediated MAPK and PI3K/AKT signaling pathways. Oncol Lett 2016;12:2894-9. https://doi.org/10.3892/ol.2016.4989
  12. Lee S, Lee M, Kim SH. Eupatilin inhibits H(2)O(2)-induced apoptotic cell death through inhibition of mitogen-activated protein kinases and nuclear factor-kappaB. Food Chem Toxicol 2008;46:2865-70. https://doi.org/10.1016/j.fct.2008.05.026
  13. Kim YW, Lee WH, Choi SM, Seo YY, Ahn BO, Kim SH, et al. DA6034 promotes gastric epithelial cell migration and wound-healing through the mTOR pathway. J Gastroenterol Hepatol 2012;27:397-405. https://doi.org/10.1111/j.1440-1746.2011.06873.x
  14. Chung HJ, Choi YH, Choi HD, Jang JM, Shim HJ, Yoo M, et al. Pharmacokinetics of DA-6034, an agent for inflammatory bowel disease, in rats and dogs: contribution of intestinal first-pass effect to low bioavailability in rats. Eur J Pharm Sci 2006;27:363-74. https://doi.org/10.1016/j.ejps.2005.11.008
  15. Kim YS, Son M, Ko JI, Cho H, Yoo M, Kim WB, et al. Effect of DA-6034, a derivative of flavonoid, on experimental animal models of inflammatory bowel disease. Arch Pharm Res 1999;22:354-60. https://doi.org/10.1007/BF02979057
  16. Jump DB, Botolin D, Wang Y, Xu J, Christian B, Demeure O. Fatty acid regulation of hepatic gene transcription. J Nutr 2005;135:2503-6. https://doi.org/10.1093/jn/135.11.2503
  17. Pettinelli P, Obregon AM, Videla LA. Molecular mechanisms of steatosis in nonalcoholic fatty liver disease. Nutr Hosp 2011;26:441-50.
  18. Kuan YC, Hashidume T, Shibata T, Uchida K, Shimizu M, Inoue J, et al. Heat shock protein 90 modulates lipid homeostasis by regulating the stability and function of sterol regulatory element-binding protein (SREBP) and SREBP cleavage-activating protein. J Biol Chem 2017;292:3016-28. https://doi.org/10.1074/jbc.M116.767277
  19. Ko SH, Yoo DY, Kim YJ, Choi SM, Kang KK, Kim H, et al. A mechanism for the action of the compound DA-6034 on NF-κB pathway activation in Helicobacter pylori-infected gastric epithelial cells. Scand J Immunol 2011;74:253-63. https://doi.org/10.1111/j.1365-3083.2011.02577.x
  20. Stienstra R, Netea-Maier RT, Riksen NP, Joosten LA, Netea MG. Specific and complex reprogramming of cellular metabolism in myeloid cells during innate immune responses. Cell Metab 2017;26:142-56. https://doi.org/10.1016/j.cmet.2017.06.001
  21. Reilly SM, Saltiel AR. Adapting to obesity with adipose tissue inflammation. Nat Rev Endocrinol 2017;13:633-43. https://doi.org/10.1038/nrendo.2017.90
  22. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003;112:1796-808. https://doi.org/10.1172/JCI200319246
  23. Stienstra R, Saudale F, Duval C, Keshtkar S, Groener JE, van Rooijen N, et al. Kupffer cells promote hepatic steatosis via interleukin-1beta-dependent suppression of peroxisome proliferator-activated receptor alpha activity. Hepatology 2010;51:511-22. https://doi.org/10.1002/hep.23337
  24. Morgan PK, Huynh K, Pernes G, Miotto PM, Mellett NA, Giles C, et al. Macrophage polarization state affects lipid composition and the channeling of exogenous fatty acids into endogenous lipid pools. J Biol Chem 2021;297:101341.
  25. Castoldi A, Monteiro LB, van Teijlingen Bakker N, Sanin DE, Rana N, Corrado M, et al. Triacylglycerol synthesis enhances macrophage inflammatory function. Nat Commun 2020;11:4107.
  26. Manne V, Handa P, Kowdley KV. Pathophysiology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Clin Liver Dis 2018;22:23-37. https://doi.org/10.1016/j.cld.2017.08.007
  27. Maeda S, Chang L, Li ZW, Luo JL, Leffert H, Karin M. IKKbeta is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFalpha. Immunity 2003;19:725-37. https://doi.org/10.1016/S1074-7613(03)00301-7
  28. Luedde T, Assmus U, Wustefeld T, Meyer zu Vilsendorf A, Roskams T, Schmidt-Supprian M, et al. Deletion of IKK2 in hepatocytes does not sensitize these cells to TNF-induced apoptosis but protects from ischemia/reperfusion injury. J Clin Invest 2005;115:849-59. https://doi.org/10.1172/JCI23493
  29. Luedde T, Schwabe RF. NF-κB in the liver: linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2011;8:108-18. https://doi.org/10.1038/nrgastro.2010.213
  30. Stone MJ, Hayward JA, Huang C, E Huma Z, Sanchez J. Mechanisms of regulation of the chemokine-receptor network. Int J Mol Sci 2017;18:342.
  31. Yang H, Zhang Q, Xu M, Wang L, Chen X, Feng Y, et al. CCL2-CCR2 axis recruits tumor associated macrophages to induce immune evasion through PD-1 signaling in esophageal carcinogenesis. Mol Cancer 2020;19:41.
  32. Parker R, Weston CJ, Miao Z, Corbett C, Armstrong MJ, Ertl L, et al. CC chemokine receptor 2 promotes recruitment of myeloid cells associated with insulin resistance in nonalcoholic fatty liver disease. Am J Physiol Gastrointest Liver Physiol 2018;314:G483-93. https://doi.org/10.1152/ajpgi.00213.2017
  33. Lee SJ, Kang JS, Kim HM, Lee ES, Lee JH, Chung CH, et al. CCR2 knockout ameliorates obesity-induced kidney injury through inhibiting oxidative stress and ER stress. PLoS One 2019;14:e0222352.
  34. Gutierrez DA, Kennedy A, Orr JS, Anderson EK, Webb CD, Gerrald WK, et al. Aberrant accumulation of undifferentiated myeloid cells in the adipose tissue of CCR2-deficient mice delays improvements in insulin sensitivity. Diabetes 2011;60:2820-9. https://doi.org/10.2337/db11-0314
  35. Kitade H, Sawamoto K, Nagashimada M, Inoue H, Yamamoto Y, Sai Y, et al. CCR5 plays a critical role in obesity-induced adipose tissue inflammation and insulin resistance by regulating both macrophage recruitment and M1/M2 status. Diabetes 2012;61:1680-90. https://doi.org/10.2337/db11-1506
  36. Huh JH, Kim HM, Lee ES, Kwon MH, Lee BR, Ko HJ, et al. Dual CCR2/5 antagonist attenuates obesity-induced insulin resistance by regulating macrophage recruitment and M1/M2 status. Obesity (Silver Spring) 2018;26:378-86. https://doi.org/10.1002/oby.22103
  37. Kim HM, Kim YM, Huh JH, Lee ES, Kwon MH, Lee BR, et al. α-Mangostin ameliorates hepatic steatosis and insulin resi stance by inhibition C-C chemokine receptor 2. PLoS One 2017;12:e0179204.
  38. Ambade A, Lowe P, Kodys K, Catalano D, Gyongyosi B, Cho Y, et al. Pharmacological inhibition of CCR2/5 signaling prevents and reverses alcohol-induced liver damage, steatosis, and inflammation in mice. Hepatology 2019;69:1105-21. https://doi.org/10.1002/hep.30249
  39. Tosello-Trampont AC, Landes SG, Nguyen V, Novobrantseva TI, Hahn YS. Kuppfer cells trigger nonalcoholic steatohepatitis development in diet-induced mouse model through tumor necrosis factor-α production. J Biol Chem 2012;287:40161-72. https://doi.org/10.1074/jbc.M112.417014
  40. Han R, Zhang F, Wan C, Liu L, Zhong Q, Ding W. Effect of perfluorooctane sulphonate-induced Kupffer cell activation on hepatocyte proliferation through the NF-κB/TNF-α/IL-6-dependent pathway. Chemosphere 2018;200:283-94. https://doi.org/10.1016/j.chemosphere.2018.02.137