한방비만학회지 (Journal of Korean Medicine for Obesity Research)

  • 제20권1호
  • /
  • Pages.1-9
  • /
  • 2020
  • /
  • 1976-9334(pISSN)
  • /
  • 2288-1522(eISSN)
한방비만학회 (The Society of Korean Medicine for obesity Research)
권호 표지
DOI QR코드

DOI QR Code

Inhibitory Effect of Dihydroartemisinin, An Active Ingredient of Artemisia annua, on Lipid Accumulation in Differentiating 3T3-L1 Preadipocytes

  • Jang, Byeong-Churl (Department of Molecular Medicine, College of Medicine, Keimyung University)
  • 투고 : 2020.04.02
  • 심사 : 2020.05.19
  • 발행 : 2020.06.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Objectives: Artemisinin and its derivatives extracted from Artemisia annua, a Chinese herbal medicine, have variable biological effects due to structural differences. Up to date, the anti-obesity effect of dihydroartemisinin (DHA), a derivative of artemisinin, is unknown. The purpose of this study was to investigate the anti-adipogenic and lipolytic effects of DHA on 3T3-L1 preadipocytes. Methods: Oil Red O staining and AdipoRed assay were used to measure lipid accumulation and triglyceride (TG) content in 3T3-L1 cells, respectively. Cell count analysis was used to determine the cytotoxicity of 3T3-L1 cells. Western blot and real-time reverse transcription polymerase chain reaction analyses were used to analyze the expression of protein and mRNA in 3T3-L1 cells, respectively. Results: DHA at 5 μM markedly inhibited lipid accumulation and reduced TG content in differentiating 3T3-L1 cells with no cytotoxicity. Furthermore, DHA at 5 μM inhibited the expression of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid synthase (FAS), and perilipin A as well as the phosphorylation of signal transducer and activator of transcription-3 (STAT-3) in differentiating 3T3-L1 cells. Moreover, while DHA at 5 μM had no effect on the mRNA expression of adiponectin, it strongly suppressed that of leptin in differentiating 3T3-L1 cells. However, DHA at 5 μM had no lipolytic effect on differentiated 3T3-L1 cells, as assessed by no enhancement of glycerol release. Conclusions: These results demonstrate that DHA at 5 μM has a strong anti-adipogenic effect on differentiating 3T3-L1 cells through the reduced expression and phosphorylation of C/EBP-α, PPAR-γ, FAS, perilipin A, and STAT-3.

키워드

참고문헌

  1. Kopelman PG. Obesity as a medical problem. Nature. 2000 ; 404(6778) : 635-43. https://doi.org/10.1038/35007508
  2. Abdelaal M, le Roux CW, Docherty NG. Morbidity and mortality associated with obesity. Ann Transl Med. 2017 ; 5(7) : 161. https://doi.org/10.21037/atm.2017.03.107
  3. Ali AT, Hochfeld WE, Myburgh R, Pepper MS. Adipocyte and adipogenesis. Eur J Cell Biol. 2013 ; 92(6-7) : 229-36. https://doi.org/10.1016/j.ejcb.2013.06.001
  4. Ghaben AL, Scherer PE. Adipogenesis and metabolic health. Nat Rev Mol Cell Biol. 2019 ; 20(4) : 242-58. https://doi.org/10.1038/s41580-018-0093-z
  5. Onal G, Kutlu O, Gozuacik D, Dokmeci Emre S. Lipid droplets in health and disease. Lipids Health Dis. 2017 ; 16(1) : 128. https://doi.org/10.1186/s12944-017-0521-7
  6. Cao Z, Umek RM, McKnight SL. Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes Dev. 1991 ; 5(9) : 1538-52. https://doi.org/10.1101/gad.5.9.1538
  7. Farmer SR. Transcriptional control of adipocyte formation. Cell Metab. 2006 ; 4(4) : 263-73. https://doi.org/10.1016/j.cmet.2006.07.001
  8. Lehrke M, Lazar MA. The many faces of PPARgamma. Cell. 2005 ; 123(6) : 993-9. https://doi.org/10.1016/j.cell.2005.11.026
  9. Lakshmanan MR, Nepokroeff CM, Porter JW. Control of the synthesis of fatty-acid synthetase in rat liver by insulin, glucagon, and adenosine 3':5' cyclic monophosphate. Proc Natl Acad Sci USA. 1972 ; 69(12) : 3516-9. https://doi.org/10.1073/pnas.69.12.3516
  10. Montalto MB, Bensadoun A. Lipoprotein lipase synthesis and secretion: effects of concentration and type of fatty acids in adipocyte cell culture. J Lipid Res. 1993 ; 34(3) : 397-407. https://doi.org/10.1016/S0022-2275(20)40731-X
  11. Beller M, Bulankina AV, Hsiao HH, Urlaub H, Jackle H, Kuhnlein RP. PERILIPIN-dependent control of lipid droplet structure and fat storage in drosophila. Cell Metab. 2010 ; 12(5) : 521-32. https://doi.org/10.1016/j.cmet.2010.10.001
  12. Kern PA, Di Gregorio G, Lu T, Rassouli N, Ranganathan G. Perilipin expression in human adipose tissue is elevated with obesity. J Clin Endocrinol Metab. 2004 ; 89(3) : 1352-8. https://doi.org/10.1210/jc.2003-031388
  13. Wolins NE, Brasaemle DL, Bickel PE. A proposed model of fat packaging by exchangeable lipid droplet proteins. FEBS Lett. 2006 ; 580(23) : 5484-91. https://doi.org/10.1016/j.febslet.2006.08.040
  14. Duncan RE, Ahmadian M, Jaworski K, Sarkadi-Nagy E, Sul HS. Regulation of lipolysis in adipocytes. Annu Rev Nutr. 2007 ; 27 : 79-101. https://doi.org/10.1146/annurev.nutr.27.061406.093734
  15. Greenberg AS, Shen WJ, Muliro K, Patel S, Souza SC, Roth RA, et al. Stimulation of lipolysis and hormone-sensitive lipase via the extracellular signal-regulated kinase pathway. J Biol Chem. 2001 ; 276(48) : 45456-61. https://doi.org/10.1074/jbc.M104436200
  16. Tu Y. Artemisinin-a gift from traditional chinese medicine to the world (nobel lecture). Angew Chem Int Ed Engl. 2016 ; 55(35) : 10210-26. https://doi.org/10.1002/anie.201601967
  17. Sevene E, Banda CG, Mukaka M, Maculuve S, Macuacua S, Vala A, et al. Efficacy and safety of dihydroartemisinin-piperaquine for treatment of plasmodium falciparum uncomplicated malaria in adult patients on antiretroviral therapy in Malawi and Mozambique: an open label non-randomized interventional trial. Malar J. 2019 ; 18(1) : 277. https://doi.org/10.1186/s12936-019-2909-5
  18. Qu C, Ma J, Liu X, Xue Y, Zheng J, Liu L, et al. Dihydroartemisinin exerts anti-tumor activity by inducing mitochondrion and endoplasmic reticulum apoptosis and autophagic cell death in human glioblastoma cells. Front Cell Neurosci. 2017 ; 11 : 310.
  19. Liu X, Lu J, Liao Y, Liu S, Chen Y, He R, et al. Dihydroartemisinin attenuates lipopolysaccharide-induced acute kidney injury by inhibiting inflammation and oxidative stress. Biomed Pharmacother. 2019 ; 117 : 109070. https://doi.org/10.1016/j.biopha.2019.109070
  20. Lu P, Zhang FC, Qian SW, Li X, Cui ZM, Dang YJ, et al. Artemisinin derivatives prevent obesity by inducing browning of WAT and enhancing BAT function. Cell Res. 2016 ; 26(10) : 1169-72. https://doi.org/10.1038/cr.2016.108
  21. Liu Y, Gao S, Zhu J, Zheng Y, Zhang H, Sun H. Dihydroartemisinin induces apoptosis and inhibits proliferation, migration, and invasion in epithelial ovarian cancer via inhibition of the hedgehog signaling pathway. Cancer Medicine. 2018 ; 7(11) : 5704-15. https://doi.org/10.1002/cam4.1827
  22. Jang BC. Artesunate inhibits adipogeneis in 3T3-L1 preadipocytes by reducing the expression and/or phosphorylation levels of $C/EBP-{\alpha}$, $PPAR-{\gamma}$, FAS, perilipin A, and STAT-3. Biochem Biophys Res Commun. 2016; 474(1) : 220-5. https://doi.org/10.1016/j.bbrc.2016.04.109
  23. Zalatan F, Krause JA, Blask DE. Inhibition of isoproterenol-induced lipolysis in rat inguinal adipocytes in vitro by physiological melatonin via a receptor-mediated mechanism. Endocrinology. 2001 ; 142(9) : 3783-90. https://doi.org/10.1210/en.142.9.3783
  24. Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, et al. $PPAR{\gamma}$ is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell. 1999 ; 4(4) : 611-7. https://doi.org/10.1016/S1097-2765(00)80211-7
  25. Linhart HG, Ishimura-Oka K, DeMayo F, Kibe T, Repka D, Poindexter B, et al. $C/EBP{\alpha}$ is required for differentiation of white, but not brown, adipose tissue. Proc Natl Acad Sci USA. 2001 ; 98(22) : 12532-7. https://doi.org/10.1073/pnas.211416898
  26. Stephens JM, Morrison RF, Pilch PF. The expression and regulation of STATs during 3T3-L1 adipocyte differentiation. J Biol Chem. 1996 ; 271(18) : 10441-4. https://doi.org/10.1074/jbc.271.18.10441
  27. Rosen ED, Hsu CH, Wang X, Sakai S, Freeman MW, Gonzalez FJ, et al. $C/EBP{\alpha}$ induces adipogenesis through $PPAR{\gamma}$: A unified pathway. Genes Dev. 2002 ; 16(1) : 22-6. https://doi.org/10.1101/gad.948702
  28. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004 ; 89(6) : 2548-56. https://doi.org/10.1210/jc.2004-0395
  29. Ahima RS. Adipose tissue as an endocrine organ. Obesity (Silver Spring). 2006 ; 14 Suppl 5 : 242S-9S. https://doi.org/10.1038/oby.2006.317
  30. Hwang CS, Loftus TM, Mandrup S, Lane MD. Adipocyte differentiation and leptin expression. Annu Rev Cell Dev Biol. 1997 ; 13 : 231-59. https://doi.org/10.1146/annurev.cellbio.13.1.231
  31. Bastard JP, Maachi M, Lagathu C, Kim MJ, Caron M, Vidal H, et al. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw. 2006 ; 17(1) : 4-12.
  32. Ceddia RB, Somwar R, Maida A, Fang X, Bikopoulos G, Sweeney G. Globular adiponectin increases GLUT4 translocation and glucose uptake but reduces glycogen synthesis in rat skeletal muscle cells. Diabetologia. 2005 ; 48(1) : 132-9. https://doi.org/10.1007/s00125-004-1609-y
  33. Shehzad A, Iqbal W, Shehzad O, Lee YS. Adiponectin: regulation of its production and its role in human diseases. Hormones (Athens). 2012 ; 11(1) : 8-20. https://doi.org/10.1007/BF03401534
  34. Yadav A, Kataria MA, Saini V, Yadav A. Role of leptin and adiponectin in insulin resistance. Clin Chim Acta Int J Clin Chem. 2013 ; 417 : 80-4. https://doi.org/10.1016/j.cca.2012.12.007
  35. Friedman J. Fat in all the wrong places. Nature. 2002 ; 415(6869) : 268-9. https://doi.org/10.1038/415268a
  36. Miyoshi H, Souza SC, Zhang HH, Strissel KJ, Christoffolete MA, Kovsan J, et al. Perilipin promotes hormone-sensitive lipase mediated adipocyte lipolysis via phosphorylation- dependent and -independent mechanisms. J Biol Chem. 2006 ; 281(23) : 15837-44. https://doi.org/10.1074/jbc.M601097200