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Silibinin Inhibits Adipogenesis and Induces Apoptosis in 3T3-L1 Adipocytes

Silibnin의 지방세포분화 억제 및 세포사멸 유도 효과

  • Lee, Seul Gi (Department of Food Science and Biotechnology, Kyungpook National University) ;
  • Kwon, Taeg Kyu (Department of Immunology, School of Medicine, Keimyung University) ;
  • Nam, Ju-Ock (Department of Food Science and Biotechnology, Kyungpook National University)
  • 이슬기 (경북대학교 농업생명과학대학 식품공학부) ;
  • 권택규 (계명대학교 의과대학 면역학교실) ;
  • 남주옥 (경북대학교 농업생명과학대학 식품공학부)
  • Received : 2016.10.24
  • Accepted : 2017.03.15
  • Published : 2017.03.28

Abstract

$C/EBP{\beta}$ and $C/EBP{\delta}$ are required for the initiation of adipogenesis and induce the expression of key adipogenic regulators, such as $PPAR{\gamma}$ and $C/EBP{\alpha}$. In the present study, we have examined the effects of silibinin and its possible molecular mechanisms in regulating adipocyte differentiation and expression of $C/EBP{\beta}$ and $C/EBP{\delta}$ in the early stage of adipogenesis. Silibinin statistically significantly inhibits intracellular lipid accumulation and the mRNA expression of various genes involved at different stages during adipogenesis. Silibinin also suppresses expression of lipoprotein lipase (LPL), fatty acid binding protein 4 (AP2), and adiponectin in 3T3-L1 adipocytes. Thus, the anti-adipogenic effect of silibinin seems to originate from the ability to inhibit the expression of $C/EBP{\beta}$ and $C/EBP{\delta}$. Furthermore, silibinin decreases cell viability for differentiation period and induces apoptotic cell death through capspase-3 activation.

CCAAT/enhancer-binding protein beta, delta ($C/EBP{\beta}$, ${\delta}$)는 지방세포분화 과정의 초기에 필수적으로 요구되며 지방생성 주요 조절인자인 proliferator-activated receptor gamma ($PPAR{\gamma}$) and CCAAT/enhancer-binding protein-alpha ($C/EBP{\alpha}$)의 발현을 유도한다. 본 연구에서는 silibinin의 지방세포 분화 억제 효과 및 이러한 효과가 지방세포 분화초기에 $C/EBP{\beta}$$C/EBP{\delta}$의 발현 조절을 통해 일어난 다는 것을 확인하였다. Silibinin은 지방세포 내 지질축적을 억제하고 세포분화 과정 동안 관여하는 다양한 유전자의 mRNA 발현을 억제하였다. 또한 lipoprotein lipase (LPL), fatty acid binding protein 4 (AP2) 및 adiponectin과 같은 지방세포 분화 관련 유전자의 발현을 억제시켰다. 따라서, Silibinin의 지방세포 분화 억제효과는 $C/EBP{\beta}$$C/EBP{\delta}$의 발현억제에 의한 것으로 보인다. 더불어, Silibinin은 capspase-3 활성을 통해 분화하는 세포에 특이적으로 세포사멸을 유도하는 것을 확인하였다.

Keywords

References

  1. Park JY, Kim Y, Im JA, You S, Lee H. 2014. Inhibition of adipogenesis by oligonol through Akt-mTOR inhibition in 3T3-L1 adipocytes. 2014: 11.
  2. Yang JY, Della-Fera MA, Rayalam S, Ambati S, Hartzell DL, Park HJ, et al. 2008. Enhanced inhibition of adipogenesis and induction of apoptosis in 3T3-L1 adipocytes with combinations of resveratrol and quercetin. Life Sci. 82: 1032-1039. https://doi.org/10.1016/j.lfs.2008.03.003
  3. Kim M, Park JE, Song SB, Cha YS. 2015. Effects of black adzuki bean (Vigna angularis) extract on proliferation and. Nutrients 7: 277-292. https://doi.org/10.3390/nu7010277
  4. Rayalam S, Yang JY, Ambati S, Della-Fera MA, Baile CA. 2008. Resveratrol induces apoptosis and inhibits adipogenesis in 3T3-L1 adipocytes. Phytotherapy Research : PTR. 22: 1367-1371. https://doi.org/10.1002/ptr.2503
  5. Min B, Lee H, Song JH, Han MJ, Chung J. 2014. Arctiin inhibits adipogenesis in 3T3-L1 cells and decreases adiposity and body weight in mice fed a high-fat diet. Nutr. Res. Pract. 8: 655-661. https://doi.org/10.4162/nrp.2014.8.6.655
  6. Lechner S, Mitterberger MC, Mattesich M, Zwerschke W. 2013. Role of C/EBPbeta-LAP and C/EBPbeta-LIP in early adipogenic differentiation of human white adipose-derived progenitors and at later stages in immature adipocytes. Differentiation 85: 20-31. https://doi.org/10.1016/j.diff.2012.11.001
  7. Hishida T, Nishizuka M, Osada S, Imagawa M. 2009. The role of C/EBPdelta in the early stages of adipogenesis. Biochimie. 91: 654-657. https://doi.org/10.1016/j.biochi.2009.02.002
  8. Moon J, Do HJ, Kim OY, Shin MJ. 2013. Antiobesity effects of quercetin-rich onion peel extract on the differentiation of 3T3-L1 preadipocytes and the adipogenesis in high fat-fed rats. Food Chem. Toxicol. 58: 347-354. https://doi.org/10.1016/j.fct.2013.05.006
  9. Meltzer HM, Malterud KE. 1997. Can dietary flavonoids influence the development of coronary heart disease? Scand. J. Nutr. Naringsforsk. 41: 50-57.
  10. Wang HJ, Jiang YY, Lu P, Wang Q, Ikejima T. 2010. An updated review at molecular pharmacological level for the mechanism of anti-tumor, antioxidant and immunoregulatory action of silibinin. Yao xue xue bao = Acta pharmaceutica Sinica. 45: 413-421.
  11. Cristofalo R, Bannwart-Castro CF, Magalhaes CG, Borges VT, Peracoli JC, Witkin SS, et al. 2013. Silibinin attenuates oxidative metabolism and cytokine production by monocytes from preeclamptic women. Free Radical Res. 47: 268-275. https://doi.org/10.3109/10715762.2013.765951
  12. Ka SO, Kim KA, Kwon KB, Park JW, Park BH. 2009. Silibinin attenuates adipogenesis in 3T3-L1 preadipocytes through a potential upregulation of the insig pathway. Int. J. Molecul. Med. 23: 633-637.
  13. Suh HJ, Cho SY, Kim EY, Choi HS. 2015. Blockade of lipid accumulation by silibinin in adipocytes and zebrafish. Chemico-biological Interactions 227: 53-62. https://doi.org/10.1016/j.cbi.2014.12.027
  14. Yoo SR, Seo CS, Shin HK, Jeong SJ. 2015. Traditional herbal formula Oyaksungi-San inhibits adipogenesis in 3T3-L1 adipocytes. 2015: 949461.
  15. Lefterova MI, Lazar MA. 2009. New developments in adipogenesis. Trends in Endocrinology and Metabolism: TEM. 20: 107-114. https://doi.org/10.1016/j.tem.2008.11.005
  16. Kim M, Park JE, Song SB, Cha YS. 2015. Effects of black adzuki bean (Vigna angularis) extract on proliferation and differentiation of 3T3-L1 preadipocytes into mature adipocytes. Nutrients 7: 277-292. https://doi.org/10.3390/nu7010277
  17. Porter AG, Janicke RU. 1999. Emerging roles of caspase-3 in apoptosis. Cell Death and Differentiation 6: 99-104. https://doi.org/10.1038/sj.cdd.4400476
  18. Zhuang S, Demirs JT, Kochevar IE. 2000. p38 mitogen-activated protein kinase mediates bid cleavage, mitochondrial dysfunction, and caspase-3 activation during apoptosis induced by singlet oxygen but not by hydrogen peroxide. J. Biol. Chem. 275: 25939-25948. https://doi.org/10.1074/jbc.M001185200
  19. Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R. 2009. Diabetes and cancer. Endocrine-related Cancer. 16: 1103-1123. https://doi.org/10.1677/ERC-09-0087
  20. Dhanalakshmi S, Singh RP, Agarwal C, Agarwal R. 2002. Silibinin inhibits constitutive and TNFalpha-induced activation of NF-kappaB and sensitizes human prostate carcinoma DU145 cells to TNFalpha-induced apoptosis. Oncogene 21: 1759-1767. https://doi.org/10.1038/sj.onc.1205240
  21. Katiyar SK. 2005. Silymarin and skin cancer prevention: antiinflammatory, antioxidant and immunomodulatory effects (Review). Int. J. Oncol. 26: 169-176.
  22. Qiu Z, Wei Y, Chen N, Jiang M, Wu J, Liao K. 2001. DNA synthesis and mitotic clonal expansion is not a required step for 3T3-L1 preadipocyte differentiation into adipocytes. J. Biol. Chem. 276: 11988-11995. https://doi.org/10.1074/jbc.M011729200
  23. Lane MD, Tang QQ, Jiang MS. 1999. Role of the CCAAT enhancer binding proteins (C/EBPs) in adipocyte differentiation. Biochemical and Biophysical Research Communications 266: 677-683. https://doi.org/10.1006/bbrc.1999.1885
  24. Sun X, Zemel MB. 2004. Role of uncoupling protein 2 (UCP2) expression and 1alpha, 25-dihydroxyvitamin D3 in modulating adipocyte apoptosis. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology 18: 1430-1432. https://doi.org/10.1096/fj.04-1971fje

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