Journal of the Society of Cosmetic Scientists of Korea (대한화장품학회지)

Society of Cosmetic Scientists of Korea (대한화장품학회)
권호 표지
DOI QR코드

DOI QR Code

Betaine Induces Epidermal Differentiation by Enhancement of Autophagy through an mTOR-independent Pathway

Betaine의 mTOR 비의존적 자가포식 작용 촉진에 의한 표피 분화 유도 효과

  • 최선국 ((주)LG생활건강 기술연구원) ;
  • 김미선 ((주)LG생활건강 기술연구원) ;
  • 김진현 ((주)LG생활건강 기술연구원) ;
  • 박선규 ((주)LG생활건강 기술연구원) ;
  • 이천구 ((주)LG생활건강 기술연구원) ;
  • 강내규 ((주)LG생활건강 기술연구원)
  • Received : 2018.03.11
  • Accepted : 2018.03.23
  • Published : 2018.03.31
Download PDF
⟨ Previous Next ⟩

Abstract

The epidermis which is stratified by epithelial tissue renewal based on keratinocyte differentiation protects the organism from various environmental insults by forming a physical barrier. Autophagy is a mechanism which mediates lysosomal delivery and degradation of protein aggregates, damaged organelles and intracellular microorganisms. Recent reports have shown that autophagy has critical roles for proper terminal differentiation to stratum corneum via removing metabolic organelles and nuclei. However, whether increasing autophagy can activate epidermal differentiation is unknown. Here, we screened a library of natural single compounds and discovered that betaine specifically increased the LC3 positive cytosolic punctate vesicles and LC3-I to LC3-II conversion in HaCaT human keratinocyte cell line, indicating increased autophagy flux. mTOR pathway, which negatively regulates autophagy, was not affected by betaine treatment, suggesting betaine-induced autophagy through an mTOR-independent pathway. Betaine-induced autophagy was also observed in primary human keratinocyte and skin equivalent. Furthermore, epidermal thickness was increased in skin equivalent under betaine treatment. Overall, our finding suggests that betaine as a novel regulator of autophagy may induce epidermal turnover and improve the skin barrier abnormality of the aged epidermis.

표피는 각질형성세포의 분화로부터 재생되어 계층화되는 상피 조직으로서 물리적 장벽을 형성함으로써 다양한 외부 오염원으로부터 개체를 보호한다. 자가포식 작용(autophagy)은 단백질 축적물, 손상된 세포 소기관, 세포내 미생물 등이 리소좀으로 운반되고 분해되도록 매개하는 기작이다. 최근 연구 결과에 의하면 자가포식 작용이 각질형성세포의 대사 기관과 핵을 제거하여 각질층으로 최종 분화하는데 중요한 역할을 하는 것이 보고 되었다. 그러나 자가포식 작용을 촉진함으로써 표피 분화를 유도할 수 있는지는 알려져 있지 않다. 본 연구에서는 천연물 유래 단일 화합물 라이브러리를 스크리닝하여 베타인(betaine)이 인간 각질형성세포주인 HaCaT 세포에서 세포질 내 LC3 punctate 소포체 및 LC3-I에서 LC3-II로의 변환을 증가시켜 자가포식 작용을 촉진함을 규명했다. 자가포식 작용의 억제 신호인 mTOR 경로는 베타인에 의해 영향을 받지 않았으므로, 베타인에 의해 유도된 자가포식 작용은 mTOR에 독립적임을 알 수 있었다. 베타인에 의해 촉진되는 자가포식 작용은 primary keratinocyte 및 skin equivalent에서도 관찰되었다. 또한, 베타인 처리된 인공피부에서 표피층 두께가 증가함을 확인하였다. 이러한 결과들로부터, 자가포식 작용의 새로운 조절소재로서 베타인이 표피의 턴오버를 촉진하여 표피의 장벽기능을 개선하고 피부노화를 방지할 수 있음을 시사한다.

Keywords

References

  1. P. A. Sotiropoulou and C. Blanpain., Development and homeostasis of the skin epidermis, Cold Spring Harb. Perspect. Biol., 4(7), a008383 (2012). https://doi.org/10.1101/cshperspect.a008383
  2. N. D. Magnani, X. M. Muresan, G. Belmonte, F. Cervellati, C. Sticozzi, A. Pecorelli, C. Miracco, T. Marchini, P. Evelson, and G. Valacchi, Skin damage mechanisms related to airborne particulate matter exposure, Toxicol. Sci., 149(1), 227 (2016). https://doi.org/10.1093/toxsci/kfv230
  3. R. R. Wickett and M. O. Visscher, Structure and function of the epidermal barrier, Am. J. Infect. Control., 34(10), S98 (2006). https://doi.org/10.1016/j.ajic.2006.05.295
  4. R. M. Lavker and A. G. Matoltsy, Formation of horny cells: the fate of cell organelles and differentiation products in ruminal epithelium, J. Cell. Biol., 44(3), 501 (1970). https://doi.org/10.1083/jcb.44.3.501
  5. R. M. Lavker, Horny cell formation in the epidermis of Rana pipiens, J. Morphol., 142(4), 365 (1974). https://doi.org/10.1002/jmor.1051420402
  6. O. Akinduro, K. Sully, A. Patel, D. J. Robinson, A. Chikh, G. McPhail, K. M. Braun, M. P. Philpott, C. A. Harwood, and C. Byrne, Constitutive autophagy and nucleophagy during epidermal differentiation, J. Invest. Dermatol., 136(7), 1460 (2016). https://doi.org/10.1016/j.jid.2016.03.016
  7. M. Moriyama, H. Moriyama, J. Uda, A. Matsuyama, M. Osawa, and T. Hayakawa, BNIP3 plays crucial roles in the differentiation and maintenance of epidermal keratinocytes, J. Invest. Dermatol., 134(6), 1627 (2014). https://doi.org/10.1038/jid.2014.11
  8. Y. Zhao, C. F. Zhang, H. Rossiter, L. Eckhart, U. Konig, S. Karner, M. Mildner, V. N. Bochkov, E. Tschachler, and F. Gruber, Autophagy is induced by UVA and promotes removal of oxidized phospholipids and protein aggregates in epidermal keratinocytes, J. Invest. Dermatol., 133(6), 1629 (2013). https://doi.org/10.1038/jid.2013.26
  9. L. Qiang, C. Wu, M. Ming, B. Viollet, and Y. Y. He, Autophagy controls p38 activation to promote cell survival under genotoxic stress, J. Biol. Chem., 288(3), 1603 (2013). https://doi.org/10.1074/jbc.M112.415224
  10. I. Hurbain, M. Romao, P. Sextius, E. Bourreau, C. Marchal, F. Bernerd, C. Duval, and G. Raposo, Melanosome distribution in keratinocytes in different skin types: melanosome clusters are not degradative organelles, J. Invest. Dermatol., 138(3), 647 (2018). https://doi.org/10.1016/j.jid.2017.09.039
  11. L. M. Griffin, L. Cicchini, and D. Pyeon, Human papillomavirus infection is inhibited by host autophagy in primary human keratinocytes, Virology, 437(1), 12 (2013). https://doi.org/10.1016/j.virol.2012.12.004
  12. K. H. Kim and M. S. Lee, Autophagy - a key player in cellular and body metabolism, Nat. Rev. Endocrinol., 10(6), 322 (2014). https://doi.org/10.1038/nrendo.2014.35
  13. S. Davidson, B. A. Hopkins, J. Odle, C. Brownie, V. Fellner, and L. W. Whitlow, Supplementing limited methionine diets with rumen-protected methionine, betaine, and choline in early lactation holstein cows, Journal of Dairy Science., 91(4), 1552 (2008). https://doi.org/10.3168/jds.2007-0721
  14. M. T. Kidd, P. R. Ferket, and J. D. Garlich, Nutritional and osmoregulatory functions of betaine, World's Poultry Science Journal, 53(2), 125 (2007).
  15. E. S. Basheva, S. Stoyanov, N. D. Denkov, K. Kasuga, N. Satoh, and K. Tsujii, Foam boosting by amphiphilic molecules in the presence of silicone oil, Langmuir, 17(4), 969 (2001). https://doi.org/10.1021/la001106a
  16. N. Mizushima, T. Yoshimorim, and B. Levine, Methods in mammalian autophagy research, Cell, 140(3), 313 (2010). https://doi.org/10.1016/j.cell.2010.01.028
  17. K. Khayati, H. Antikainen, E. M. Bonder, G. F. Weber, W. D. Kruger, H. Jakubowski, and R. Dobrowolski, The amino acid metabolite homocysteine activates mTORC1 to inhibit autophagy and form abnormal proteins in human neurons and mice, The FASEB Journal, 31(2), 598 (2017). https://doi.org/10.1096/fj.201600915R
  18. Q. Feng, K. Kalari, B. L. Fridley, G. Jenkins, Y. Ji, R. Abo, S. Hebbring, J. Zhang, M. D. Nye, J. S. Leeder, and R. M. Weinshilboum, Betaine-homocysteine methyltransferase: human liver genotype-phenotype correlation, Molecular genetics and metabolism, 102(2), 126 (2011). https://doi.org/10.1016/j.ymgme.2010.10.010
  19. E. Aymard, V. Barruche, T. Naves, S. Bordes, B. Closs, M. Verdier, and M. H. Ratinaud, Autophagy in human keratinocytes: an early step of the differentiation?, Exp. Dermatol., 20(3), 263 (2011). https://doi.org/10.1111/j.1600-0625.2010.01157.x
  20. Q. Dong, J. E. Oh, J. K. Yi, R. H. Kim, K. H. Shin, R. Mitsuyasu, N. H. Park, and M. K. Kang, Efavirenz induces autophagy and aberrant differentiation in normal human keratinocytes, Int. J. Mol. Med., 31(6), 1305 (2013). https://doi.org/10.3892/ijmm.2013.1327
  21. B. B. Bridgeman, P. Wang, B. Ye, J. C. Pelling, O. V. Volpert, and X. Tong, Inhibition of mTOR by apigenin in UVB-irradiated keratinocytes: A new implication of skin cancer prevention, Cellular signalling, 28(5), 460 (2016). https://doi.org/10.1016/j.cellsig.2016.02.008
  22. X. Chen, M. Li, L. Li, S. Xu, D. Huang, M. Ju, J. Huang, K. Chen, and H. Gu, Trehalose, sucrose and raffinose are novel activators of autophagy in human keratinocytes through an mTOR-independent pathway, Sci. Rep., 6, 28423 (2016). https://doi.org/10.1038/srep28423