Abstract
The oxysterol nuclear receptors, LXRα (liver X receptor α; NR1H3) and LXRβ (NR1H2), coordinately regulate the expression of genes involved in lipid metabolism, anti-inflammation, and cholesterol transport. Previous studies have demonstrated that ligands of LXRα are important in the maintenance of the normal epidermal barrier function and keratinocyte differentiation. In this study, we examined whether LXRα and its ligands regulate lipid synthesis in HaCaT cells, a spontaneously transformed human keratinocyte cell line. When HaCaT cells were treated with the LXRα ligand TO901317, lipid droplets accumulated in the majority of cells, which were stained by Oil Red O. A luciferase reporter construct containing the LXR response element was activated about fourfold in HaCaT cells by TO901317 treatment, suggesting that LXR has a role in lipid synthesis in these cells. The expression of LXRα target genes, such as those encoding sterol regulatory binding protein and fatty acid synthase, were induced time dependently by TO901317, as measured by RT-PCR and western blotting. The expression of PPAR-α, -β, and -γ which regulate lipid metabolism, was also increased by TO901317 treatment. In contrast, TO901317 reduced the lipopolysaccharide-induced expression of cyclooxygenase 2 and inducible nitric oxide synthase in HaCaT cells. These results indicate that LXRα activation leads to lipogenesis in keratinocytes, which may enhance the epidermal barrier function of the skin.
Similar content being viewed by others
References
Blumenberg, M., Connolly, D. M., and Freedberg, I. M., Regulation of keratin gene expression: the role of the nuclear receptors for retinoic acid, thyroid hormone, and vitamin D3. J. Invest. Dermatol., 98, 42S–49S (1992).
Boukamp, P., Petrussevska, R. T., Breitkreutz, D., Hornung, J., Markham, A., and Fusenig, N. E., Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J. Cell Biol., 106, 761–771 (1988).
Chang, K. C., Shen, Q., Oh, I. G., Jelinsky, S. A., Jenkins, S. F., Wang, W., Wang, Y., LaCava, M., Yudt, M. R., Thompson, C. C., Freedman, L. P., Chung, J. H., and Nagpal, S., Liver X receptor is a therapeutic target for photoaging and chronological skin aging. Mol. Endocrinol., 22, 2407–2419 (2008).
Chua, R. A. and Arbiser, J. L., The role of angiogenesis in the pathogenesis of psoriasis. Autoimmunity, 42, 574–579 (2009).
Fisher, G. J., Datta, S. C., Talwar, H. S., Wang, Z. Q., Varani, J., Kang, S., and Voorhees, J. J., Molecular basis of sun induced premature skin ageing and retinoid antagonism. Nature, 379, 335–339 (1996).
Fisher, G. J., Kang, S., Varani, J., Bata-Csorgo, Z., Wan, Y., Datta, S., and Voorhees, J. J., Mechanisms of photoaging and chronological skin aging. Arch. Dermatol., 138, 1462–1470 (2002).
Fowler, A. J., Sheu, M. Y., Schmuth, M., Kao, J., Fluhr, J. W., Rhein, L., Collins, J. L., Willson, T. M., Mangelsdorf, D. J., Elias, P. M., and Feingold, K. R., Liver X receptor activators display anti-inflammatory activity in irritant and allergic contact dermatitis models: liver-X-receptorspecific inhibition of inflammation and primary cytokine production. J. Invest. Dermatol., 120, 246–255 (2003).
Hanley, K., Jiang, Y., He, S. S., Friedman, M., Elias, P. M., Bikle, D. D., Williams, M. L., and Feingold, K. R., Keratinocyte differentiation is stimulated by activators of the nuclear hormone receptor PPARalpha. J. Invest. Dermatol., 110, 368–375 (1998).
Hanley, K., Ng, D. C., He, S. S., Lau, P., Min, K., Elias, P. M., Bikle, D. D., Mangelsdorf, D. J., Williams, M. L., and Feingold, K. R., Oxysterols induce differentiation in human keratinocytes and increase Ap-1-dependent involucrin transcription. J. Invest. Dermatol., 114, 545–553 (2000).
Hatano, Y., Man, M. Q., Uchida, Y., Crumrine, D., Mauro, T. M., Feingold, K. R., Elias, P. M., and Holleran, W. M., Murine atopic dermatitis responds to peroxisome proliferator-activated receptors alpha and beta/delta (but not gamma) and liver X receptor activators. J. Allergy. Clin. Immunol., 125, 160–169 (2010).
Hong, I., Lee, M. H., Na, T. Y., Zouboulis, C. C., and Lee, M. O., LXRalpha enhances lipid synthesis in SZ95 Sebocytes. J. Invest. Dermatol., 128, 1266–1272 (2008).
Janowski, B. A., Grogan, M. J., Jones, S. A., Wisely, G. B., Kliewer, S. A., Corey, E. J., and Mangelsdorf, D. J., Structural requirements of ligands for the oxysterol liver X receptors LXRalpha anLXRbeta. Proc. Natl. Acad. Sci. U. S. A., 96, 266–271 (1999).
Joseph, S. B., Laffitte, B. A., Patel, P. H., Watson, M. A., Matsukuma, K. E., Walczak, R., Collins, J. L., Osborne, T. F., and Tontonoz, P., Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors. J. Biol. Chem., 277, 11019–11025 (2002).
Kalinin, A. E., Kajava, A. V., and Steinert, P. M., Epithelial barrier function: assembly and structural features of the cornified cell envelope. Bioessays, 24, 789–800 (2002).
Komuves, L. G., Schmuth, M., Fowler, A. J., Elias, P. M., Hanley, K., Man, M. Q., Moser, A. H., Lobaccaro, J. M., Williams, M. L., Mangelsdorf, D. J., and Feingold, K. R., Oxysterol stimulation of epidermal differentiation is mediated by liver X receptor-beta in murine epidermis. J. Invest. Dermatol., 118, 25–34 (2002).
Lehmann, J. M., Kliewer, S. A., Moore, L. B., Smith-Oliver, T. A., Oliver, B. B., Su, J. L., Sundseth, S. S., Winegar, D. A., Blanchard, D. E., Spencer, T. A., and Willson, T. M., Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J. Biol. Chem., 272, 3137–3140 (1997).
Lu, T. T., Repa, J. J., and Mangelsdorf, D. J., Orphan nuclear receptors as eLiXiRs and FiXeRs of sterol metabolism. J. Biol. Chem., 276, 37735–37738 (2001).
Marks, R., The stratum corneum barrier: The final frontier. J. Nutr., 134(8 Suppl), 2017S–2021S (2004).
Mao-Qiang, M., Fowler, A. J., Schmuth, M., Lau, P., Chang, S., Brown, B. E., Moser, A. H., Michalik, L., Desvergne, B., Wahli, W., Li, M., Metzger, D., Chambon, P. H., Elias, P. M., and Feingold, K. R., Peroxisome-proliferator-activated receptor (PPAR)-gamma activation stimulates keratinocyte differentiation. J. Invest. Dermatol., 123, 305–312 (2004).
Mitro, N., Vargas, L., Romeo, R., Koder, A., and Saez, E., T0901317 is a potent PXR ligand: Implications for the biology ascribed to LXR. FEBS Lett., 581, 1721–1726 (2007).
Na, T. Y., Shin, Y. K., Roh, K. J., Kang, S. A., Hong, I., Oh, S. J., Seong, J. K., Park, C. K., Choi, Y. L., and Lee, M. O., Liver X receptor mediates hepatitis B virus X proteininduced lipogenesis in hepatitis B virus-associated hepatocellular carcinoma. Hepatology, 49, 1122–1131 (2009).
Repa, J. J., Liang, G., Ou, J., Bashmakov, Y., Lobaccaro, J. M., Shimomura, I., Shan, B., Brown, M. S., Goldstein, J. L., and Mangelsdorf, D. J., Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev., 14, 2819–2830 (2000).
Repa, J. J. and Mangelsdorf, D. J., The role of orphan nuclear receptors in the regulation of cholesterol homeostasis. Annu. Rev. Cell Dev. Biol., 16, 459–481 (2000).
Rosenfield, R. L., Kentsis, A., Deplewski, D., and Ciletti, N., Rat preputial sebocyte differentiation involves peroxisome proliferator-activated receptors. J. Invest. Dermatol., 112, 226–232 (1999).
Rosenfield, R. L., Deplewski, D., and Greene, M. E., Peroxisome proliferator-activated receptors and skin development. Horm. Res., 54, 269–274 (2000).
Rundhaug, J. E., Mikulec, C., Pavone, A., and Fischer, S. M., A role for cyclooxygenase-2 in ultraviolet light-induced skin carcinogenesis. Mol. Carcinog., 46, 692–698 (2007).
Schmuth, M., Haqq, C. M., Cairns, W. J., Holder, J. C., Dorsam, S., Chang, S., Lau, P., Fowler, A. J., Chuang, G., Moser, A. H., Brown, B. E., Mao-Qiang, M., Uchida, Y., Schoonjans, K., Auwerx, J., Chambon, P., Willson, T. M., Elias, P. M., and Feingold, K. R., Peroxisome proliferatoractivated receptor (PPAR)-beta/delta stimulates differentiation and lipid accumulation in keratinocytes. J. Invest. Dermatol., 122, 971–983 (2004).
Schmuth, M., Jiang, Y. J., Dubrac, S., Elias, P. M., and Feingold, K. R., Thematic review series: skin lipids. Peroxisome proliferator-activated receptors and liver X receptors in epidermal biology. J. Lipid Res., 49, 499–509 (2008).
Schultz, J. R., Tu, H., Luk, A., Repa, J. J., Medina, J. C., Li, L., Schwendner, S., Wang, S., Thoolen, M., Mangelsdorf, D. J., Lustig, K. D., and Shan, B., Role of LXRs in control of lipogenesis. Genes Dev., 14, 2831–2838 (2000).
Seo, J. B., Moon, H. M., Kim, W. S., Lee, Y. S., Jeong, H. W., Yoo, E. J., Ham, J., Kang, H., Park, M. G., Steffensen, K. R., Stulnig, T. M., Gustafsson, J. A., Park, S. D., and Kim, J. B., Activated liver X receptors stimulate adipocyte differentiation through induction of peroxisome proliferator-activated receptor gamma expression. Mol. Cell. Biol., 24, 3430–3444 (2004).
Sheu, M. Y., Fowler, A. J., Kao, J., Schmuth, M., Schoonjans, K., Auwerx, J., Fluhr, J. W., Man, M. Q., Elias, P. M., and Feingold, K. R., Topical peroxisome proliferator activated receptor-alpha activators reduce inflammation in irritant and allergic contact dermatitis models. J. Invest. Dermatol., 118, 94–101 (2002).
Vollberg, T. M. S.r., Nervi, C., George, M. D., Fujimoto, W., Krust, A., and Jetten, A. M., Retinoic acid receptors as regulators of human epidermal keratinocyte differentiation. Mol. Endocrinol., 6, 667–676 (1992).
Weller, R., Nitric oxide: a key mediator in cutaneous physiology. Clin. Exp. Dermatol., 28, 511–514 (2003).
Yokoyama, A., Makishima, M., Choi, M., Cho, Y., Nishida, S., Hashimoto, Y., and Terui, T., Induction of SREBP-1c mRNA by differentiation and LXR ligand in human keratinocytes. J. Invest. Dermatol., 129, 1395–1401 (2009).
Zhang, Q., Seltmann, H., Zouboulis, C. C., and Konger, R. L. Involvement of PPARgamma in oxidative stress-mediated prostaglandin E2 production in SZ95 human sebaceous gland cells. J. Invest. Dermatol., 126, 42–48 (2006).
Zelcer, N. and Tontonoz, P., Liver X receptors as integrators of metabolic and inflammatory signaling. J. Clin. Invest., 116, 607–614 (2006).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hong, I., Rho, H.S., Kim, DH. et al. Activation of LXRα induces lipogenesis in HaCaT cells. Arch. Pharm. Res. 33, 1443–1449 (2010). https://doi.org/10.1007/s12272-010-0919-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-010-0919-5