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Journal of Lipid Research, Vol. 43, 1293-1302, August 2002
Copyright © 2002 by Lipid Research, Inc.

Glucosylceramide synthesis and synthase expression protect against ceramide-induced stress

Yoshikazu Uchida^*,, Satoru Murata^*,, Matthias Schmuth^*,, Martin J. Behne^*,, Jeong Deuk Lee^*,, Shinichi Ichikawa, Peter M. Elias^*,, Yoshio Hirabayashi and Walter M. Holleran^1,*,,

^* Dermatology Service, Department of Veterans Affairs Medical Center, San Francisco, CA
Department of Dermatology, School of Pharmacy, University of California San Francisco
School of Medicine, and Pharmaceutical Chemistry, School of Pharmacy, University of California San Francisco
The Institute of Physical and Chemical Research, Brain Science Institute (RIKEN), Wako, Japan

¹ To whom correspondence should be addressed. e-mail: walth{at}itsa.ucsf.edu

Ceramides (Cers), critical for epidermal barrier function, also can inhibit keratinocyte proliferation, while glucosylceramides (GlcCers) exert pro-mitogenic effects. Since alterations in Cer-to-GlcCer ratios appear to modulate cellular growth versus apoptosis, we assessed whether keratinocytes up-regulate GlcCer synthesis as a protective mechanism against Cer-induced stress. Exogenous sphingomyelinase (SMase) treatment of cultured human keratinocytes (CHK) initially decreased proliferation and cellular sphingomyelin (50–60% decrease; P < 0.001), and increased Cer levels (6.1- to 6.8-fold; P < 0.001). Proliferation recovered to normal rates by 24 h, in parallel with increased cellular GlcCer. Both GlcCer synthesis and GlcCer synthase activity increased significantly by 8 h following SMase (8.2- and 2.4-fold, respectively; P < 0.01 each vs. control), attributed to antecedent increases in GlcCer synthase mRNA and protein expression. Further evidence that GlcCer production is responsible for normalized CHK proliferation includes: a) attenuation of SMase-induced inhibition of proliferation by exogenous GlcCer; and b) enhancement of the SMase effect in cells cotreated with the GlcCer synthase inhibitor, PDMP (D-threo-1-phenyl-2(decanoylamino)-3-morpholino-1-propanol). Finally, although proliferation in immortalized, nontransformed keratinocytes (HaCaT) also was inhibited by SMase, HaCaT cells that overexpress GlcCer synthase were resistant to this effect.

Thus, SMase-induced stress initiates a response in keratinocytes that includes upregulation of GlcCer synthesis which may protect against the deleterious effects of excess Cer.

Abbreviations: Cer, ceramide; CHK, cultured human keratinocyte; GlcCer, glucosylceramide; HPTLC, high-performance thin-layer chromatography; SM, sphingomyelin; SMase, sphingomyelinase

Supplementary key words keratinocytes • apoptosis • cutaneous • sphingomyelin • sphingolipids

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