Ceramides (Cer), along with cholesterol (Chol) and free fatty acids, are the major lipids of the stratum corneum lamellar membrane domains that comprise the mammalian permeability barrier. In extracutaneous tissues, reciprocal effects of Chol and certain Cer species (eg, sphingomyelin) on their respective levels also have been noted. Given that formation of the three critical barrier lipids is simultaneously elevated during epidermal differentiation, we investigated possible mechanisms for coordinate regulation of their respective biosynthetic pathways. First, low-dose (2.5-5 μM) mevinolin (Mev; lovastatin), an inhibitor of HMG-CoA reductase, modestly reduced cultured keratinocyte (CHK) growth (10-15% decrease vs vehicle control; p < .01) after 24 h incubation, while higher dose Mev (10 μM) further inhibited cell growth (31%; p < .001); however, none of these Mev doses was associated with CHK cell death. As expected, Mev (5 μM) significantly decreased Chol synthesis (to 30 ± 4% of control; p < .0001), as determined by [14 C]-acetate incorporation; however, syntheses ([3 H]-serine incorporation) of the major sphingolipids (Cer, glucosylCer and sphingomyelin) also were significantly diminished (ie, to 44 ± 14%, 65 ± 18%, and 67 ± 23%, of controls, respectively; p < .01). mRNA levels (Northern analysis) for HMG-CoA reductase were elevated by Mev, as anticipated, while levels for serine palmitoyltransferase (SPT), a key enzyme in Cer synthesis, were diminished, an effect overridden by 25-OH-Chol co-application. Finally, TO901317, a synthetic, non-sterol agonist for the nuclear hormone receptor LXR, significantly elevated Cer synthesis with corresponding increases in SPT mRNA (quant-rt-PCR), protein (Western), and enzyme activities. Thus, decreased Chol levels are associated with down-regulation of Cer de novo synthesis; conversely, LXR activation upregulates Cer production, suggesting coordinate regulatory mechanisms for Chol and Cer generation in mammalian epidermis.
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