Permeability Barrier Disruption Coordinately Regulates mRNA Levels for Key Enzymes of Cholesterol, Fatty Acid, and Ceramide Synthesis in the Epidermis

Abstract

The extracellular lipids of the stratum corneum, which are comprised mainly of cholesterol, fatty acids, and ceramides, are essential for epidermal permeability barrier function. Moreover, disruption of the permeability barrier results in an increased cholesterol, fatty acid, and ceramide synthesis in the underlying epidermis. This increase in lipid synthesis has been shown previously to be due to increased activities of HMG-CoA reductase, acetyl-CoA carboxylase, fatty acid synthase and serine palmitoyl transferase, key enzymes of cholesterol, fatty acid, and ceramide synthesis, respectively. In the present study, we determined whether the mRNA levels for the key enzymes required for synthesis of these three classes of lipids increase coordinately during barrier recovery. By northern blotting, the steady-state mRNA levels for HMG-CoA reductase, HMG-CoA synthase, farnesyl pyrophosphate synthase, and squalene synthase, key enzymes for cholesterol synthesis, all increased significantly after barrier disruption by either acetone or tape stripping. Additionally, the steady-state mRNA levels of acetyl-CoA carboxylase and fatty acid synthase, required for fatty acid synthesis, as well as serine palmitoyl transferase, the rate-limiting enzyme of de novo ceramide synthesis, also increased. Furthermore, artificial restoration of the permeability barrier by occlusion after barrier disruption prevented the increase in mRNA levels for all of these enzymes, except farnesyl pyrophosphate synthase, indicating a specific link of the increase in mRNA levels to barrier requirements. The parallel increase in epidermal mRNA levels for the enzymes required for cholesterol, fatty acid, and ceramide synthesis may be due to one or more transcription factors that regulate lipid requirements for permeability barrier function in keratinocytes.

Sphingosine-1-phosphate Phosphatase 1 Regulates Keratinocyte Differentiation and Epidermal Homeostasis

“…Overall, the results are consistent with the possibility that the activation of sphingolipid metabolism signals keratinocytes to differentiate via the attendant production of bioactive S1P. De novo sphingolipid synthesis in epidermis is up-regulated after epidermal damage (63). One function of this increased de novo synthesis after injury is believed to be for the replenishment of barrier lipids.…”

Thematic review series: Skin Lipids. The role of epidermal lipids in cutaneous permeability barrier homeostasis

“…The increase in HMGCoA reductase activity occurs in both the upper and lower epidermis (79). Additionally, mRNA levels of other key enzymes in the cholesterol synthetic pathway, including HMG-CoA synthase, farnesyl diphosphate synthase, and squalene synthase, also increase after acute barrier disruption (80). Preliminary studies by our laboratory have suggested that the active forms of sterol-regulatory element binding protein-1 (SREBP-1) and SREBP-2 increase after barrier disruption, which could explain the concordant increase in the enzymes of the cholesterol synthetic pathway.…”

“…Under these conditions, the increase in epidermal cholesterol synthesis and the increase in mRNA levels of the cholesterol synthetic enzymes are inhibited (75,77,80). Most importantly, if one inhibits the increase in epidermal cholesterol synthesis by topical application of statins, which inhibit HMG-CoA reductase activity and decrease cholesterol synthesis, the recovery of permeability barrier function is delayed (81).…”

“…Barrier disruption increases the activities and mRNA levels of both of the key enzymes required for de novo fatty acid synthesis, acetyl-CoA carboxylase and fatty acid synthase (80,84). The increase in acetyl-CoA carboxylase and fatty acid synthase induced by permeability barrier disruption is likely attributable to an increase in the activation of SREBPs.…”

“…The increase in acetyl-CoA carboxylase and fatty acid synthase induced by permeability barrier disruption is likely attributable to an increase in the activation of SREBPs. Once again, occlusion with an impermeable membrane that restores permeability barrier function prevents the increase in fatty acid synthesis and the increase in the expression of acetyl-CoA carboxylase and fatty acid synthase (80,83,84). Moreover, after acute barrier disruption, inhibition of fatty acid synthesis by the topical application of the acetyl-CoA carboxylase inhibitor, 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA), delays the recovery of permeability barrier function (85).…”