| Summary: | Topical lovastatin stimulates epidermal fatty acid synthesis in vivo; therefore, studies were undertaken to examine the effects of HMG-CoA reductase inhibitors on fatty acid metabolism in cultured keratinocytes. When exposed to fluindostatin or lovastatin for greater than or equal to 24 h, keratinocytes in serum-free media accumulated nile red-fluorescent lipid droplets. By 72 h, the triacylglycerol and phospholipid content were increased 2.5- and 1.3-fold, respectively. Reductase inhibitors (1-10 microM) increased fatty acid synthesis approximately 1.5-fold; increased synthesis was noted only after greater than 15 h exposure and was distributed among phospholipids and triacylglycerols. Oxidation of [14C]palmitate to CO2 was decreased greater than 50% in inhibitor-treated cultures, and label accumulated in triacylglycerols. Inhibitor-treated keratinocytes exhibited increased numbers of peroxisomes, using diaminobenzidene ultracytochemistry. Peroxisomal hyperplasia was also demonstrated by increased catalase activity (1.5- to 2.5-fold), increased dihydroxyacetone phosphate acyltransferase activity (1.4-fold) and increased peroxisomal (KCN-insensitive) fatty acid oxidation (1.4-fold) in inhibitor-treated cultures. Thus HMG-CoA reductase inhibitors increase fatty acid synthesis, induce triacylglycol and phospholipid accumulation, and induce peroxisomes in cultured keratinocytes. Coincubations with either low density lipoproteins or 25-hydroxycholesterol prevented both the peroxisomal hyperplasia and increased fatty acid synthesis, suggesting that these effects of reductase inhibitors may be linked to their effects on the cholesterol biosynthetic pathway.
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