HMG-CoA reductase inhibitors perturb fatty acid metabolism and induce peroxisomes in keratinocytes.
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.
Williams
M L
ML
Dermatology Service, Veterans Administration Medical Center, San Francisco, CA 94121.
Menon
G K
GK
Hanley
K P
KP
D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis; D005227:Fatty Acids / Q000378:metabolism*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles / Q000494:pharmacology; D007231:Infant, Newborn; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D050356:Lipid Metabolism; D008148:Lovastatin / Q000494:pharmacology; D008830:Microbodies / Q000201:enzymology / Q000378:metabolism*; D008854:Microscopy, Electron; D010078:Oxazines; D010084:Oxidation-Reduction
D005227:Fatty Acids; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D010078:Oxazines; D000077340:Fluvastatin; D002784:Cholesterol; D008148:Lovastatin; C044808:nile red