Abstract
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.
Highlights
Topical lovastatin stimulates epidermal fatty acid synthesis in vivo; studies were undertaken to examine the effects of 3hydroxy-3methylglutaaryl coenzyme A (HMGCoA) reductase inhibitors on fatty acid metabolism in cultured keratinocytes
Fatty acid metabolism is generally considered to be unaffected by lovastatin and related compounds [2,3,4,5] ; modest increases in fatty acid synthesis have been observed in mouse L cells [3], rat lens [6], and in normal and low density lipoproteins (LDL) receptor-negative human fibroblasts [7]
While hepatic peroxisomal hyperplasia is a well-recognized phenomenon in rodents fed clofibrate and related hypocholesterolemic drugs, this has not been reported to occur with lovastatin
Summary
Topical lovastatin stimulates epidermal fatty acid synthesis in vivo; studies were undertaken to examine the effects of HMGCoA reductase inhibitors on fatty acid metabolism in cultured keratinocytes. HMGCoA reductase inhibitors increase fatty acid synthesis, induce triacylglycol and phospholipid accumulation, and induce peroxisomes in cultured keratinocytes. Fatty acid metabolism is generally considered to be unaffected by lovastatin and related compounds [2,3,4,5] ; modest increases in fatty acid synthesis have been observed in mouse L cells [3], rat lens [6], and in normal and LDL receptor-negative human fibroblasts [7] Prolonged exposure to these inhibitors results in a marked increase in reductase content, due both to increased gene transcription and to decreased degradation of message and enzyme [8], and is associated with a striking proliferation of smooth endoplasmic reticulum in liver [9] and UT-1 cells [10].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
