Effects of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor and low-density lipoprotein on proliferation and migration of keratinocytes.
BACKGROUND
Keratinocytes can obtain cholesterol either by de novo synthesis or by extraction, primarily from low-density lipoprotein (LDL). LDL is internalized following binding to the LDL receptor (LDLR). Because LDLR is expressed at a higher level in the cells of the basal layer of the epidermis, it might be assumed that LDLR upregulation is associated with keratinocyte proliferation. However, the effect of LDLR stimulation on keratinocyte function remains unclear.


OBJECTIVE
To investigate the effects and mechanism of action of pitavastatin and effects of LDL on proliferation and migration of keratinocytes.


METHODS
Pitavastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, was used to induce upregulation of LDLR. LDLR expression was evaluated by immunofluorescence staining, fluorescence-activated cell sorting, immunohistochemical staining and real-time polymerase chain reaction (PCR). HaCaT cells and normal human keratinocytes (NHKs) were used for evaluation of migration. 5-Bromo-2'-deoxyuridine incorporation was used to evaluate keratinocyte proliferation and differentiation. C57BL6 mice were used for in vivo evaluation of the effect of topical pitavastatin or lovastatin.


RESULTS
Pitavastatin was most effective in LDLR induction at a concentration of 1 micromol L(-1) in NHKs. Real-time PCR showed that pitavastatin significantly increased LDLR and liver X receptor (LXR) beta mRNA expression in these cells. Similar results were obtained in vivo. However, pitavastatin had no effect on the migration of NHKs. After the addition of LDL and/or mevalonate concomitantly with pitavastatin to NHK cultures, or topical application of pitavastatin on mouse skin, keratinocyte proliferation was significantly increased.


CONCLUSIONS
Pitavastatin significantly upregulates LDLR in both NHKs and C57BL6 mouse skin, resulting in increased keratinocyte proliferation. LXRbeta may be involved in the pitavastatin-induced keratinocyte proliferation.
Abd El-Latif
M I A
MI
Department of Dermatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan.
Murota
H
H
Terao
M
M
Katayama
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I
D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects*; D002784:Cholesterol / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D015603:Keratinocytes / Q000378:metabolism* / Q000502:physiology; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D011804:Quinolines / Q000494:pharmacology*; D011973:Receptors, LDL / Q000378:metabolism
D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; D011804:Quinolines; D011973:Receptors, LDL; D002784:Cholesterol; C108475:pitavastatin