Lovastatin increases surface low density lipoprotein receptor expression by retarding the receptor internalization rate in proliferating lymphocytes.
We examined the effects of Lovastatin on LDL receptor (LDL-R) expression and rate of internalization in interleukin-2 (IL-2) expanded phytohemagglutinin-stimulated lymphocytes. Lovastatin increased the surface LDL-R expression, but not DiI-LDL uptake, by up to 30% regardless of whether cell proliferation was affected. It caused a dose-dependent reduction in the LDL-R internalization rate as determined with monensin. Lovastatin had no effect on IL-2 receptor internalization. Inhibition of DNA synthesis by hydroxyurea or protein tyrosine kinase activity by genistein failed to affect the LDL-R internalization rate. Co-incubation of cells with Lovastatin and mevalonate or LDL completely restored the rate of LDL-R internalization. We conclude that Lovastatin increases the apparent surface LDL-R expression by retarding the rate of LDL-R internalization. The effect is mediated through the mevalonate pathway but not the anti-mitogenic property of Lovastatin.
Chan
P C
PC
Department of Pediatrics and Medical Genetics, University of Calgary, Alberta, Canada.
Lafrenière
R
R
Parsons
H G
HG
D002232:Carbocyanines; D002455:Cell Division; D004705:Endocytosis / Q000187:drug effects; D005434:Flow Cytometry; D005456:Fluorescent Dyes; D019833:Genistein; D006918:Hydroxyurea / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D007529:Isoflavones / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology*; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D008798:Mevalonic Acid / Q000494:pharmacology; D008985:Monensin / Q000494:pharmacology; D010835:Phytohemagglutinins / Q000494:pharmacology; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism*
D002232:Carbocyanines; D005456:Fluorescent Dyes; D007376:Interleukin-2; D007529:Isoflavones; D008077:Lipoproteins, LDL; D010835:Phytohemagglutinins; D015375:Receptors, Interleukin-2; D011973:Receptors, LDL; C024286:3,3'-dioctadecylindocarbocyanine; D008985:Monensin; D008148:Lovastatin; D019833:Genistein; D008798:Mevalonic Acid; D006918:Hydroxyurea