Abrogation of insulin-like growth factor-I (IGF-I) and insulin action by mevalonic acid depletion: synergy between protein prenylation and receptor glycosylation pathways.
The vasculoprotective effects of hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors (statins) correlate with cholesterol lowering. HMG-CoA reductase inhibitors also disrupt cellular processes by the depletion of isoprenoids and dolichol. Insulin and insulin-like growth factor (IGF) signaling appear particularly prone to such disruption as intracellular receptor processing requires dolichol for correct N-glycosylation, whereas downstream signaling through Ras requires the appropriate prenylation (farnesol). We determined how HMG-CoA reductase inhibition affected the mitogenic effects of IGF-I and metabolic actions of insulin in 3T3-L1 cells and examined the respective roles of receptor glycosylation and Ras prenylation. IGF-I- and insulin-induced proliferation was significantly reduced by all statins tested, although cerivastatin (10 nm) had the greatest effect (p < 0.005). Although inhibitors of Ras prenylation induced similar results (10 microm FTI-277 89% +/- 7.4%, p < 0.01), the effect of HMG-CoA reductase inhibition could only be partially reversed by farnesyl pyrophosphate refeeding. Treatment with statins resulted in decreased membrane expression of receptors and accumulation of proreceptors, suggesting disruption of glycosylation-dependent cleavage. Glycosylation inhibitors inhibited IGF-I-induced proliferation (tunicamycin p < 0.005, castanospermine p < 0.01, deoxymannojirimycin p < 0.01). High concentrations of statin were necessary to impair insulin-mediated glucose uptake (300 nm = 33% +/- 12% p < 0.05), and this process was not effected by farnesyl transferase inhibition. Gycosylation inhibitors mimicked the effect of statin treatment (tunicamycin p < 0.001, castanospermine p < 0.05, deoxymannojirimycin p < 0.05), and there was insulin proreceptor accumulation. These data imply that HMG-CoA reductase inhibitors disrupt IGF-I signaling by combined effects on Ras prenylation and IGF receptor glycosylation, whereas insulin signaling is only affected by disrupted receptor glycosylation.
Siddals
Kirk W
KW
Diabetes and Endocrinology, Hope Hospital, Salford, M6 8HD and Endocrine Sciences, University of Manchester, Manchester, M13 9PT, United Kingdom.
Marshman
Emma
E
Westwood
Melissa
M
Gibson
J Martin
JM
D041721:3T3-L1 Cells; D000818:Animals; D017209:Apoptosis; D019921:Biotinylation; D015153:Blotting, Western; D002454:Cell Differentiation; D002455:Cell Division; D002462:Cell Membrane / Q000378:metabolism; D003847:Deoxyglucose / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism; D006031:Glycosylation; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007212:Indolizines / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008798:Mevalonic Acid / Q000378:metabolism*; D051379:Mice; D011233:Precipitin Tests; D017368:Protein Prenylation; D011725:Pyridines / Q000494:pharmacology; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction; D013936:Thymidine / Q000737:chemistry; D014415:Tunicamycin / Q000494:pharmacology; D018631:ras Proteins / Q000378:metabolism; D054836:Indolizidines
D003847:Deoxyglucose; D005947:Glucose; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007212:Indolizines; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D008798:Mevalonic Acid; D011725:Pyridines; D011972:Receptor, Insulin; D013936:Thymidine; D014415:Tunicamycin; D018631:ras Proteins; C086276:cerivastatin; C037806:castanospermine; D054836:Indolizidines