Statins, which specifically inhibit HMG Co-A reductase, the rate-limiting step 
of cholesterol biosynthesis, are widely prescribed to reduce serum cholesterol 
and cardiac risk, but many other effects are seen. We now show an effect of 
these drugs to induce profound changes in the step-wise synthesis of 
glycosphingolipids (GSLs) in the Golgi. Glucosylceramide (GlcCer) was increased 
several-fold in all cell lines tested, demonstrating a widespread effect. 
Additionally, de novo or elevated lactotriaosylceramide (Lc3Cer; 
GlcNAcβ1-3Galβ1-4GlcCer) synthesis was observed in 70%. Western blot showed that 
GlcCer synthase (GCS) was elevated by statins, and GCS and Lc3Cer synthase 
(Lc3S) activities were increased; however, transcript was elevated for Lc3S 
only. Supplementation with the isoprenoid precursor, geranylgeranyl 
pyrophosphate (GGPP), a downstream product of HMG Co-A reductase, reversed 
statin-induced glycosyltransferase and GSL elevation. The Rab geranylgeranyl 
transferase inhibitor 3-PEHPC, but not specific inhibitors of farnesyl 
transferase, or geranylgeranyl transferase I, was sufficient to replicate 
statin-induced GlcCer and Lc3Cer synthesis, supporting a Rab 
prenylation-dependent mechanism. While total cholesterol was unaffected, the 
trans-Golgi network (TGN) cholesterol pool was dissipated and medial Golgi GCS 
partially relocated by statins. GSL-dependent vesicular retrograde transport of 
Verotoxin and cholera toxin to the Golgi/endoplasmic reticulum were blocked 
after statin or 3-PEHPC treatment, suggesting aberrant, prenylation-dependent 
vesicular traffic as a basis of glycosyltransferase increase and GSL remodeling. 
These in vitro studies indicate a previously unreported link between Rab 
prenylation and regulation of GCS activity and GlcCer metabolism.