2^nd Glycobiology World Congress

Biography

Biography: Clifford A Lingwood

Abstract

Glycosphingolipids (GSLs) accumulate together with cholesterol in membrane lipid rafts, dynamic domains of increased order, which provide foci for transmembrane signaling, membrane trafficking and portals for microbial pathogens. Membrane cholesterol can also complex with GSLs to alter the carbohydrate from a membrane perpendicular to parallel conformation and thereby restrict ligand access to GSLs. Cholesterol ligand access is also restricted in the GSL complex. Since statins are widely used to decrease serum cholesterol levels, we question whether cholesterol depletion affected GSL synthesis. While we found that statins are unable to reduce cholesterol in serum cultured cells, statins nevertheless had a remarkable effect on cell GSL synthesis in that glucosyl ceramide was markedly increased and downstream GSLs increased according to cell line. The enzyme glucosyl ceramide synthase was mislocalized within statin treated cells. This correlated with a loss of cholesterol accumulation in the transGolgi network. The trihexoside, lactotriaosyl ceramide, was induced in 70% of cell lines. This effect was duplicated by the Rab prenylation inhibitor, 3-PEPHC and reversed by addition of the isoprenoid precursor, geranylgeranyl pyrophosphate, a downstream product of HMG Co-A reductase, which is inhibited by statins. These results are consistent with statin induced depletion of Rab prenylation, subsequent aberrant Golgi vesicular traffic, mislocalization of GSL anabolic enzymes and remodeling of GSL synthesis. This process also inhibits the normal retrograde transport of GSLs and the internalization of cholera and Shiga toxins, which hijack GSL retrograde transport for endoplasmic reticulum targeting, are also mislocalized intracellular, thereby protecting statin treated cells.