The Yin and Yang of lactosylceramide metabolism: implications in cell function.

Although lactosylceramide (LacCer) plays a pivotal role in the biosynthesis of nearly all the major glycosphingolipids, its function in regulating cellular function has begun to emerge only recently. Our current opinion is that several physiologically critical molecules such as modified/oxidized LDL, growth factors, pro-inflammatory cytokines and fluid shear stress converge upon and activate lactosylceramide synthase to generate LacCer. In turn, LacCer activates an "oxygen-sensitive" signaling pathway involving superoxides, nitric oxide, p21 Ras GTP loading, kinase cascade, PI3kinase/Akt activation, nuclear factor up-regulation ultimately contributing to phenotypic changes such as cell proliferation, adhesion, migration and angiogenesis. Since dys-regulation of such phenotypic changes constitute a hallmark in several diseases of the cardiovascular system, proliferative disorders such as cancer, polycystic kidney disease and inflammatory diseases, LacCer synthase and LacCer provide novel targets for the development of therapeutics aimed at these health conditions.