In this review, recent studies of
membrane lipid transport in
sphingolipid (SL) storage disease (SLSD) fibroblasts are summarized. Several fluorescent
glycosphingolipid (GSL) analogues are internalized from the plasma membrane via caveolae and are subsequently transported to the Golgi complex of normal fibroblasts, while in 10 different SLSD cell types, these
lipids accumulate in endosomes and lysosomes. Additional studies have shown that
cholesterol homeostasis is perturbed in multiple SLSDs secondary to accumulation of endogenous SLs, and that mis-targeting of the GSLs is regulated by cellular
cholesterol. Golgi targeting of GSLs internalized via caveolae is dependent on microtubules and
phosphoinositide 3-kinase(s) and is inhibited by expression of dominant-negative rab7 and rab9 constructs. Overexpression of wild-type rab7 or rab9 (but not rab11) in Niemann-Pick C fibroblasts results in correction of
lipid trafficking defects, including restoration of Golgi targeting of fluorescent
lactosylceramide and endogenous
GM1 ganglioside (monitored by the transport of fluorescent
cholera toxin), and a dramatic reduction in accumulation of intracellular
cholesterol. These results suggest an approach for restoring normal
lipid trafficking in this, and perhaps other, SLSD cell types, and may provide a basis for future
therapy of these diseases.