Trafficking Of Lipids And Proteins In Living Cells

Diabetes, Digestive, Kidney Diseases

Investigators

Linked publications & trials

Abstract

The complex process of intracellular cholesterol trafficking is involved in many physiological events,including lipoprotein synthesis and secretion, steroidogenesis and maintenance of neuronal cell membranes. The basic knowledge of this process at the cellular and molecular levels will facilitate and improve treatment of major diseases, that include atherosclerosis, endocrine abnormalities, and neurodegenerative diseases. Our studies on the inherited metabolic disorder, Niemann Pick Type C (NP-C) disease, have generated important new information about lipid trafficking in storage disease fibroblasts and further have provided insight on the mechanisms and pathways involved in the regulation and transport of membrane lipids in normal cells. We have seen, in living cells, that exogeneously derived lipoprotein cholesterol and the Niemann Pick C1 and C2 proteins traffic in kinetically active, tubular components of the late endosomal pathway whose dynamic mobility is disrupted by cellular cholesterol overload. Thus, cellular cholesterol levels have the capacity to interrupt a dynamic trafficking pathway vital for cell function. In addition to cholesterol, we find that glycolipids are sorted in NPC1 containing late endosomes and that normal endocytic trafficking of glycolipids depends on a functional NPC1 late endosomal compartment. This important finding relates to the known pathology of glycolipid accumulation in NPC-cells and tissues. Our studies, on the late endosomal tubular conduit and its role in trafficking of lipids and proteins, are begining to elucidate a cellular pathology that may be common to several inherited lysosomal storage diseases. Identification of proteins that traverse this heretofore unappreciated trafficking conduit is vital to our understanding of their roles in cellular lipid metabolism.