Molecular Mechanisms of Lysosomal Cholesterol ExportMolecular Mechanisms of Lysosomal Cholesterol ExportThe heterogeneous distribution of lipids among the membranes of cellular organelles involves processes of transport and sorting that remain poorly understood. Among the many lipids that are found in mammalian cells cholesterol has attracted particular interest. The importance of cholesterol homeostasis is exemplified on the systemic level by its role in the development of atherosclerosis and on the cellular level by its profound effects on the properties of membranes and on many membrane proteins.
Mammalian cells acquire a large fraction of their cholesterol by receptor-mediated endocytosis of serum lipoproteins such as low-density lipoprotein (LDL). LDL particles carry cholesterol predominantly in modified form as cholesteryl esters, i.e. cholesterol covalently attached to a fatty acid molecule. Following endocytosis, cholesteryl esters are transported to late endosomes and lysosomes where they are hydrolyzed to generate cholesterol and fatty acid. Cholesterol is then transported to other destinations in the cell by largely unknown processes.
Defects in transport can lead to the pathological accumulation of cholesterol in lysosomes. Examples include the cholesterol-engorged "foam cells" that are characteristic of atherosclerotic lesions, as well as a number of lysosomal lipid storage disorders. One lysosomal storage disorder in particular, Niemann Pick disease type C, has attracted our attention because the affected proteins, NPC1 and NPC2, seem to have a direct role in cholesterol transport. One focus of the lab is therefore to try to understand how NPC1 and NPC2 contribute to cellular cholesterol homeostasis.
Understanding the mechanisms of cholesterol transport in detail will ultimately require the ability to measure this process directly. Therefore, we are also developing new methodologies to study the movement of cholesterol both in living cells as well as in vitro.