Submitted on January 31, 2007
Revised on June 15, 2007
Accepted on July 8, 2007
Cholesterol efflux via HDL resecretion occurs when cholesterol transport out of the lysosome is impaired
Tamara A. Pagler, Angelika Neuhofer, Hildegard Laggner, Wolfgang Strobl, and Herbert Stangl
Medical Chemistry, Medical University of Vienna, Vienna, Vienna 1090
Corresponding Author: Herbert.Stangl{at}meduniwien.ac.at
Recently we have shown that holo HDL particle uptake and resecretion occurs in physiologically relevant cell lines and that HDL uptake is mediated by SR-BI. Further we established that HDL resecretion is accompanied by 3H-cholesterol efflux. The current study shows that HDL uptake and resecretion occurs even when LDL uptake and cholesterol trafficking is disturbed. First, we used a set of inhibitors that block cholesterol transport out of the lysosome: chloroquine, imipramine, U18666A and monensin. In all cases HDL retroendocytosis occurred and HDL resecretion mediated 3H-cholesterol efflux though to a lesser extent. Second, cell lines carrying somatic mutations in intracellular cholesterol transport were used: CHO 2-2 and CHO 3-6 cells accumulate LDL-derived lipid in the lysosome, but showed all components of HDL retroendocytosis. SR-BI over-expression increased HDL uptake, resecretion and 3H-cholesterol efflux in these mutant cells. Finally we used Niemann-Pick Type C (NPC) patient fibroblast cells, which carry a defect in cholesterol transfer out of the lysosome. NPC fibroblast cells accumulate cholesterol in the lysosome due to a mutation in the NPC1 gene. Despite disturbed intracellular cholesterol transfer NPC fibroblast cells exhibited HDL retroendocytosis and 3H-cholesterol efflux via HDL resecretion although to a lesser extent. Thus, 3H-cholesterol efflux via HDL resecretion is independent of the cholesterol uptake pathway via the LDL receptor and may be an alternative way to remove excess cholesterol.
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