Plasma high density lipoproteins show an inverse relationship to atherosclerosis, reflecting the role of HDL in reverse cholesterol transport i.e. the transport of cholesterol from macrophage foam cells in the arterial wall to the liver, followed by excretion into bile. Scavenger receptor B1 (SRB1) has been shown to promote the selective uptake of HDL cholesterol in the liver (i.e. the uptake of HDL cholesterol without degradation of HDL protein), and its excretion in bile. The PI's recent studies in polarized primary hepatocytes show that SRB1 mediates HDL particle uptake, recycling or degradation. HDL particles and SRB1 move together through the endocytic-recycling compartment to the apical canalicular region. In polarized cells, SRB1 mediates selective sorting with HDL protein being recycled from the basolateral membrane, and HDL-derived cholesterol being secreted through the apical membrane.
The aims of the proposal are: 1) to further characterize the pathways of endocytosis and transcytosis of SRB1 in hepatocytes and other polarized epithelial cells, and to evaluate the relationship of these processes to selective uptake or selective transcytosis of HDL cholesterol, and the resecretion or degradation of HDL protein; 2) to define internalization, basolateral and apical targeting signals of SRB1 in polarized epithelial cells and to assess their significance in HDL metabolism in cell culture and transgenic mice; and 3) to determine alternative pathways of hepatic HDL catabolism, other than SRB1. SRB1 represents a superb opportunity to work out the molecular determinants of targeting and transcytosis in a novel system where lipid and protein have separate fates. The work will provide crucial insights into the cellular mechanisms underlying the final step of reverse cholesterol transport. The findings will be relevant to the relationship between HDL, atherosclerosis and gallstone formation.
