Abstract 13493: Intracellular Cholesterol Transport Proteins Enhance Hydrolysis of HDL-delivered Cholesteryl Esters and Facilitate Preferential Elimination of Resulting Cholesterol Into Bile as Bile Acids

Abstract

HDL-associated cholesterol, >80% esterified (HDL-CE) entering the hepatocyte via SR-BI can have multiple fates: 1) re-secretion as nascent HDL; 2) re-esterification and either storage of resulting CE or secretion of CE as VLDL; 3) secretion of free cholesterol into bile; and 4) conversion to and secretion of bile acids into bile. While fates 1 and 2 will lead to recirculation of HDL-CE returning to the liver from the periphery including plaque associated macrophage foam cells, fates 3 and 4 will lead to final elimination of cholesterol from the body and would be anti-atherogenic. Although we earlier identified cholesteryl ester hydrolase (CEH) as the hepatic enzyme responsible for the hydrolysis of SR-BI delivered HDL-CE, intracellular factors affecting the directional movement of HDL-derived FC remain undefined. In the present study, we examined the hypothesis that intracellular cholesterol transport proteins (SCP-2 and FABP1) not only facilitate CEH mediated hydrolysis of HDL-CE but also enhance elimination of cholesterol into bile. Primary C57BL/6 mouse hepatocytes were used and expression of CEH, FABP1 or SCP2 was modulated by using respective adenoviruses; AdLacZ was used as control. Over-expression of SCP2 or FABP1 significantly increased hydrolysis of HDL-[ 3 H]-CE (A) and reduced the re-secretion of HDL-derived cholesterol as nascent HDL (B). However, over-expression of SCP2 or FABP1 increased the secretion of cholesterol from HDL-[ 3 H]-CE as bile acids (C). Flux of HDL-[ 3 H]-CE into bile was monitored in vivo using C57BL/6 mice. Similar to the effects seen in vitro, adenovirus-mediated over-expression of FABP1 and SCP2 significantly increased the flux of cholesterol from HDL-[ 3 H]-CE to bile acids (D). Taken together, these studies demonstrate that SCP2 and FABP1 facilitate the preferential movement of HDL-associated cholesterol to bile for final elimination from the body. Studies are in progress to establish the anti-atherogenic role of these proteins