Abstract 10710: Deficiency of Newly Identified Intracellular Cholesteryl Ester Hydrolase (NCEH1) Does neither Decrease the Total Hydrolytic Activity in Macrophages nor Result in Diet-Induced Atherosclerosis
Hydrolysis of stored intracellular cholesteryl esters (CE) is the obligatory first and rate-limiting step in removal of cholesterol and attenuation of foam cell formation that is central to attenuation of atherosclerosis. Several enzymes with the demonstrated ability to hydrolyze CE are considered to be responsible. Consistent with its role in mobilizing CE and reducing foam cell formation, we have earlier demonstrated that transgenic expression of one of the CE hydrolases (gene symbol CES1) attenuates diet-induced atherosclerosis. NCEH1 (alias KIAA1363) was recently identified as yet another CE hydrolase present in macrophages and described as the only enzyme that requires attention when dealing with macrophage CE hydrolysis. If NCEH1 is the primary CE hydrolase in macrophages, then its deficiency alone should abolish macrophage CE hydrolytic activity, promote foam cell formation and induce atherogenesis. The objective of the present study was to test this hypothesis. NCEH1 deficiency was confirmed by examining the expression in NCEH1-/- mice. Bone marrow-derived macrophages from NCEH1-/- mice did not express any detectable protein (Panel A) and showed <10% expression of mRNA compared to wild-type mice (Panel B). Despite almost complete lack of NCEH1, the total CE hydrolytic activity of macrophages remained unchanged (Panel B). Wild type and NCEH1-/- mice were fed high-fat, high cholesterol diet for 16 weeks and development of atherosclerotic lesions was monitored by en face analyses. As shown in Panel C, NCEH1 deficiency did not induce atherogenesis. Taken together with reported evidence for the presence of other CE hydrolase in macrophages, these data suggest that intracellular CE hydrolysis is likely to be a multi-enzyme process and no single enzyme can be considered as the major CE hydrolase. To establish the anti-atherosclerotic function of any candidate enzyme it will be a more relevant to demonstrate attenuation of atherosclerosis by over-expression.
- © 2011 by American Heart Association, Inc.