Macrophage-specific overexpression of
cholesteryl ester hydrolysis in
hormone-sensitive lipase transgenic (HSL Tg) female mice paradoxically increases
cholesterol esterification and
cholesteryl ester accumulation in macrophages, and thus susceptibility to diet-induced
atherosclerosis compared to nontransgenic C57BL/6 mice. The current studies suggest that whereas increased
cholesterol uptake could contribute to transgenic foam cell formation, there are no differences in
cholesterol synthesis and the expression of
cholesterol efflux mediators (ABCA1, ABCG1,
apoE,
PPARgamma, and LXRalpha) compared to wild-type macrophages. HSL Tg macrophages exhibit twofold greater efflux of
cholesterol to
apoA-I in vitro, suggesting the potential rate-limiting role of
cholesteryl ester hydrolysis in efflux. However, macrophage
cholesteryl ester levels appear to depend on the relative efficacy of alternate pathways for free
cholesterol in either efflux or re-esterification. Thus, increased
atherosclerosis in HSL Tg mice appears to be due to the coupling of the efficient re-esterification of excess free
cholesterol to its limited removal mediated by the
cholesterol acceptors in these mice. The overexpression of
cholesterol acceptors in HSL-
apoA-IV double-transgenic mice increases plasma HDL levels and decreases diet-induced
atherosclerosis compared to HSL Tg mice, with aortic lesions reduced to sizes in nontransgenic littermates. The results in vivo are consistent with the effective efflux from HSL Tg macrophages supplemented with HDL and
apoA-I in vitro, and highlight the importance of
cholesterol acceptors in inhibiting
atherosclerosis caused by imbalances in the
cholesteryl ester cycle.