Abstract 12417: Hepatic Overexpression of Endothelial Lipase Induces a Marked Hypoalphalipoproteinemia but Maintains Macrophage Reverse Cholesterol Transport in vivo
Reverse cholesterol transport (RCT) is a major mechanism by which HDL protects against atherosclerosis. As endothelial lipase (EL) contributes to reducing HDL levels, which is atherogenic in theory, we investigated whether EL modulates RCT in mice. We intravenously injected recombinant adenoviral vectors overexpressing human EL or luciferase (Luc) into C57BL/6 mice and performed a macrophage RCT assay 4 days after injection. As expected, hepatic overexpression of EL induced a marked reduction in HDL levels compared to the control. In parallel with this, plasma 3H-cholesterol tracer counts obtained from EL-injected mice decreased by 85% compared to the control. Surprisingly, however, there was no difference in fecal 3H-cholesterol counts between EL- and Luc-injected mice. Kinetic studies revealed a significantly increased fractional catabolic rate and hepatic uptake of labeled HDL-cholesteryl ether (CE), resulting in no change in fecal HDL-CE excretion in the EL-injected mice as compared to Luc-injected mice. To further explore underlying mechanisms for the preservation of in vivo RCT despite extremely low HDL levels in the EL-injected mice, we investigated effects of hepatic scavenger receptor class B type I (SR-BI) knockdown by adenoviruses expressing microRNA (Ad-miR) under the presence/absence of EL-overexpression. A macrophage RCT assay revealed that knockdown of SR-BI alone resulted in reduced tracer appearance in feces as previously reported. Interestingly, SR-BI inhibition together with hepatic overexpression of EL further attenuated fecal counts of tracer as compared to the control (Ad-miR-LacZ) (Figure). In summary, hepatic EL overexpression produces marked hypoalphalipoproteinemia but maintains the overall RCT system through upregulation of hepatic SR-BI-mediated uptake of EL-modified HDL particles. Therefore, EL may be a novel therapeutic target to facilitate antiatherogenic function of HDL.
- © 2010 by American Heart Association, Inc.