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Papers In Press, published online ahead of print January 1, 2007
J. Lipid Res., doi:10.1194/jlr.M600321-JLR200

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Journal of Lipid Research, Vol. 48, 104-113, January 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Lipolytic and ligand-binding functions of hepatic lipase protect against atherosclerosis in LDL receptor-deficient mice

Lita Freeman^1,*, Marcelo J. A. Amar^*, Robert Shamburek^*, Beverly Paigen, H. Bryan Brewer, Jr., Silvia Santamarina-Fojo^* and Herminia González-Navarro^*

^* Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892
Jackson Laboratory, Bar Harbor, ME 04609
Cardiovascular Research Institute, Washington Hospital Center, Washington, DC 20010

The online version of this article (available at http://www.jlr.org) contains additional two figures.

Published, JLR Papers in Press, October 27, 2006.

¹ To whom correspondence should be addressed. e-mail: litaf{at}mail.nih.gov

To elucidate the separate contributions of the lipolytic versus ligand-binding functions of hepatic lipase (HL) to lipoprotein metabolism and atherosclerosis, and to investigate the role of the low density lipoprotein receptor (LDLr) in these processes, we compared mice expressing catalytically active HL (HL-WT) with mice expressing inactive HL (HL-S145G) in a background lacking endogenous HL and the LDLr (LDLr-KOxHL-KO). HL-WT and HL-S145G reduced (P < 0.05 for all) cholesterol (55% vs. 20%), non-HDL-cholesterol (63% vs. 22%), and apolipoprotein B (apoB; 34% vs. 16%) by enhancing the catabolism of autologous ¹²⁵I-apoB-intermediate density lipoprotein (IDL)/LDL (fractional catabolic rate in day^–1: 6.07 ± 0.25, LDLr-KOxHL-WT; 4.76 ± 0.30, LDLr-KOxHL-S145G; 3.70 ± 0.13, LDLr-KOxHL-KO); HL-WT had a greater impact on the concentration, composition, particle size, and catabolism of apoB-containing lipoproteins (apoB-Lps) and HDL. Importantly, consistent with the changes in apoB-Lps, atherosclerosis in LDLr-KOxHL-KO mice fed a regular chow diet (RCD) was reduced by both HL-WT and HL-S145G (by 71% and 51% in cross-sectional analysis, and by 85% and 67% in en face analysis; P < 0.05 for all). These data identify physiologically relevant but distinct roles for the lipolytic versus ligand-binding functions of HL in apoB-Lp metabolism and atherosclerosis and demonstrate that their differential effects on these processes are mediated by changes in catabolism via non-LDLr pathways. These changes, evident even in the presence of apoE, establish an antiatherogenic role of the ligand-binding function of HL in LDLr-deficient mice.

Supplementary key words low density lipoprotein receptor • lipase • lipoprotein metabolism • aortic atherosclerosis

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