Submitted on July 20, 2006
Revised on October 17, 2006
Accepted on October 27, 2006
Lipolytic and ligand-binding functions of hepatic lipase protect against atherosclerosis in LDL receptor-deficient mice
Lita A. Freeman, Marcelo J. A. Amar, Robert Shamburek, Beverly Paigen, H. Bryan Brewer Jr., Silvia Santamarina-Fojo, and Herminia Gonzalez-Navarro
Molecular Disease Branch, NIH, NHLBI, Bethesda, MD 20892-1666
Corresponding Author: 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 LDLr in these processes, we compared mice expressing catalytically active HL (HL-WT) to 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; all) cholesterol (55% vs. 20%), non-HDL-cholesterol (63% vs. 22%) and apoB (34% vs. 16%) by enhancing catabolism of autologous 125I-apoB-IDL/LDL (FCR in d-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 RCD was reduced by both HL-WT and HL-S145G (by 71% and 51%, cross-sectional analysis, and by 85% and 67%, en face analysis; p<0.05, all). These data identify physiologically relevant but distinct roles for the lipolytic vs. 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 anti-atherogenic role of the ligand-binding function of HL in LDLr-deficient mice.
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