title: Lipolytic and ligand-binding functions of hepatic lipase protect against atherosclerosis in LDL receptor-deficient mice.
abstract: 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 (125)I-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.
authors.affiliation: Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. litaf@mail.nih.gov
authors.forename: Lita
authors.initials: L
authors.lastname: Freeman
authors.forename: Marcelo J A
authors.initials: MJ
authors.lastname: Amar
authors.forename: Robert
authors.initials: R
authors.lastname: Shamburek
authors.forename: Beverly
authors.initials: B
authors.lastname: Paigen
authors.forename: H Bryan
authors.initials: HB
authors.lastname: Brewer
authors.forename: Silvia
authors.initials: S
authors.lastname: Santamarina-Fojo
authors.forename: Herminia
authors.initials: H
authors.lastname: González-Navarro
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000517:prevention & control*; D005260:Female; D008024:Ligands; D008049:Lipase / Q000378:metabolism*; D008066:Lipolysis; D008074:Lipoproteins / Q000097:blood / Q000737:chemistry; D008075:Lipoproteins, HDL / Q000172:deficiency / Q000235:genetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D018110:Receptors, Lipoprotein / Q000172:deficiency / Q000235:genetics; D012727:Sex Characteristics
chemical_list: D008024:Ligands; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; C031616:high density lipoprotein receptors; D012313:RNA; D008049:Lipase