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

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 acti...

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Main Authors: Lita Freeman, Marcelo J.A. Amar, Robert Shamburek, Beverly Paigen, H. Bryan Brewer, Jr., Silvia Santamarina-Fojo, Herminia González-Navarro
Format: Article
Language:English
Published: Elsevier 2007-01-01
Series:Journal of Lipid Research
Subjects:
Online Access:http://www.sciencedirect.com/science/article/pii/S0022227520436417
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spelling doaj-30b42f6bb4c049c084f4aeede4f15d452021-04-27T04:48:03ZengElsevierJournal of Lipid Research0022-22752007-01-01481104113Lipolytic and ligand-binding functions of hepatic lipase protect against atherosclerosis in LDL receptor-deficient mices⃞Lita Freeman0Marcelo J.A. Amar1Robert Shamburek2Beverly Paigen3H. Bryan Brewer, Jr.4Silvia Santamarina-Fojo5Herminia González-Navarro6Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892Jackson Laboratory, Bar Harbor, ME 04609Cardiovascular Research Institute, Washington Hospital Center, Washington, DC 20010Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892To 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-KO×HL-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-KO×HL-WT; 4.76 ± 0.30, LDLr-KO×HL-S145G; 3.70 ± 0.13, LDLr-KO×HL-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-KO×HL-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.http://www.sciencedirect.com/science/article/pii/S0022227520436417low density lipoprotein receptorlipaselipoprotein metabolismaortic atherosclerosis
collection DOAJ
language English
format Article
sources DOAJ
author Lita Freeman
Marcelo J.A. Amar
Robert Shamburek
Beverly Paigen
H. Bryan Brewer, Jr.
Silvia Santamarina-Fojo
Herminia González-Navarro
spellingShingle Lita Freeman
Marcelo J.A. Amar
Robert Shamburek
Beverly Paigen
H. Bryan Brewer, Jr.
Silvia Santamarina-Fojo
Herminia González-Navarro
Lipolytic and ligand-binding functions of hepatic lipase protect against atherosclerosis in LDL receptor-deficient mices⃞
Journal of Lipid Research
low density lipoprotein receptor
lipase
lipoprotein metabolism
aortic atherosclerosis
author_facet Lita Freeman
Marcelo J.A. Amar
Robert Shamburek
Beverly Paigen
H. Bryan Brewer, Jr.
Silvia Santamarina-Fojo
Herminia González-Navarro
author_sort Lita Freeman
title Lipolytic and ligand-binding functions of hepatic lipase protect against atherosclerosis in LDL receptor-deficient mices⃞
title_short Lipolytic and ligand-binding functions of hepatic lipase protect against atherosclerosis in LDL receptor-deficient mices⃞
title_full Lipolytic and ligand-binding functions of hepatic lipase protect against atherosclerosis in LDL receptor-deficient mices⃞
title_fullStr Lipolytic and ligand-binding functions of hepatic lipase protect against atherosclerosis in LDL receptor-deficient mices⃞
title_full_unstemmed Lipolytic and ligand-binding functions of hepatic lipase protect against atherosclerosis in LDL receptor-deficient mices⃞
title_sort lipolytic and ligand-binding functions of hepatic lipase protect against atherosclerosis in ldl receptor-deficient mices⃞
publisher Elsevier
series Journal of Lipid Research
issn 0022-2275
publishDate 2007-01-01
description 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-KO×HL-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-KO×HL-WT; 4.76 ± 0.30, LDLr-KO×HL-S145G; 3.70 ± 0.13, LDLr-KO×HL-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-KO×HL-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.
topic low density lipoprotein receptor
lipase
lipoprotein metabolism
aortic atherosclerosis
url http://www.sciencedirect.com/science/article/pii/S0022227520436417
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