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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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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