The ligand-binding function of hepatic lipase modulates the development of atherosclerosis in transgenic mice.
To investigate the separate contributions of the lipolytic versus ligand-binding function of hepatic lipase (HL) to plasma lipoprotein metabolism and atherosclerosis, we compared mice expressing catalytically active wild-type HL (HL-WT) and inactive HL (HL-S145G) with no endogenous expression of mouse apoE or HL (E-KO x HL-KO, where KO is knockout). HL-WT and HL-S145G reduced plasma cholesterol (by 40 and 57%, respectively), non-high density lipoprotein cholesterol (by 48 and 61%, respectively), and apoB (by 36 and 44%, respectively) (p < 0.01), but only HL-WT decreased high density lipoprotein cholesterol (by 67%) and apoA-I (by 54%). Compared with E-KO x HL-KO mice, both active and inactive HL lowered the pro-atherogenic lipoproteins by enhancing the catabolism of autologous (125)I-apoB very low density/intermediate density lipoprotein (VLDL/IDL) (fractional catabolic rates of 2.87 +/- 0.04/day for E-KO x HL-KO, 3.77 +/- 0.03/day for E-KO x HL-WT, and 3.63 +/- 0.09/day for E-KO x HL-S145G mice) and (125)I-apoB-48 low density lipoprotein (LDL) (fractional catabolic rates of 5.67 +/- 0.34/day for E-KO x HL-KO, 18.88 +/- 1.72/day for E-KO x HL-WT, and 9.01 +/- 0.14/day for E-KO x HL-S145G mice). In contrast, the catabolism of apoE-free, (131)I-apoB-100 LDL was not increased by either HL-WT or HL-S145G. Infusion of the receptor-associated protein (RAP), which blocks LDL receptor-related protein function, decreased plasma clearance and hepatic uptake of (131)I-apoB-48 LDL induced by HL-S145G. Despite their similar effects on lowering pro-atherogenic apoB-containing lipoproteins, HL-WT enhanced atherosclerosis by up to 50%, whereas HL-S145G markedly reduced aortic atherosclerosis by up to 96% (p < 0.02) in both male and female E-KO x HL-KO mice. These data identify a major receptor pathway (LDL receptor-related protein) by which the ligand-binding function of HL alters remnant lipoprotein uptake in vivo and delineate the separate contributions of the lipolytic versus ligand-binding function of HL to plasma lipoprotein size and metabolism, identifying an anti-atherogenic role of the ligand-binding function of HL in vivo.
Molecular Disease Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA.
Herminia
H
González-Navarro
Zengxuan
Z
Nong
Marcelo J A
MJ
Amar
Robert D
RD
Shamburek
Jamila
J
Najib-Fruchart
Beverly J
BJ
Paigen
H Bryan
HB
Brewer
Silvia
S
Santamarina-Fojo
D000818:Animals; D053283:Apolipoprotein B-48; D001055:Apolipoproteins B / Q000032:analysis / Q000097:blood; D001161:Arteriosclerosis / Q000209:etiology / Q000517:prevention & control*; D002384:Catalysis; D005260:Female; D006801:Humans; D008024:Ligands; D008049:Lipase / Q000502:physiology*; D008066:Lipolysis; D008077:Lipoproteins, LDL / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
D053283:Apolipoprotein B-48; D001055:Apolipoproteins B; C504173:LIPC protein, human; D008024:Ligands; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D008049:Lipase