© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
In Vivo Evidence for Both Lipolytic and Nonlipolytic Function of Hepatic Lipase in the Metabolism of HDL
From the Molecular Disease Branch (K.A.D., M.J.A.A., C.C.H., R.D.S., H.B.B., S.S.-F.) and Laboratory of Animal Medicine and Surgery (R.F.H.), NHLBI, National Institutes of Health, Bethesda, Md; Cornell University, Ithaca, NY (A.B.); and the Faculté de Pharmacie, Institut Pasteur, INSERM U325, Lille, France (J.F.-N., Z.M.). K.A. Dugi is now at the Department of Internal Medicine I, Endocrinology and Metabolism, Heidelberg University, Heidelberg, Germany.
Correspondence to S. Santamarina-Fojo, National Institutes of Health, Molecular Disease Branch, National Heart, Lung, and Blood Institute, Building 10, Room 7N115, 10 Center Dr, MSC 1666, Bethesda, MD 20892.
Abstract—To investigate the in vivo role that hepatic lipase (HL) plays in HDL metabolism independently of its lipolytic function, recombinant adenovirus (rAdV) expressing native HL, catalytically inactive HL (HL-145G), and luciferase control was injected in HL-deficient mice. At day 4 after infusion of 2x108 plaque-forming units of rHL-AdV and rHL-145G-AdV, similar plasma concentrations were detected in postheparin plasma (HL=8.4±0.8 µg/mL and HL-145G=8.3±0.8 µg/mL). Mice expressing HL had significant reductions of cholesterol (-76%), phospholipids (PL; -68%), HDL cholesterol (-79%), apolipoprotein (apo) A-I (-45%), and apoA-II (-59%; P<0.05 for all), whereas mice expressing HL-145G decreased their cholesterol (-49%), PL (-40%), HDL cholesterol (-42%), and apoA-II (-89%; P<0.005 for all) but had no changes in apoA-I. The plasma kinetics of 125I-labeled apoA-I HDL, 131I-labeled apoA-II HDL, and [3H]cholesteryl ester (CE) HDL revealed that compared with mice expressing luciferase control (fractional catabolic rate [FCR] in d-1: apoA-I HDL=1.3±0.1; apoA-II HDL=2.1±0; CE HDL=4.1±0.7), both HL and HL-145G enhanced the plasma clearance of CEs and apoA-II present in HDL (apoA-II HDL=5.6±0.5 and 4.4±0.2; CE HDL=9.3±0.0 and 8.3±1.1, respectively), whereas the clearance of apoA-I HDL was enhanced in mice expressing HL (FCR=4.6±0.3) but not HL-145G (FCR=1.4±0.4). These combined findings demonstrate that both lipolytic and nonlipolytic functions of HL are important for HDL metabolism in vivo. Our study provides, for the first time, in vivo evidence for a role of HL in HDL metabolism independent of lipolysis and provides new insights into the role of HL in facilitating distinct metabolic pathways involved in the catabolism of apoA-I– versus apoA-II–containing HDL.
Key Words: hepatic lipase • HDL metabolism • lipolysis • nonlipolytic function
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