In vivo evidence for both lipolytic and nonlipolytic function of hepatic lipase in the metabolism of HDL

To investigate the in vivo role that hepatic lipase (HL) plays in HDL metab olism 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 2x10 (8) plaque-forming units of rHL-AdV and rHL-145G-AdV, similar plasma concen trations were detected in postheparin plasma (HL=8.4+/-0.8 mu g/mL and HL-1 45G= 8.3+018 mu g/mL). Mice expressing HL had significant reductions of cho lesterol (- 76%), phospholipids (PL; -68%), HDL cholesterol (-79%), apolipo protein (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 chole sterol (-42%), and apoA-II (-89%; P<0.005 for all) but had no changes in ap oA-I. The plasma kinetics of I-125-labeled apoA-I HDL, I-131-labeled apoA-I I HDL, and [H-3]cholesteryl ester (CE) HDL revealed that compared with mice expressing luciferase control (fractional catabolic rate [FCR] in d(-1): a poA-I HDL=1.3+0.1; apoA-II HDL=2.1+/-0; CE HDL=4.1+/-0.7), both HL and HL-1 45G enhanced the plasma clearance of CEs and apoA-II present in HDL (apoA-I I 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 dem onstrate that both lipolytic and nonlipolytic functions of HL are important for HDL metabolism in vivo. Our study provides, for the first time, in viv o evidence for a role of HL in HDL metabolism independent of lipolysis and provides new insights into the role of HL in facilitating distinct metaboli c pathways involved in the catabolism of apoA-I- versus apoA-II-containing HDL.