title: In vivo evidence for both lipolytic and nonlipolytic function of hepatic lipase in the metabolism of HDL.
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 2 x 10(8) plaque-forming units of rHL-AdV and rHL-145G-AdV, similar plasma concentrations were detected in postheparin plasma (HL=8.4+/-0.8 microg/mL and HL-145G=8.3+/-0.8 microg/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 (125)I-labeled apoA-I HDL, (131)I-labeled apoA-II HDL, and [(3)H]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.
authors.affiliation: Molecular Disease Branch, NHLBI, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Dugi
authors.forename: M J
authors.initials: MJ
authors.lastname: Amar
authors.forename: C C
authors.initials: CC
authors.lastname: Haudenschild
authors.forename: R D
authors.initials: RD
authors.lastname: Shamburek
authors.forename: A
authors.initials: A
authors.lastname: Bensadoun
authors.forename: R F
authors.initials: RF
authors.lastname: Hoyt
authors.forename: J
authors.initials: J
authors.lastname: Fruchart-Najib
authors.forename: Z
authors.initials: Z
authors.lastname: Madj
authors.forename: H B
authors.initials: HB
authors.lastname: Brewer
authors.forename: S
authors.initials: S
authors.lastname: Santamarina-Fojo
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D002460:Cell Line; D008076:Cholesterol, HDL / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D007457:Iodine Radioisotopes; D007668:Kidney / Q000166:cytology; D008049:Lipase / Q000235:genetics* / Q000378:metabolism*; D008066:Lipolysis / Q000502:physiology*; D008099:Liver / Q000201:enzymology*; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011993:Recombinant Fusion Proteins / Q000235:genetics; D014162:Transfection; D014316:Tritium
chemical_list: D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D007457:Iodine Radioisotopes; D011993:Recombinant Fusion Proteins; D014316:Tritium; D008156:Luciferases; D008049:Lipase