title: Impact of combined deficiency of hepatic lipase and endothelial lipase on the metabolism of both high-density lipoproteins and apolipoprotein B-containing lipoproteins.
abstract: BACKGROUND
  Hepatic lipase (HL) and endothelial lipase (EL) are extracellular lipases that both hydrolyze triglycerides and phospholipids and display potentially overlapping or complementary roles in lipoprotein metabolism.
  
  
  OBJECTIVE
  We sought to dissect the overlapping roles of HL and EL by generating mice deficient in both HL and EL (HL/EL-dko) for comparison with single HL-knockout (ko) and EL-ko mice, as well as wild-type mice.
  
  
  RESULTS
  Reproduction and viability of the HL/EL-dko mice were impaired compared with the single-knockout mice. The plasma levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, non-HDL cholesterol, and phospholipids in the HL/EL-dko mice were markedly higher than those in the single-knockout mice. Most notably, the HL/EL-dko mice exhibited an unexpected substantial increase in small low-density lipoproteins. Kinetic studies with [(3)H]cholesteryl ether-labeled very-low-density lipoproteins demonstrated that the HL/EL-dko mice accumulated counts in the smallest low-density lipoprotein-sized fractions, as assessed by size exclusion chromatography, suggesting that it arises from lipolysis of very-low-density lipoproteins. HDL from all 3 lipase knockout models had an increased cholesterol efflux capacity but reduced clearance of HDL cholesteryl esters versus control mice. Despite their higher HDL cholesterol levels, neither HL-ko, EL-ko, nor HL/EL-dko mice demonstrated an increased rate of macrophage reverse cholesterol transport in vivo.
  
  
  CONCLUSIONS
  These studies reveal an additive effect of HL and EL on HDL metabolism but not macrophage reverse cholesterol transport in mice and an unexpected redundant role of HL and EL in apolipoprotein B lipoprotein metabolism.
authors.affiliation: Department of Medicine and Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Brown
authors.forename: William R
authors.initials: WR
authors.lastname: Lagor
authors.forename: Sandhya
authors.initials: S
authors.lastname: Sankaranaravanan
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yasuda
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
authors.forename: George H
authors.initials: GH
authors.lastname: Rothblat
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism*; D001692:Biological Transport; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D003433:Crosses, Genetic; D005260:Female; D006579:Heterozygote; D006937:Hypercholesterolemia / Q000097:blood / Q000235:genetics; D007700:Kinetics; D008049:Lipase / Q000172:deficiency* / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010743:Phospholipids / Q000097:blood; D014945:Wound Healing / Q000235:genetics
chemical_list: D001055:Apolipoproteins B; D008075:Lipoproteins, HDL; D010743:Phospholipids; D002784:Cholesterol; D008049:Lipase; C495700:Lipc protein, mouse; C498741:Lipg protein, mouse