Hepatic lipase overexpression lowers remnant and LDL levels by a noncatalytic mechanism in LDL receptor-deficient mice

J Lipid Res. 2001 Feb;42(2):201-10.

Abstract

To address the role of the noncatalytic ligand function of hepatic lipase (HL) in low density lipoprotein (LDL) receptor-mediated lipoprotein metabolism, we characterized transgenic mice lacking the LDL receptor (LDLR) that express either catalytically active (Ldlr(-/-)HL) or inactive (Ldlr(-/-)HL(S145G)) human HL on both chow and high fat diets and compared them with nontransgenic Ldlr(-/-) mice. In mice fed a chow diet, apolipoprotein (apo)B-containing lipoprotein levels were 40-60% lower in Ldlr(-/-)HL and Ldlr(-/-)HL(S145G) mice than in Ldlr(-/-) mice. This decrease was mainly reflected by decreased apoB-48 levels in the Ldlr(-/-)HL mice and by decreased apoB-100 levels in Ldlr(-/-) HL(S145G) mice. These findings indicate that HL can reduce apoB-100-containing lipoproteins through a noncatalytic ligand activity that is independent of the LDLR. Cholesterol enrichment of the apoB-containing lipoproteins induced by feeding Ldlr(-/-)HL and Ldlr(-/-)HL(S145G) mice a cholesterol-enriched high fat (Western) diet resulted in parallel decreases in both apoB-100 and apoB-48 levels, indicating that HL is particularly efficient at reducing cholesterol-enriched apoB-containing lipoproteins through both catalytic and noncatalytic mechanisms. These data suggest that the noncatalytic function of HL provides an alternate clearance pathway for apoB-100- and apoB-48-containing lipoproteins that is independent of the LDLR and that contributes to the clearance of high density lipoproteins.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animal Feed
  • Animals
  • Apolipoprotein B-100
  • Apolipoprotein B-48
  • Apolipoproteins B / blood
  • Blotting, Western
  • Catalysis
  • Diet
  • Humans
  • Lipase / metabolism*
  • Lipoproteins, LDL / blood
  • Lipoproteins, LDL / metabolism*
  • Liver / enzymology*
  • Mice
  • Mice, Transgenic
  • Receptors, LDL / genetics
  • Receptors, LDL / physiology*
  • Triglycerides / blood

Substances

  • Apolipoprotein B-100
  • Apolipoprotein B-48
  • Apolipoproteins B
  • Lipoproteins, LDL
  • Receptors, LDL
  • Triglycerides
  • Lipase