Hepatic lipase overexpression lowers remnant and LDL levels by a noncatalytic mechanism in LDL receptor-deficient mice.
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.
Dichek
H L
HL
Children's Hospital Oakland Research Institute (CHORI), Oakland, CA 94609, USA.hdichek@chori.org
Johnson
S M
SM
Akeefe
H
H
Lo
G T
GT
Sage
E
E
Yap
C E
CE
Mahley
R W
RW
D000821:Animal Feed; D000818:Animals; D053299:Apolipoprotein B-100; D053283:Apolipoprotein B-48; D001055:Apolipoproteins B / Q000097:blood; D015153:Blotting, Western; D002384:Catalysis; D004032:Diet; D006801:Humans; D008049:Lipase / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000097:blood / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D051379:Mice; D008822:Mice, Transgenic; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology*; D014280:Triglycerides / Q000097:blood
D053299:Apolipoprotein B-100; D053283:Apolipoprotein B-48; D001055:Apolipoproteins B; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D014280:Triglycerides; D008049:Lipase