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 metaboli sm, we characterized transgenic mice lacking the LDL receptor (LDLR) that e xpress either catalytically active (Ldlr(-/-)HL) or inactive (Ldlr(-/-)HL(S 145G)) human HL on both chow and high fat diets and compared them with nont ransgenic Ldlr(-/-) mice, In mice fed a chow diet, apolipoprotein (apo)B-co ntaining lipoprotein levels were 40-60% lower in Ldlr(-/-)HL and Ldlr(-/-)H L(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 red uce apoB-100-containing lipoproteins through a noncatalytic ligand activity that is independent of the LDLR, Cholesterol enrichment of the apoB-contai ning lipoproteins induced by feeding Ldlr(-/-)HL and Ldlr(-/-)HL(S145G) mic e a cholesterol-enriched high fat (Western) diet resulted in parallel decre ases in both apoB-100 and apoB-48 levels, indicating that HL is particularl y efficient at reducing cholestlerol-enriched apoB-containing lipoproteins through both catalytic and noncatalytic mechanisms. These data suggest that the noncatalytic function of HL provides an alternate clearance pathway fo r apoB-100- and apoB-48-containing lipoproteins that is independent of the LDLR and that contributes to the clearance of high density lipoproteins.