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 cholesterolenriched 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.