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

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−/−HLS145G) 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−/−HLS145G 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−/− HLS145G 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−/−HLS145G 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., S. M. Johnson, H. Akeefe, G. T. Lo, E. Sage, C. E. Yap, and R. W. Mahley. Hepatic lipase overexpression lowers remnant and LDL levels by a noncatalytic mechanism in LDL receptor-deficient mice.

Keywords

• noncatalytic function
• ligand function
• apoB-100
• FPLC
• Western diet
• phospholipase A1 activity