To elucidate the separate contributions of the lipolytic versus
ligand-binding functions of hepatic
lipase (HL) to
lipoprotein metabolism and
atherosclerosis, and to investigate the role of the
low density lipoprotein receptor (LDLr) in these processes, we compared mice expressing catalytically active HL (HL-WT) with mice expressing inactive HL (HL-S145G) in a background lacking endogenous HL and the LDLr (LDLr-KOxHL-KO). HL-WT and HL-S145G reduced (P < 0.05 for all)
cholesterol (55% vs. 20%), non-
HDL-cholesterol (63% vs. 22%), and
apolipoprotein B (
apoB; 34% vs. 16%) by enhancing the catabolism of autologous (125)I-apoB-intermediate density
lipoprotein (IDL)/
LDL (fractional catabolic rate in day(-1): 6.07 +/- 0.25, LDLr-KOxHL-WT; 4.76 +/- 0.30, LDLr-KOxHL-S145G; 3.70 +/- 0.13, LDLr-KOxHL-KO); HL-WT had a greater impact on the concentration, composition, particle size, and catabolism of
apoB-containing
lipoproteins (
apoB-Lps) and HDL. Importantly, consistent with the changes in
apoB-Lps,
atherosclerosis in LDLr-KOxHL-KO mice fed a regular chow diet (RCD) was reduced by both HL-WT and HL-S145G (by 71% and 51% in cross-sectional analysis, and by 85% and 67% in en face analysis; P < 0.05 for all). These data identify physiologically relevant but distinct roles for the lipolytic versus
ligand-binding functions of HL in
apoB-Lp metabolism and
atherosclerosis and demonstrate that their differential effects on these processes are mediated by changes in catabolism via non-LDLr pathways. These changes, evident even in the presence of
apoE, establish an antiatherogenic role of the
ligand-binding function of HL in LDLr-deficient mice.