HEPATIC LIPASE DEFICIENCY INCREASES PLASMA-CHOLESTEROL BUT REDUCES SUSCEPTIBILITY TO ATHEROSCLEROSIS IN APOLIPOPROTEIN E-DEFICIENT MICE

The effect of hepatic lipase (HL) deficiency on the susceptibility to atherosclerosis was tested using mice with combined deficiencies in HL and apoE, Mice lacking both HL and apoE (hhee) have a plasma total ch olesterol of 917 +/- 252 mg/dl (n = 24), which is 184% that of mice la cking only apoE (HHee; 497 +/- 161 mg/dl, n = 20, p < 0.001), The incr ease in cholesterol was mainly in beta-migrating very low density lipo proteins, although high density lipoprotein cholesterol (HDLc) was als o increased (53 +/- 37 versus 20 +/- 13 mg/dl, p < 0.01), Despite the increase in plasma cholesterol, we found that HL deficiency significan tly decreased aortic plaque sizes in female mice fed normal chow (31 x 10(3) +/- 22 x 10(3) mu m(2) in hhee versus 115 x 10(3) +/- 69 x 10(3 ) mu m(2) in HHee, p < 0.001), Reduction of plaque sizes was also obse rved in female heterozygous apoE-deficient mice fed an atherogenic die t (2 x 10(3) +/- 2.5 x 10(3) mu m(2) in hhEe versus 56 x 10(3) +/- 49 x 10(3) mu m(2) in HHEe, p < 0.01), Changes in aortic lesion size were not apparent in the small number of male mice studied, In HHee female s, both HDLe and the capacity of high density lipoprotein (HDL) partic les to promote cholesterol efflux from cultured cells were 26% of the wild type, The absence of HL in hhee females partially restored HDLc l evels to 57% and cholesterol efflux to 55% of the wild type, Circulati ng pre-beta(1)-migrating HDL were present in all mutants, suggesting t hat there are alternative pathways in the formation of these pre-beta- HDL not involving apoE, HL, or cholesteryl ester transfer protein, The improved capacity to promote cholesterol efflux, together with increa sed HDL, may explain why these animals can overcome the increase in at herogenic lipoproteins.