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 cholesterol of 917 ؎ 252 mg/dl (n ‫؍‬ 24), which is 184% that of mice lacking only apoE (HHee; 497 ؎ 161 mg/dl, n ‫؍‬ 20, p < 0.001). The increase in cholesterol was mainly in ␤-migrating very low density lipoproteins, although high density lipoprotein cholesterol (HDLc) was also increased (53 ؎ 37 versus 20 ؎ 13 mg/dl, p < 0.01). Despite the increase in plasma cholesterol, we found that HL deficiency significantly decreased aortic plaque sizes in female mice fed normal chow (31 ؋ 10 3 ؎ 22 ؋ 10 3 m 2 in hhee versus 115 ؋ 10 3 ؎ 69 ؋ 10 3 m 2 in HHee, p < 0.001). Reduction of plaque sizes was also observed in female heterozygous apoE-deficient mice fed an atherogenic diet (2 ؋ 10 3 ؎ 2.5 ؋ 10 3 m 2 in hhEe versus 56 ؋ 10 3 ؎ 49 ؋ 10 3 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 females, both HDLc and the capacity of high density lipoprotein (HDL) particles to promote cholesterol efflux from cultured cells were 26% of the wild type. The absence of HL in hhee females partially restored HDLc levels to 57% and cholesterol efflux to 55% of the wild type. Circulating pre-␤ 1 -migrating HDL were present in all mutants, suggesting that there are alternative pathways in the formation of these pre-␤-HDL not involving apoE, HL, or cholesteryl ester transfer protein. The improved capacity to promote cholesterol efflux, together with increased HDL, may explain why these animals can overcome the increase in atherogenic lipoproteins.In circulation, nascent lipoproteins are remodeled by removal of core lipids and transfer of surface proteins and lipids prior to their removal through receptor-mediated mechanisms (1). Hepatic lipase (HL) 1 is a 60-kDa lipolytic enzyme involved in the processing of chylomicrons, intermediate density lipoproteins (IDL), and high density lipoproteins (HDL) (2). HL efficiently hydrolyzes both triglycerides (TG) and phospholipids, while lipoprotein lipase is mainly responsible for hydrolysis of plasma TG. The preferred enzymatic substrates for HL are intermediate-size particles, such as IDL, and HDL 2 . Changes observed in lipoprotein profiles in humans with congenital HL deficiencies are the presence of ␤-migrating very low density lipoproteins (␤-VLDL) and larger HDL (3). The ␤-VLDL that accumulate in HL deficiency are more TG-rich than ␤-VLDL in typical type III hyperlipoproteinemia subjects (4). We previously reported that HL-deficient mice have a mild dyslipidemia with increased cholesterol and phospholipid, and the plasma contains large HDL floating in the 1.02-1.04 g/ml density range (5). Consistent with these observations, overexpression of HL decreases HDL cholesterol and HDL particle size in mice (6) and decreases HDL cholesterol and IDL in rabbits (7).Both HL and cholesteryl ester transfer protein (CETP) parti...

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Studies assessing fatty streak formation in mice have revealed that human apolipoprotein A-I (apoAI) transgenic mice (TgAI) have 15-fold less atherosclerosis susceptibility than combined human apolipoprotein A-I/human apolipoprotein A-II (apoAI:AII) transgenics (TgAI:AII) and 40-fold less than nontransgenic control mice. In order to examine the biochemical mechanisms underlying those in vivo observations, we have compared in vitro properties of serum from the different groups of animals for participation in cholesterol efflux, LCAT activation, and pre-beta particle formation. Analysis of cholesterol efflux from both Fu5AH hepatoma and Ob1771 adipose cells revealed serum from the TgAI to be the most efficient in promoting efflux. The two-dimensional electrophoresis of mouse serum shows that control mice have exclusively apoAI in alpha particles. TgAI and TgAI:AII mice have 30 and 38% of total apoAI in particles with pre-beta electrophoretic mobility, respectively. The distribution of cell-derived cholesterol between these apoAI-containing lipoprotein subspecies after 1 and 60 min of incubation with Fu5AH hepatoma cells was examined. This revealed after a 1 min incubation 66 +/- 8 and 83 +/- 9% of the counts in particles with pre-beta mobility for TgAI and TgAI:AII mice, respectively; while after 60 min of incubation, only 6 +/- 2% of counts remained in pre-beta particles from the TgAI and 30 +/- 3% for the TgAI:AII. This suggests faster movement of cholesterol from pre-beta to alpha particles in plasma from the TgAI. Consistent with this is the observation that LCAT activity with both exogenous and endogenous substrate increased in the TgAI versus the TgAI:AII mice. The previously observed decrease in fatty streak formation in the TgAI versus the TgAI:AII and control mice is consistent with the in vitro studies presented here and suggests that HDL containing human apoAI is a more effective participant in the postulated early steps in reverse cholesterol transport than HDL containing both human apoAI and human apoAII, and/or murine HDL.