Clearance of cationized LDL cholesterol from a muscle depot is not enhanced in human apolipoprotein A-IV transgenic mice

Human apolipoprotein A-IV (apoA-IV) transgenic mice fed an atherogenic diet were shown previously to develop less atherosclerosis than control mice. T he question arose whether the antiatherogenic effect of human apoA-IV is du e to enhancement of reverse cholesterol transport despite no increase in pl asma high-density lipoprotein (HDL) cholesterol, We studied male and female mice overexpressing human apoA-IV and their wild-type (WT) controls, all o f which were fed a chow diet. Plasma total and HDL cholesterol and total ph ospholipids were not increased in the transgenic mice, and regression analy sis showed no correlation between plasma levels of cholesterol or phospholi pids and plasma human apoA-IV, To study reverse cholesterol transport in vi vo, the disappearance of cholesterol from a depot of [H-3]cholesterol-label ed cationized low-density lipoprotein injected into the rectus femoris musc le was compared in high expressers of human apoA-IV and WT controls. The lo ss of radioactivity and the diminution of the exogenous cholesterol mass we re determined on days 8 and 12 after injection, No enhanced loss of radioac tivity or cholesterol mass was seen in the transgenic mice even at levels o f 2500 mg/dL of human apoA-IV. In some instances, there was even slower los s of exogenous cholesterol (radioactivity and mass) in the transgenic mice. Although [H-3]cholesterol efflux from cultured human skin fibroblasts and mouse peritoneal macrophages was only approximate to 30% higher in the pres ence of sera from high expressers of human apoA-IV, addition of phosphatidy lcholine liposomes enhanced the efflux in both groups to the same extent, A nother paradoxical finding was that the cholesterol esterification rate in plasma was 34% to 36% lower in human apoA-IV mice than in WT controls. In c onclusion, even though apoA-IV was found previously to be atheroprotective under hypercholesterolemic conditions, high plasma levels of human apoA-IV did not enhance cholesterol mobilization in vivo in normocholesterolemic mi ce.