INCREASED RESPONSE TO CHOLESTEROL FEEDING IN APOLIPOPROTEIN C1-DEFICIENT MICE

The function of apolipoprotein (apo) C1 in vivo is not well understood . From in vitro studies it has been reported that an excess of apoC1 r elative to apoE inhibits receptor-mediated uptake of remnant lipoprote ins [Sehayek and Eisenberg (1991) J. Biol. Chem. 266, 22453-22459]. In order to gain a better understanding of the role of apoC1 in lipoprot ein metabolism in vivo, we have generated apoC1-deficient mice by gene targeting in embryonic stem cells. Homozygous mutant mice ate viable and do not show overt abnormalities. Serum triacylglycerol levels are increased by 60% on both a standard mouse diet and a mild hypercholest erolaemic diet compared with controls. Total serum cholesterol levels are similar to controls on the two diets. However, the level of high-d ensity lipoprotein cholesterol in the apoC1-deficient mice fed on the mild hypercholesterolaemic diet is slightly decreased, which is accomp anied by a 3-fold increase in very-low-density plus low-density lipopr otein (VLDL + LDL) cholesterol. On a severe atherogenic diet, the homo zygous apoC1-defficient mice become hypercholesterolaemic, with a seru m cholesterol level of 10.7 +/- 3.3 mM compared with 6.7 +/- 1.8 mM an d 5.1 +/- 1.6 mM in heterozygous and control mice respectively. The in crease in cholesterol is mainly confined to the VLDL + LDL-sized fract ions. Binding experiments revealed that lipoproteins lacking apoC1 wit h d < 1.006 g/ml are poor competitors for I-125-labelled LDL binding t o the LDL receptor on HepG2 cells. This suggests that total apoC1 defi ciency leads to impaired receptor-mediated clearance of remnant lipopr oteins rather than enhanced uptake, as was expected from data reported in the literature.