BOTH LIPOLYSIS AND HEPATIC-UPTAKE OF VLDL ARE IMPAIRED IN TRANSGENIC MICE COEXPRESSING HUMAN APOLIPOPROTEIN E-ASTERISK-3LEIDEN AND HUMAN APOLIPOPROTEIN C1

Transgenic mice overexpressing human APOE3Leiden are highly susceptib le to diet-induced hyperlipoproteinemia and atherosclerosis due to a d efect in hepatic uptake of remnant lipoproteins. In addition to the hu man APOE3Leiden gene, these mice carry the human APOC1 gene (APOE*3Le iden-C1). To investigate the possible effect of simultaneous expressio n of the human APOC1 gene, we examined the phenotypic expression in th ese APOE3Leiden-C1 mice in relation to transgenic mice expressing the APOE3Leiden gene without the APOC1 gene (APOE*3Leiden-HCR). APOE*3Le iden-C1 and APOE3Leiden-HCR mice had comparable liver expression for the APOE3Leiden transgene and high total cholesterol levels on a sucr ose-based diet compared with control mice (4.3 and 4.3 versus 2.1 mmol /L). In addition, on this diet APOE3Leiden-C1 mice displayed signific antly higher serum triglyceride levels than APOE3Leiden-HCR mice and control mice (4.4 versus 0.6 and 0.2 mmol/L). Elevated triglyceride an d cholesterol levels were mainly in the VLDL-sized lipoproteins. In vi vo turnover studies with endogenously triglyceride-labeled VLDL showed a reduced VLDL triglyceride fractional catabolic rate for APOE3Leide n-C1 and APOE3Leiden-HCR mice compared with control mice (3.5 and 11. 0 versus 20.4 pools per hour). To study whether the difference in frac tional catabolic rates between the two transgenic strains was due to a n inhibiting effect of apoC1 on the extrahepatic lipolysis or hepatic- mediated uptake of VLDL, turnover experiments were performed in functi onally hepatectomized mice. Strikingly, both APOE3Leiden-C1 and APOE* 3Leiden-HCR mice showed a decreased lipolytic rate of VLDL triglycerid e in the extrahepatic circulation compared with control mice (1.5 and 1.8 versus 6.3 pools per hour). We conclude that next to an impaired h epatic uptake, overexpression of the APOE3Leiden gene influences the extrahepatic lipolysis of VLDL triglycerides, whereas simultaneous ove rexpression of the APOC1 gene leads to a further decrease in hepatic c learance of VLDL.