IN THE ABSENCE OF THE LOW-DENSITY-LIPOPROTEIN RECEPTOR, HUMAN APOLIPOPROTEIN C1 OVEREXPRESSION IN TRANSGENIC MICE INHIBITS THE HEPATIC-UPTAKE OF VERY-LOW-DENSITY LIPOPROTEINS VIA A RECEPTOR-ASSOCIATED PROTEIN-SENSITIVE PATHWAY

To study the role of apoC1 in lipoprotein metabolism, we have generate d transgenic mice expressing the human APOC1 gene. On a sucrose-rich d iet, male transgenic mice with high APOC1 expression in the liver show ed elevated levels of serum cholesterol and triglyceride compared with control mice (5.7 +/- 0.7 and 3.3 +/- 2.1 vs. 2.7 +/- 0.1 and 0.4 +/- 0.1 mmol/liter, respectively). These elevated levels were mainly conf ined to the VLDL fraction. Female APOC1 transgenic mice showed less pr onounced elevated serum lipid levels, In vivo VLDL turnover studies re vealed that, in hyperlipidemic APOC1 transgenic mice, VLDL particles a re cleared less efficiently from the circulation as compared with cont rol mice, No differences were observed in the hepatic production and e xtrahepatic lipolysis of VLDL-triglyceride, Also, VLDL isolated from c ontrol and APOC1 transgenic mice were found to be equally good substra tes for bovine lipoprotein lipase in vitro. These data indicate that t he hyperlipidemia in APOC1 transgenic mice results primarily from impa ired hepatic VLDL particle clearance, rather than a defect in the hydr olysis of VLDL-triglyceride, To investigate which hepatic receptor is involved in the apoC1-mediated inhibition of VLDL clearance, APOC1 tra nsgenic mice were bred with an LDL receptor-deficient (LDLR(-/-)) back ground, In addition, control, LDLR(-/-), and LDLR(-/-)/APOC1 mice were transfected with adenovirus carrying the gene for the receptor-associ ated protein (Ad-RAP). Both serum cholesterol and triglyceride levels were strongly elevated in LDLR(-/-)/APOC1 mice compared with LDLR(-/-) mice (52 +/- 19 and 36 +/- 19 vs, 8.4 +/- 0.9 and 0.5 +/- 0.2 mmol/li ter, respectively), indicating that apoC1 inhibits the alternative VLD L clearance pathway via the remnant receptor, Transfection of LDLR(-/- ) mice with Ad-RAP strongly increased serum cholesterol and triglyceri de levels, but to a lesser extent than those found in LDLR(-/-)/APOC1 mice (39 +/- 8 and 17 +/- 8 vs, 52 +/- 19 and 36 +/- 19 mmol/liter, re spectively), However, in LDLR(-/-)/APOC1 mice the transfection with Ad -RAP did not further increase serum cholesterol and triglyceride level s (52 +/- 19 and 36 +/- 19 vs. 60 +/- 10 and 38 +/- 7 mmol/liter, resp ectively), From these studies we conclude that, in the absence of the LDLR, apoC1 inhibits the hepatic uptake of VLDL via a RAP-sensitive pa thway.