SECRETION-RECAPTURE PROCESS OF APOLIPOPROTEIN-E IN HEPATIC-UPTAKE OF CHYLOMICRON REMNANTS IN TRANSGENIC MICE

To investigate the role of apoE in hepatic uptake of chylomicron remna nts, we studied chylomicron metabolism in transgenic mice overexpressi ng apoE in the liver. Plasma clearance of injected I-125-labeled human chylomicrons was fivefold faster in transgenic mice than in controls. Immunohistochemistry demonstrated that apoE was specifically localize d at the basolateral surface of hepatocytes from fasted transgenic mic e. After injection of a large amount of chylomicrons, the density of t he cell surface apoE was markedly reduced and vesicular staining was o bserved in the cytoplasm, suggesting that the cell surface apoE was us ed for hepatic endocytosis of chylomicrons and remnants. Polyacrylamid e gel analysis of chylomicrons and remnants that had been reisolated f rom plasma and from liver membrane after the injection of chylomicrons showed the particles to be enriched with apoE mainly after their infl ux into the liver rather than during their residence in plasma. These results provide strong evidence for the secretion-recapture process of apoE, whereby chylomicron remnants enter the sinusoidal space, acquir e apoE molecules, and subsequently are endocytosed. Data from experime nts with very low density lipoprotein and LDL showed that this system is specific for chylomicron remnants.