Submitted on July 26, 2004
Revised on September 15, 2004
Accepted on September 24, 2004
Chylomicron remnant uptake in the livers of mice expressing human apolipoproteins E3, E2 (Arg158_Cys), and E3-Leiden
Sung-Joon Lee, Itamar Grosskopf, Sungshin Y. Choi, and Allen D. Cooper
Department of Medicine, Stanford University School of Medicine, Stanford, Ca 94305
Corresponding Author: adc{at}stanford.edu
ApoE2 and apoE3-Leiden cause chylomicron remnant accumulation (typeIII hyperlipidemia). However, the degree of dyslipidemia and its penetrance are different in humans and mice. Remnant uptake by isolated liver from apoE-/- mice transgenic for human apoE2, apoE3-Leiden, or apoE3 was measured. In the presence of both LDL receptor (LDLR) and LDL receptor-related protein (LRP), remnant uptake was apoE3>E3-Leiden>E2 mice. Absence of LDLR reduced uptake in apoE3 and apoE3-Leiden secreting livers but not in apoE2 secreting livers. LRP inhibition with receptor associated protein (RAP) reduced uptake in apoE3 and apoE2 secreting livers, but not in apoE3-Leiden secreting livers regardless the presence of LDLR. Fluorescently-labeled remnants clustered with LRP in apoE3 secreting livers only in the absence of LDLR but clustered in livers that express apoE2 even in the presence of LDLR and do not cluster with LRP in livers of apoE3-Leiden even in the absence of LDLR. Remnants were reconstituted with the three human apoE isoforms. Removal by liver of mApoe-/-/mLdlr-/- mice expressing the human LDLR was slightly greater than removal in the previous experiments with apoE3>E2>E3-Leiden. Thus, in vivo, human apoE2 is cleared primarily by LRP, apoE3-Leiden is cleared only by the LDLR, and apoE3 is cleared by both.
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