Chylomicron remnant uptake in the livers of mice expressing human apolipoproteins E3, E2 (Arg158→Cys), and E3-Leiden

Abstract

Apolipoprotein E2 (apoE2) and apoE3-Leiden cause chylomicron remnant accumulation (type III 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 Ͼ E3-Leiden Ͼ 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 reduced uptake in apoE3-and apoE2-secreting livers, but not in apoE3-Leiden-secreting livers, regardless of 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 expressed apoE2 even in the presence of LDLR, and did 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 Ͼ E2 Ͼ 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. -Lee, S-J., I. Grosskopf, S. Y. Choi, and A. D. Cooper. Chylomicron remnant uptake in the livers of mice expressing human apoE3, apoE2 (Arg158 → Cys), and apoE3-Leiden.

Specific collagen XVIII isoforms promote adipose tissue accrual via mechanisms determining adipocyte number and affect fat deposition

“…1E). The implication, which seems entirely consistent with studies on apoE-lipoprotein clearance in liver (33,34) and this study's observation that N-terminal HS-modified collagen XVIII species interact with apoE ( Fig. 5F), is that collagen XVIII serves to delay the clearance of triglyceride-rich lipoproteins by binding/sequestering apoE, and therefore total ablation of collagen XVIII in the liver sinusoidal space is more consequential than the lack of only the medium/long isoforms, particularly in the setting of a primary defect in adipogenesis.…”

“…4A and Fig. S9), indicating that loss of medium/long collagen XVIII did not impair hepatic free fatty acid uptake or apoE-mediated internalization of chylomicron and VLDL remnants (33,34). The anti-all-18 antibody produced comparable staining signals in WT and P1-null mice livers, but only stained the portal regions of P2-null mice livers (Fig.…”

Apolipoprotein E does not cross the blood-cerebrospinal fluid barrier, as revealed by an improved technique for sampling CSF from mice

“…Besides having similar molecular size to mouse apoE, the human apoE3 induced by adenovirus in mice has been demonstrated functionally to interact with mouse apoE receptors, e.g., LDL receptor (LDLR) and LDL receptor-related protein 1 (LRP1) (13). Because its molecular weight is 34 kDa, apoE should theoretically be excluded from the CNS by the BBB.…”

“…Human apoE induced by adenovirus has been broadly used to study endogenous apoE functions in mice (13,31,32). Besides having similar molecular size to mouse apoE, the human apoE3 induced by adenovirus in mice has been demonstrated functionally to interact with mouse apoE receptors, e.g., LDL receptor (LDLR) and LDL receptor-related protein 1 (LRP1) (13).…”

Digestion-resistant fraction from soybean [Glycine max (L.) Merrill] induces hepatic LDL receptor and CYP7A1 expression in apolipoprotein E-deficient mice

“…These two receptors mediate approximately 80-90% of the hepatic removal of triglyceride-rich lipoproteins such as chylomicron remnants [27,28]. The LRP expression was significantly increased by 35.9% and 21.2% in C57BL/6J and apoE -/-(21.2%) mice, respectively, after RRF-GLY consumption.…”