Binding of rat chylomicrons and their remnants to the hepatic low-density-lipoprotein receptor and its role in remnant removal

Abstract

Binding and uptake of rat chylomicrons of different metabolic stages by the hepatic low-density-lipoprotein (LDL) receptor were studied. Pure chylomicrons, characterized by apolipoprotein B-48 devoid of contaminating B-100, were labelled in their cholesteryl esters. Lymph chylomicrons and serum chylomicrons, enriched in apolipoprotein E and the C-apolipoproteins, bound poorly to rat hepatic membranes. In contrast, chylomicron remnants, containing the apolipoproteins B-48 and E, bound with high affinity. Specific binding of remnants was virtually completely competed for by LDL free of apolipoprotein E. In addition, in ligand blots both remnants and LDL associated with the same protein with an Mr characteristic of the LDL receptor. Uptake of remnants during a single pass through isolated perfused rat livers was decreased to about 50% by an excess of LDL. It is concluded that rat chylomicron remnants are a ligand of the hepatic LDL receptor. The much higher affinity as compared with LDL is mediated by apolipoprotein E but not B-48, and is inhibited by the C-apolipoproteins. This explains why serum chylomicrons are not taken up by the liver, whereas remnants are rapidly removed from the circulation. Results from experiments in vivo suggest that the LDL receptor makes an important contribution to the hepatic uptake of remnants and may be the principal binding site of the liver responsible for remnant removal.

Role of the Low Density Lipoprotein (LDL) Receptor Pathway in the Metabolism of Chylomicron Remnants

“…On the other hand, chylomicron remnants have been demonstrated to bind to the LDLR through apoE that forms a major surface component of the lipoproteins in in vitro studies (15,(17)(18)(19). When the LDLR was blocked by its monospecific antibody in mice (20) and rats (21), the clearance of chylomicron remnants was partially delayed.…”

“…In support of this, the intravenously injected chylomicrons was cleared from the plasma of LDLR-deficient rabbits at a rate similar to wild-type (15). Upon vitamin A fat tolerance tests, moreover, no significant delay of the excursion of the esterified form of vitamin A, which represents chylomicron remnants, was shown in LDLR-deficient humans (16).On the other hand, chylomicron remnants have been demonstrated to bind to the LDLR through apoE that forms a major surface component of the lipoproteins in in vitro studies (15,(17)(18)(19). When the LDLR was blocked by its monospecific antibody in mice (20) and rats (21), the clearance of chylomicron remnants was partially delayed.…”

Lipoprotein lipase enhances the binding of chylomicrons to low density lipoprotein receptor-related protein.

“…Previous experiments (2-6, 10) showed that the uptake of CRs is mediated by apolipoprotein E (apoE) but is independent of apoB (11). Since the low density lipoprotein (LDL) receptor is able to recognize apoE with high affinity, one line of thinking assumed that the LDL receptor was responsible for CR catabolism (12), and this appears to be true in part. However, tissue culture studies as well as in vivo experiments have shown that most of the apoE-mediated uptake of CR is independent of the LDL receptor (13,14).…”

Secretion-recapture process of apolipoprotein E in hepatic uptake of chylomicron remnants in transgenic mice.

“…Hepatic LDL receptors were reported to be situated at the basolateral surface of hepatocytes (23). The similar pattern of apoE and LDL receptors suggests that enrichment of chylomicrons and remnants with apoE may be immediately followed by hepatic uptake through LDL receptors, since several lines ofevidence indicate that LDL receptors play a major role in plasma clearance ofchylomicron remnants in rodents (21,22,24). LRP, which is as likely a candidate as chylomicron remnant receptors, appears to be also similarly localized and involved in hepatic uptake of chylomicrons and remnants.…”

“…It is now established that hepatic overexpression of apoE markedly enhances plasma clearance of chylomicron remnants. A high apoE content on chylomicron remnants would be essential to an efficient receptor mediated-endocytosis, although functional proposition of LDL receptors and chylomicron remnant receptors that might be LRP is controversial (19)(20)(21)(22). The chylomicrons used in this study were prepared from pleural effusions of a patient with chylothorax and were relatively poor in apoE.…”