Structure, chromosome location, and expression of the human very low density lipoprotein receptor gene.

The processes responsible for the uptake of chylomicron remnants by macrophages were investigated using freshly isolated cells from low density lipoprotein (LDL) receptor, very low density lipoprotein (VLDL) receptor and apolipoprotein E knockout mice. In peritoneal macrophages from normal mice, the metabolism of chylomicron remnants was inhibited 40% by anti-LDL receptor antibody and 60% by a high concentration of receptor-associated protein (RAP). Together they reduced the amount processed by 70%. Digestion of cell proteoglycans decreased remnant degradation by 20% while the addition of acetyl-LDL had no effect. When LDL receptors were absent, the absolute rates of metabolism were less than that of normal cells and were not inhibited by the anti-LDL receptor antibody; the rates, however, were reduced to less than half by RAP. These suggest that the LDL receptor-related protein (LRP) or another LDL receptor family member(s) contributes to chylomicron remnant uptake and becomes the major mechanism of uptake when LDL receptors are absent. In contrast, the VLDL receptor was not involved as its absence did not affect chylomicron remnant metabolism. Similarly, the absence of apoE production did not affect the amount of remnant uptake; however, the proportion that was sensitive to RAP was eliminated. The level of LRP expression was not altered in these cells whereas there was a decrease in LDL receptors. This suggests that the apoE content of chylomicron remnants is sufficient for its recognition by LDL receptors but additional apoE is required for its uptake by the LRP and that there is an up-regulation of a non-LDL receptor family mechanism in apoE deficiency. Together these studies suggest that even in the absence of LDL receptors or apoE secretion, chylomicron remnants could contribute to lipid accumulation in the artery wall during atherogenesis.-Fujioka, Y., A. D. Cooper, and L. G. Fong. Multiple processes are involved in the uptake of chylomicron remnants by mouse peritoneal macrophages.

Section: Discussioncontrasting

confidence: 61%

Multiple processes are involved in the uptake of chylomicron remnants by mouse peritoneal macrophages

Fujioka

Cooper

Fong

1998

“…These results demonstrate the simultaneous expression in HUVEC of VLDL and LDL receptors, both with a potential for endocytosis of VLDL particles. Furthermore, they show that VLDL receptor expression in HUVEC did not change in response to withdrawal of sterols, whereas LDL receptors were up-regulated in agreement with what has been shown for THP-1 cells (44).…”

Section: Serum Regulation Of Ldl and Vldl Receptor Expression In Endothelial Cellssupporting

confidence: 86%

VLDL activation of plasminogen activator inhibitor-1 (PAI-1) expression: involvement of the VLDL receptor

Nilsson

Gåfvels

Musakka

et al. 1999

The potential role of the very low density lipoprotein (VLDL) receptor in mediating VLDL-induced plasminogen activator inhibitor-1 (PAI-1) expression was studied in vitro. Cultured endothelial cells incubated with VLDL showed an increased secretion of PAI-1. This response to VLDL could be completely prevented by the receptor-associated protein (RAP) and partially blocked by rabbit polyclonal anti-VLDL receptor IgG. Furthermore, Chinese hamster ovary (CHO) control cells and cells overexpressing the VLDL receptor were transiently transfected with a PAI-1 promoter-reporter construct and incubated with VLDL. The PAI-1 promoter activity in response to VLDL was significantly higher in the VLDL receptor overexpressing cells compared to the control cells. Addition of RAP completely blocked the VLDL-activated PAI-1 transcription. Electromobility shift assay was performed to investigate whether the enhanced PAI-1 promoter activity seen in the VLDL receptor overexpressing cells in response to VLDL involved induction of the previously described VLDL-inducible factor(s) binding to the ؊ 675 to ؊ 653 region of the PAI-1 promoter. We found that the binding of the VLDL-inducible factor in VLDL receptor overexpressing cells was markedly enhanced by addition of VLDL as compared to control cells where no increased binding could be seen in response to VLDL. In summary, these results indicate that the VLDL receptor is a strong candidate for mediating VLDL effects on PAI-1 synthesis and secretion in cells expressing this re-

“…Detailed studies in the chicken have demonstrated that a 95-kDa protein binds not only VTG but also very low density lipoprotein (VLDL), triglyceride-rich particles of hepatic origin (12,13). Indeed, molecular characterization of the chicken oocyte protein revealed extensive homology between it (14) and the mammalian so-called VLDL receptors (VLDLR) (15,16), a branch of the low density lipoprotein receptor (LDLR) superfamily (14). Elements characteristic of this gene family are i ) clusters of cysteine-rich repeats constituting the ligand-binding domain; ii ) epidermal growth factor-precursor repeats, also containing six cysteines each; iii ) usually 5 consensus tetrapeptide motifs, Phe/Tyr-Trp-Xaa-Asp, within subdo-mains of 50 residues each (17); iv ) a transmembrane domain anchoring the receptor in the plasma membrane; and v ) a consensus peptide in the cytoplasmic domain, Phe-Glu-Asn-Pro-Xaa-Tyr, that mediates the internalization of the receptor via coated pits (18).…”

mentioning

confidence: 99%

Evolution of oogenesis: the receptor for vitellogenin from the rainbow trout

Davail

Pakdel

Bujo

et al. 1998

Receptors that transport vitellogenin (VTG) into oocytes are of vital importance to egg-laying species because they mediate a key step in oocyte development. Here we describe the cloning of the first piscine oocyte-specific receptor cDNA, i.e., that encoding the VTG receptor from the rainbow trout ( Oncorhynchus mykiss ). The receptor, a 826-residue type-I membrane protein, is a member of the low density lipoprotein receptor (LDLR) superfamily. It closely resembles the mammalian so-called very low density lipoprotein receptors, in that its aminoterminal ligand binding domain consists of a cluster of 8 cysteine-rich repeats. The short intracellular portion contains the internalization signal typical for the LDLR superfamily, Phe-Glu-Asn-Pro-Val-Tyr. Notably, the receptor lacks a domain with a high density of potential O-glycosylation sites often found in somatic cell-specific members of the LDLR family. A specific transcript of 3.9 kb is abundant in ovary, but undetectable in muscle and heart, which are the major sites of expression of very low density lipoprotein receptors in mammals. In vitro translation of the full-length cDNA produced a 97-kDa protein, and transient expression in COS-1 cells showed that the cDNA encodes a protein of the same size that binds vitellogenin in ligand blots. As revealed by in situ hybridization, transcripts are present in previtellogenic oocytes, indicating that production of receptor protein precedes the phase of yolk deposition. Our results in fish, together with those in birds (Bujo, H., et al. 1994. EMBO J. 13: 5165-5175) suggest that vitellogenesis provides a prime model for the study of ligand/receptor systems designed to sustain reproduction.-Davail, B.