Low Density Lipoprotein Receptor-related Protein Mediates Uptake of Cholesteryl Esters Derived from Apoprotein E-enriched Lipoproteins

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1989 Aug 1

PMID 2762297

Citations 143

Authors

R C Kowal

J Herz

J L Goldstein

V ESSER

M S Brown

Affiliations

Soon will be listed here.

Abstract

Low density lipoprotein receptor-related protein (LRP) is a recently described cell-surface protein of 4544 amino acids that contains reiterated sequences found in the 839-amino acid receptor for low density lipoprotein (LDL). In the current studies, we purified LRP from rat liver, prepared polyclonal antibodies that recognize the extracellular domain, and demonstrated an immunoreactive protein of approximately 600 kDa in human fibroblasts. The function of this LRP was studied in mutant human fibroblasts that do not produce LDL receptors. The mutant cells were incubated with beta-migrating very low density lipoprotein (beta-VLDL) that was isolated from cholesterol-fed rabbits and artificially enriched with apoprotein (apo) E by incubation in vitro with human apo E produced in a bacterial expression system. The apo E-enriched beta-VLDL, but not unincubated beta-VLDL, stimulated incorporation of [14C]-oleate into cholesteryl [14C]oleate 20- to 40-fold in the mutant cells. This stimulation was blocked by chloroquine, suggesting that such stimulation resulted from receptor-mediated uptake and lysosomal hydrolysis of the cholesteryl esters in apo E-enriched beta-VLDL. Stimulation of cholesterol esterification was blocked by the antibody against LRP, but not by an antibody against the LDL receptor. Unlike the LDL receptor, the amount of LRP was not reduced when cells were incubated with oxygenated sterols. We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E.

Citing Articles

Effects of coagulation factors on bone cells and consequences of their absence in haemophilia a patients.

Battafarano G, Lancellotti S, Sacco M, Rossi M, Terreri S, Di Gregorio J Sci Rep. 2024; 14(1):25001.

PMID: 39443571 PMC: 11499919. DOI: 10.1038/s41598-024-75747-w.

Prognostic significance of alpha-2-macrglobulin and low-density lipoprotein receptor-related protein-1 in various cancers.

Olbromski M, Mrozowska M, Piotrowska A, Kmiecik A, Smolarz B, Romanowicz H Am J Cancer Res. 2024; 14(6):3036-3058.

PMID: 39005669 PMC: 11236788. DOI: 10.62347/VUJV9180.

Characterising the genetic architecture of changes in adiposity during adulthood using electronic health records.

Venkatesh S, Ganjgahi H, Palmer D, Coley K, Linchangco Jr G, Hui Q Nat Commun. 2024; 15(1):5801.

PMID: 38987242 PMC: 11237142. DOI: 10.1038/s41467-024-49998-0.

LRP1 Deficiency Promotes Mitostasis in Response to Oxidative Stress: Implications for Mitochondrial Targeting after Traumatic Brain Injury.

Velmurugan G, Hubbard W, Prajapati P, Vekaria H, Patel S, Rabchevsky A Cells. 2023; 12(10).

PMID: 37408279 PMC: 10217498. DOI: 10.3390/cells12101445.

Intrahepatic macrophage reprogramming associated with lipid metabolism in hepatitis B virus-related acute-on-chronic liver failure.

Peng B, Li H, Liu K, Zhang P, Zhuang Q, Li J J Transl Med. 2023; 21(1):419.

PMID: 37380987 PMC: 10303321. DOI: 10.1186/s12967-023-04294-1.

References

Kovanen P, Brown M, Basu S, Bilheimer D, Goldstein J . Saturation and suppression of hepatic lipoprotein receptors: a mechanism for the hypercholesterolemia of cholesterol-fed rabbits. Proc Natl Acad Sci U S A. 1981; 78(3):1396-400. PMC: 319137. DOI: 10.1073/pnas.78.3.1396. View

Beisiegel U, Kita T, Anderson R, Schneider W, Brown M, Goldstein J . Immunologic cross-reactivity of the low density lipoprotein receptor from bovine adrenal cortex, human fibroblasts, canine liver and adrenal gland, and rat liver. J Biol Chem. 1981; 256(8):4071-8. View

Kita T, Goldstein J, Brown M, Watanabe Y, Hornick C, HAVEL R . Hepatic uptake of chylomicron remnants in WHHL rabbits: a mechanism genetically distinct from the low density lipoprotein receptor. Proc Natl Acad Sci U S A. 1982; 79(11):3623-7. PMC: 346475. DOI: 10.1073/pnas.79.11.3623. View

Fainaru M, Mahley R, Hamilton R, Innerarity T . Structural and metabolic heterogeneity of beta-very low density lipoproteins from cholesterol-fed dogs and from humans with type III hyperlipoproteinemia. J Lipid Res. 1982; 23(5):702-14. View

Kita T, Brown M, Bilheimer D, Goldstein J . Delayed clearance of very low density and intermediate density lipoproteins with enhanced conversion to low density lipoprotein in WHHL rabbits. Proc Natl Acad Sci U S A. 1982; 79(18):5693-7. PMC: 346971. DOI: 10.1073/pnas.79.18.5693. View

Tolleshaug H, Goldstein J, Schneider W, Brown M . Posttranslational processing of the LDL receptor and its genetic disruption in familial hypercholesterolemia. Cell. 1982; 30(3):715-24. DOI: 10.1016/0092-8674(82)90276-8. View

HAVEL R, Kita T, KOTITE L, Kane J, Hamilton R, Goldstein J . Concentration and composition of lipoproteins in blood plasma of the WHHL rabbit. An animal model of human familial hypercholesterolemia. Arteriosclerosis. 1982; 2(6):467-74. DOI: 10.1161/01.atv.2.6.467. View

Brown M, Goldstein J . Lipoprotein receptors in the liver. Control signals for plasma cholesterol traffic. J Clin Invest. 1983; 72(3):743-7. PMC: 1129238. DOI: 10.1172/JCI111044. View

Goldstein J, Basu S, Brown M . Receptor-mediated endocytosis of low-density lipoprotein in cultured cells. Methods Enzymol. 1983; 98:241-60. DOI: 10.1016/0076-6879(83)98152-1. View

10.

Russell D, Schneider W, Yamamoto T, Luskey K, Brown M, Goldstein J . Domain map of the LDL receptor: sequence homology with the epidermal growth factor precursor. Cell. 1984; 37(2):577-85. DOI: 10.1016/0092-8674(84)90388-x. View

11.

Yamamoto T, Davis C, Brown M, Schneider W, CASEY M, Goldstein J . The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. Cell. 1984; 39(1):27-38. DOI: 10.1016/0092-8674(84)90188-0. View

12.

Williams D, Dawson P, Newman T, Rudel L . Apolipoprotein E synthesis in peripheral tissues of nonhuman primates. J Biol Chem. 1985; 260(4):2444-51. View

13.

Windler E, HAVEL R . Inhibitory effects of C apolipoproteins from rats and humans on the uptake of triglyceride-rich lipoproteins and their remnants by the perfused rat liver. J Lipid Res. 1985; 26(5):556-65. View

14.

Vogel T, Weisgraber K, Zeevi M, Levanon A, Rall Jr S, Innerarity T . Human apolipoprotein E expression in Escherichia coli: structural and functional identity of the bacterially produced protein with plasma apolipoprotein E. Proc Natl Acad Sci U S A. 1985; 82(24):8696-700. PMC: 391503. DOI: 10.1073/pnas.82.24.8696. View

15.

Davis C, Elhammer A, Russell D, Schneider W, Kornfeld S, Brown M . Deletion of clustered O-linked carbohydrates does not impair function of low density lipoprotein receptor in transfected fibroblasts. J Biol Chem. 1986; 261(6):2828-38. View

16.

Spitz M . "Single-shot" intrasplenic immunization for the production of monoclonal antibodies. Methods Enzymol. 1986; 121:33-41. DOI: 10.1016/0076-6879(86)21006-x. View

17.

Lehrman M, Russell D, Goldstein J, Brown M . Alu-Alu recombination deletes splice acceptor sites and produces secreted low density lipoprotein receptor in a subject with familial hypercholesterolemia. J Biol Chem. 1987; 262(7):3354-61. View

18.

Davis C, van Driel I, Russell D, Brown M, Goldstein J . The low density lipoprotein receptor. Identification of amino acids in cytoplasmic domain required for rapid endocytosis. J Biol Chem. 1987; 262(9):4075-82. View

19.

Oswald B, QUARFORDT S . Effect of apoE on triglyceride emulsion interaction with hepatocyte and hepatoma G2 cells. J Lipid Res. 1987; 28(7):798-809. View

20.

Hobbs H, Brown M, Russell D, Davignon J, Goldstein J . Deletion in the gene for the low-density-lipoprotein receptor in a majority of French Canadians with familial hypercholesterolemia. N Engl J Med. 1987; 317(12):734-7. DOI: 10.1056/NEJM198709173171204. View