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The two-receptor model of lipoprotein clearance: tests of the hypothesis in "knockout" mice lacking the low density lipoprotein receptor, apolipoprotein E, or both proteins.
Proc Natl Acad Sci U S A. 1994 May 10; 91(10):4431-5.PN

Abstract

Apolipoprotein E (apoE) is hypothesized to mediate lipoprotein clearance by binding to two receptors: (i) the low density lipoprotein receptor (LDLR) and (ii) a chylomicron remnant receptor. To test this hypothesis, we have compared plasma lipoproteins in mice that are homozygous for targeted disruptions of the genes for apoE [apoE(-/-)], the LDLR [LDLR(-/-)], and both molecules [poE(-/-); LDLR(-/-)]. On a normal chow diet, apoE(-/-) mice had higher mean plasma cholesterol levels than LDLR(-/-) mice (579 vs. 268 mg/dl). Cholesterol levels in the apoE(-/-); LDLR(-/-) mice were not significantly different from those in the apoE(-/-) mice. LDLR(-/-) mice had a relatively isolated elevation in plasma LDL, whereas apoE(-/-) mice had a marked increase in larger lipoproteins corresponding to very low density lipoproteins and chylomicron remnants. The lipoprotein pattern in apoE(-/-); LDLR(-/-) mice resembled that of apoE(-/-) mice. The LDLR(-/-) mice had a marked elevation in apoB-100 and a modest increase in apoB-48. In contrast, the apoE(-/-) mice had a marked elevation in apoB-48 but not in apoB-100. The LDLR(-/-); apoE(-/-) double homozygotes had marked elevations of both apolipoproteins. The observation that apoB-48 increases more dramatically with apoE deficiency than with LDLR deficiency supports the notion that apoE binds to a second receptor in addition to the LDLR. This conclusion is also supported by the observation that superimposition of a LDLR deficiency onto an apoE deficiency [apoE(-/-); LDLR(-/-) double homozygotes] does not increase hypercholesterolemia beyond the level observed with apoE deficiency alone.

Authors+Show Affiliations

Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas 75235-9046.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

8183926

Citation

Ishibashi, S, et al. "The Two-receptor Model of Lipoprotein Clearance: Tests of the Hypothesis in "knockout" Mice Lacking the Low Density Lipoprotein Receptor, Apolipoprotein E, or Both Proteins." Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 10, 1994, pp. 4431-5.
Ishibashi S, Herz J, Maeda N, et al. The two-receptor model of lipoprotein clearance: tests of the hypothesis in "knockout" mice lacking the low density lipoprotein receptor, apolipoprotein E, or both proteins. Proc Natl Acad Sci U S A. 1994;91(10):4431-5.
Ishibashi, S., Herz, J., Maeda, N., Goldstein, J. L., & Brown, M. S. (1994). The two-receptor model of lipoprotein clearance: tests of the hypothesis in "knockout" mice lacking the low density lipoprotein receptor, apolipoprotein E, or both proteins. Proceedings of the National Academy of Sciences of the United States of America, 91(10), 4431-5.
Ishibashi S, et al. The Two-receptor Model of Lipoprotein Clearance: Tests of the Hypothesis in "knockout" Mice Lacking the Low Density Lipoprotein Receptor, Apolipoprotein E, or Both Proteins. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4431-5. PubMed PMID: 8183926.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The two-receptor model of lipoprotein clearance: tests of the hypothesis in "knockout" mice lacking the low density lipoprotein receptor, apolipoprotein E, or both proteins. AU - Ishibashi,S, AU - Herz,J, AU - Maeda,N, AU - Goldstein,J L, AU - Brown,M S, PY - 1994/5/10/pubmed PY - 1994/5/10/medline PY - 1994/5/10/entrez SP - 4431 EP - 5 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 91 IS - 10 N2 - Apolipoprotein E (apoE) is hypothesized to mediate lipoprotein clearance by binding to two receptors: (i) the low density lipoprotein receptor (LDLR) and (ii) a chylomicron remnant receptor. To test this hypothesis, we have compared plasma lipoproteins in mice that are homozygous for targeted disruptions of the genes for apoE [apoE(-/-)], the LDLR [LDLR(-/-)], and both molecules [poE(-/-); LDLR(-/-)]. On a normal chow diet, apoE(-/-) mice had higher mean plasma cholesterol levels than LDLR(-/-) mice (579 vs. 268 mg/dl). Cholesterol levels in the apoE(-/-); LDLR(-/-) mice were not significantly different from those in the apoE(-/-) mice. LDLR(-/-) mice had a relatively isolated elevation in plasma LDL, whereas apoE(-/-) mice had a marked increase in larger lipoproteins corresponding to very low density lipoproteins and chylomicron remnants. The lipoprotein pattern in apoE(-/-); LDLR(-/-) mice resembled that of apoE(-/-) mice. The LDLR(-/-) mice had a marked elevation in apoB-100 and a modest increase in apoB-48. In contrast, the apoE(-/-) mice had a marked elevation in apoB-48 but not in apoB-100. The LDLR(-/-); apoE(-/-) double homozygotes had marked elevations of both apolipoproteins. The observation that apoB-48 increases more dramatically with apoE deficiency than with LDLR deficiency supports the notion that apoE binds to a second receptor in addition to the LDLR. This conclusion is also supported by the observation that superimposition of a LDLR deficiency onto an apoE deficiency [apoE(-/-); LDLR(-/-) double homozygotes] does not increase hypercholesterolemia beyond the level observed with apoE deficiency alone. SN - 0027-8424 UR - https://www.unboundmedicine.com/medline/citation/8183926/The_two_receptor_model_of_lipoprotein_clearance:_tests_of_the_hypothesis_in_"knockout"_mice_lacking_the_low_density_lipoprotein_receptor_apolipoprotein_E_or_both_proteins_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=8183926 DB - PRIME DP - Unbound Medicine ER -