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
Open accessAbstract
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.
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LDLR is one of the two primary metabolic receptors mediating the clearance of apoE lipoproteins.
“Low-density lipoprotein receptor (LDLR) is one of the two primary metabolic receptors (the other is low-density lipoprotein receptor-related protein 1, LRP1) mediating the clearance of apoE lipoproteins (Holtzman et al., 2012; Ishibashi et al., 1994).”
From Overexpressing low‐density lipoprotein receptor reduces tau‐associated neurodegeneration in relation to apoE‐linked mechanisms (2021) · cites this paper as Ishibashi et al., 1994
The Discussion supports LDLR as one of two receptors involved in apoE-mediated lipoprotein clearance. It cautions, however, that the identity of the second receptor is not known for certain, so the citing sentence’s definite identification of it as LRP1 goes beyond the paper’s conclusion. Page numbers are not given in the supplied passages. (LLM, conf=0.84)
Experimental — accuracy not yet measuredTwo case studies and one small population study showed that lipid-lowering therapies are linked to improved renal status in LPG patients.
“Two case studies and one small population study showed that lipid-lowering therapies are linked to improved renal status in LPG patients (27)(28)(29).”
From Macrophage-derived apoESendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic mice (2014) · cites this paper as [29]
The Results and Discussion (page numbers unavailable) examine lipoprotein clearance in knockout mice, not renal outcomes in LPG patients. Searches for LPG, lipid-lowering therapy, renal status, and patient case studies found no passage addressing the claim. (LLM, conf=0.75)
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- Authors
- Ishibashi, S., Herz, J., Maeda, N., Goldstein, J. L., & Brown, M. S.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1994-05-10
- Volume
- 91
- Issue
- 10
- Pages
- 4431-4435
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC43799
- OpenAlex
- W1982789996
- Cited by
- 430
- References
- 3
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 8 · 2023: 3 · 2022: 8 · 2021: 8 · 2020: 9 · 2019: 11 · 2018: 18 · 2017: 15 · 2016: 22 · 2015: 18 · 2014: 15 · 2013: 11 · 2012: 13
- FWCI
- 17.83
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- W. M. Keck Foundation
- National Institutes of Health (HL20948)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- apolipoprotein E, LDL receptor, lipoprotein clearance, ApoE-deficient mice, Ldlr knockout mice, double knockout mice, serum cholesterol, hypercholesterolemia, apolipoprotein B-48, apolipoprotein B-100, VLDL, chylomicron remnants, receptor binding
- MeSH terms
- Animals, Apolipoproteins E, Cholesterol, Cholesterol, Dietary, Crosses, Genetic, Diet, Female, Genotype, Homozygote, Lipoproteins, Male, Mice, Mutant Strains, Models, Biological, Receptors, LDL, Mice
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