Hepatic apo E expression is required for remnant lipoprotein clearance in the absence of the low density lipoprotein receptor
Open accessAbstract
According to the secretion-capture model of remnant lipoprotein clearance, apo E secreted by hepatocytes into the space of Disse serves to enrich the remnants with a ligand for receptor-mediated lipoprotein endocytosis. Current evidence supports a two-receptor model of lipoprotein removal, in which apo E-containing remnants bind either the low density lipoprotein receptor (LDLR) or the LDLR-related protein (LRP). Recently, we demonstrated that reconstitution of apo E(-/-) mice with apo E(+/+) marrow results in normalization of plasma lipoprotein levels, indicating that hepatic expression of apo E is not required for remnant clearance and calling into question the relevance of the secretion-capture mechanism. To dissect the relative contributions of LDLR and LRP to the cellular catabolism of remnant lipoproteins by the hepatocyte, bone marrow transplantation (BMT) was used to reconstitute macrophage expression of apo E in mice that were null for expression of both apo E and the LDLR. Reconstitution of macrophage apo E in apo E(-/-)/LDLR(-/-) mice had no effect on serum lipid and lipoprotein concentrations, although it produced plasma apo E levels up to 16-fold higher than in C57BL/6 controls. Immunocytochemistry of hepatic sections revealed abundant staining for apo E in the space of Disse, but no evidence of receptor-mediated endocytosis of remnant lipoproteins. Transient expression of human LDLR in the livers of apo E(+/+)--> apo E(-/-)/LDLR(-/-) mice by adenoviral gene transfer resulted in normalization of serum lipid levels and in the clearance of apo E-containing lipoproteins from the space of Disse. We conclude that whereas the LDLR efficiently clears remnant lipoproteins irrespective of the site of origin of apo E, endocytosis by the chylomicron remnant receptor (LRP) is absolutely dependent on hepatic expression of apo E. These data demonstrate in vivo the physiologic relevance of the apo E secretion-capture mechanism in the liver.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
It was previously shown that expression of apoE in DKO model does not reduce serum lipid levels, and that macrophage-expressed apoE can protect against atherosclerosis, even in the absence of cholesterol changes.
“It was previously shown that expression of apoE in this model does not reduce serum lipid levels, and that macrophage-expressed apoE can protect against atherosclerosis, even in the absence of cholesterol changes ( 15,37 ).”
From Macrophage-derived apoESendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic mice (2014) · cites this paper as [37]
The Results (page unavailable) report that restoring macrophage apoE in mice lacking both apoE and LDLR did not significantly change serum cholesterol or triglycerides. The paper does not report whether that intervention protected those mice against atherosclerosis despite unchanged cholesterol; its References list related atherosclerosis studies but do not establish that part of the claim. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThrough bone marrow transplantation, the authors produced two types of chimeric mice expressing apoE exclusively from macrophages: apoE-/- mice, whose dyslipidemia is corrected by apoE expression; and apoE-/-/LDLR-/- DKO mice, whose dyslipidemia is not affected by apoE expression.
“Through bone marrow transplantation, we produced two types of chimeric mice expressing apoE exclusively from macrophages: 1 ) apoE Ϫ / Ϫ mice, whose dyslipidemia is corrected by apoE expression; and 2 ) apoE Ϫ / Ϫ /LDLR Ϫ / Ϫ double KO (DKO) mice, whose dyslipidemia is not affected by apoE expression ( 15,37 ).”
From Macrophage-derived apoESendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic mice (2014) · cites this paper as [37]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Plump, A. S., Smith, J. D., Hayek, T., Aalto-Setälä, K., Walsh, A., Verstuyft, J. G., Rubin, E. M., & Breslow, J. L. (1992) · Cell · doi:10.1016/0092-8674(92)90362-g · Cited by 2,263 · see citing works
Rohlmann, A., Gotthardt, M., Hammer, R. E., & Herz, J. (1998) · Journal of Clinical Investigation · doi:10.1172/jci1240 · Cited by 455 · see citing works
Phenotypes of apolipoprotein B and apolipoprotein E after liver transplantation.
Linton, M. F., Gish, R., Hubl, S. T., Bütler, E., Esquivel, C., Bry, W. I., Boyles, J. K., Wardell, M. R., & Young, S. G. (1991) · Journal of Clinical Investigation · doi:10.1172/jci115288 · Cited by 367 · see citing works
Self-citationFamilial apolipoprotein E deficiency.
Schaefer, E. J., Gregg, R. E., Ghiselli, G., Forte, T. M., Ordovas, J. M., Zech, L. A., & Brewer, H. B. (1986) · Journal of Clinical Investigation · doi:10.1172/jci112704 · Cited by 313 · see citing works
Flagged first, then by citations
Research works printed but not linked: 8
- Kita, T., J.L. Goldstein, M.S. Brown, Y. Watanabe, C.A. Hornick, and R.J. Havel. 1982. Hepatic uptake of chylomicron remnants in WHHL rabbits: a mechanism genetically distinct from the low density lipoprotein receptor. Proc. Natl. Acad. Sci. USA. 79:3623-3627.
- Kowal, R.C., J. Herz, J.L. Goldstein, V. Esser, and M.S. Brown. 1989. Low density lipoprotein receptor-related protein mediates uptake of choles- teryl esters derived from apoprotein E-enriched lipoproteins. Proc. Natl. Acad. Sci. USA. 86:5810-5814.
- Basu, S.K., M.S. Brown, Y.K. Ho, R.J. Havel, and J.L. Goldstein. 1981. Mouse macrophages synthesize and secrete a protein resembling apolipopro- tein E. Proc. Natl. Acad. Sci. USA. 78:7545-7549.
- Ishibashi, S., J. Herz, N. Maeda, J.L. Goldstein, and M.S. Brown. 1994. The two-receptor model of lipoprotein clearance: tests of the hypothesis in "knock-out" mice lacking the low density lipoprotein receptor, apolipoprotein E, or both proteins. Proc. Natl. Acad. Sci. USA. 91:4431-4435.
- Herz, J., and R.D. Gerard. 1993. Adenovirus-mediated transfer of low density lipoprotein receptor gene acutely accelerates cholesterol clearance in normal mice. Proc. Natl. Acad. Sci. USA. 90:2812-2816.
- Fazio, S., V.R. Babaev, A.B. Murray, A.H. Hasty, K.J. Carter, L.A. Gleaves, J.B. Atkinson, and M.F. Linton. 1997. Increased atherosclerosis in C57BL/6 mice reconstituted with apolipoprotein E null macrophages. Proc. Natl. Acad. Sci. USA. 94:4647-4652.
- Herz, J., S.-Q. Qiu, A. Oesterle, H.V. DeSilva, S. Shafi, and R.J. Havel. 1995. Initial hepatic removal of chylomicron remnants is unaffected but en- docytosis is delayed in mice lacking the low density lipoprotein receptor. Proc. Natl. Acad. Sci. USA. 92:4611-4615.
- Willnow, T.E., S.A. Armstrong, R.E. Hammer, and J. Herz. 1995. Func- tional expression of low density lipoprotein receptor-related protein is con- trolled by receptor-associated protein in vivo. Proc. Natl. Acad. Sci. USA. 92: 4537-4541.
Cited by
Sorted by citations
Mahley, R. W., & Ji, Z.-S. (1999) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)33334-4 · Cited by 693 · see citing works
Moulin, P., Dufour, R., Averna, M., Arca, M., Cefalù, A. B., Noto, D., D'Erasmo, L., Di Costanzo, A., Marçais, C., Alvarez-Sala Walther, L. A., et al. (2018) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2018.06.814 · Cited by 247 · see citing works
Macrophage LRP-1 Controls Plaque Cellularity by Regulating Efferocytosis and Akt Activation
Yancey, P. G., Blakemore, J., Ding, L., Fan, D., Overton, C. D., Zhang, Y., Linton, M. F., & Fazio, S. (2010) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.109.202051 · Cited by 168 · see citing works
Self-citationDeletion of Macrophage LDL Receptor–Related Protein Increases Atherogenesis in the Mouse
Overton, C. D., Yancey, P. G., Major, A. S., Linton, M. F., & Fazio, S. (2007) · Circulation Research · doi:10.1161/01.res.0000260204.40510.aa · Cited by 159 · see citing works
Self-citationOrth, M., Weng, W., Funke, H., Steinmetz, A., Assmann, G., Nauck, M., Dierkes, J., Ambrosch, A., Weisgraber, K. H., Mahley, R. W., et al. (1999) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.19.5.1306 · Cited by 42 · see citing works
Okoro, E. U., Zhao, Y., Guo, Z., Zhou, L., Lin, X., & Yang, H. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044430 · Cited by 25 · see citing works
Olin-Lewis, K., Benton, J. L., Rutledge, J. C., Baskin, D. G., Wight, T. N., & Chait, A. (2002) · Circulation Research · doi:10.1161/01.res.0000024691.82864.f0 · Cited by 19 · see citing works
Burgess, J. W., Liang, P., Vaidyanath, C., & Marcel, Y. L. (1999) · Biochemistry · doi:10.1021/bi9819778 · Cited by 16 · see citing works
Tavori, H., Fan, D., Giunzioni, I., Zhu, L., Linton, M. F., Fogo, A. B., & Fazio, S. (2014) · Journal of Lipid Research · doi:10.1194/jlr.m049874 · Cited by 10 · see citing works
Self-citation
- Authors
- Linton, M. F., Hasty, A. H., Babaev, V. R., & Fazio, S.
- Affiliations
- Vanderbilt University Medical Center (US)
- Vanderbilt University (US)
- Corresponding author
- Fazio, S
- Venue
- Journal of Clinical Investigation
- Published
- 1998-04-15
- Volume
- 101
- Issue
- 8
- Pages
- 1726-1736
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC508755
- OpenAlex
- W2061317455
- Cited by
- 100
- References
- 4
- Citations by year
- 2025: 2 · 2024: 1 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 3 · 2017: 1 · 2015: 4 · 2014: 2 · 2013: 4 · 2012: 3
- FWCI
- 13.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL057986, HL57986, HL-02925, K08HL002925)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- apolipoprotein E, LDL receptor, space of Disse, receptor-mediated endocytosis, bone marrow transplantation, serum lipids, adenoviral gene transfer
- MeSH terms
- Animals, Apolipoproteins E, Endocytosis, Humans, Immunohistochemistry, Lipids, Lipoproteins, Liver, Macrophages, Mice, Inbred C57BL, Mice, Transgenic, Receptors, Immunologic, Receptors, LDL, RNA, Messenger, Gene Expression, Bone Marrow Transplantation, Mice, Knockout, Low Density Lipoprotein Receptor-Related Protein-1, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
