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Characterization of a New Form of Inherited Hypercholesterolemia: Familial Recessive Hypercholesterolemia
Abstract
Abstract —We previously described a Sardinian family in which the probands had a severe form of hypercholesterolemia, suggestive of familial hypercholesterolemia (FH). However, low density lipoprotein (LDL) receptor activity in fibroblasts from these subjects and LDL binding ability were normal. The characteristics of the pedigree were consistent with an autosomal recessive trait. Sitosterolemia and pseudohomozygous hyperlipidemia were ruled out. A second Sardinian kindred with similar characteristics was identified. Probands showed severe hypercholesterolemia, whereas their parents and grandparents were normolipidemic. FH, familial defective apoprotein (apo) B, sitosterolemia, and cholesteryl ester storage disease were excluded by in vitro studies. We addressed the metabolic basis of this inherited disorder by studying the in vivo metabolism of LDL in 3 probands from these 2 families. 125 I-LDL turnover studies disclosed a marked reduction in the fractional catabolic rate (0.19±0.01 versus 0.36±0.03 pools per day, respectively; P <0.001) and a significant increase in the production rate [20.7±4.4 versus 14.0±2.4 mg · kg −1 · d −1 , respectively; P <0.01] of LDL apoB in the probands compared with normolipidemic controls. We then studied the in vivo biodistribution and tissue uptake of 99m technetium-labeled LDL in the probands and compared them with those in normal controls and 1 FH homozygote. The probands showed a significant reduction in hepatic LDL uptake, similar to that observed in the FH homozygote. A reduced uptake of LDL by the kidney and spleen was also observed in all patients. Our findings suggest that this recessive form of hypercholesterolemia is due to a marked reduction of in vivo LDL catabolism. This appears to be caused by a selective reduction in hepatic LDL uptake. We propose that in this new lipid disorder, a recessive defect causes a selective impairment of LDL receptor function in the liver.
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Patients with ARH have normal LDLR but markedly reduced clearance of circulating LDL by the liver.
“Patients with ARH have normal LDLR but markedly reduced clearance of circulating LDL by the liver (2,3).”
ARH is an adaptor protein required for efficient endocytosis of LDL receptors in selected tissues.
“ARH is an adaptor protein required for efficient endocytosis of low density lipoprotein (LDL) receptors (LDLRs) in selected tissues.”
From The Modular Adaptor Protein ARH Is Required for Low Density Lipoprotein (LDL) Binding and Internalization but Not for LDL Receptor Clustering in Coated Pits (2004) · cites this paper as [3]
The available indexed passages are repository metadata, not the article’s substantive text; the passage labeled Abstract lists keywords but contains no abstract. Searches for ARH as an adaptor protein and for LDL-receptor endocytosis found no passage addressing the claim, so this copy cannot verify it. (LLM, conf=0.73)
Experimental — accuracy not yet measuredAutosomal recessive hypercholesterolemia is characterized by a cell type-specific defect in LDLR endocytosis.
“Autosomal recessive hypercholesterolemia is characterized by a cell type-specific defect in low density lipoprotein receptor (LDLR) endocytosis.”
From The Modular Adaptor Protein Autosomal Recessive Hypercholesterolemia (ARH) Promotes Low Density Lipoprotein Receptor Clustering into Clathrin-coated Pits (2005) · cites this paper as [5]
The available indexed passages are repository metadata: the title identifies familial recessive hypercholesterolemia, and the passage labeled Abstract lists “LDL receptor” and “LDL turnover” only as keywords. Searches for cell-type specificity, LDLR endocytosis, and internalization found no passage addressing the claimed defect; the listed PDF's contents are not present in the passages. (LLM, conf=0.73)
Experimental — accuracy not yet measuredAutosomal recessive hypercholesterolemia is caused by defective internalization of LDL receptors in the liver.
“a disorder caused by defective internalization of low density lipoprotein receptors (LDLR) in the liver.”
From ARH Is a Modular Adaptor Protein That Interacts with the LDL Receptor, Clathrin, and AP-2 (2002) · cites this paper as [3]
The indexed copy shows the paper’s title and, in a repository entry labelled Abstract, keywords including “LDL receptor” and “LDL turnover.” It contains no passage about defective LDL-receptor internalization in the liver. Searches for that mechanism and for hepatic LDL uptake returned only repository metadata, so the claim cannot be verified from this copy. (LLM, conf=0.73)
Experimental — accuracy not yet measuredLDLR function is markedly impaired in hepatocytes of ARH patients.
“This finding indicates that LDLR function is markedly impaired in the hepatocytes of ARH patients.”
From ARH Is a Modular Adaptor Protein That Interacts with the LDL Receptor, Clathrin, and AP-2 (2002) · cites this paper as [3]
The indexed passages contain a bibliographic record and keywords under an Abstract label, but no substantive passage about LDLR function in hepatocytes. Searches for hepatocyte LDLR impairment, hepatic receptor activity, and LDL turnover returned only that record, so our copy does not establish the attributed claim. (LLM, conf=0.76)
Experimental — accuracy not yet measured
LDLR function is normal or only moderately reduced in fibroblasts from patients with ARH.
“In contrast, LDLR function is normal or only moderately reduced in fibroblasts from patients with this disorder (3”
From ARH Is a Modular Adaptor Protein That Interacts with the LDL Receptor, Clathrin, and AP-2 (2002) · cites this paper as [3]
An unlabeled passage (page unavailable) describes reduced LDL uptake in the liver and proposes a selective hepatic LDL-receptor defect. The supplied passages and searches for fibroblast LDL-receptor activity do not address whether function in patients’ fibroblasts is normal or moderately reduced. (LLM, conf=0.70)
Experimental — accuracy not yet measuredIn vivo studies demonstrated that ARH patients show a markedly reduced hepatic uptake of LDL similar to that found in homozygous FH.
“In vivo studies demonstrated that ARH patients show a markedly reduced hepatic uptake of LDL similar to that found in homozygous FH (10).”
From Adaptor Protein ARH Is Recruited to the Plasma Membrane by Low Density Lipoprotein (LDL) Binding and Modulates Endocytosis of the LDL/LDL Receptor Complex in Hepatocytes (2005) · cites this paper as [10]
The available copy contains an IRIS catalog entry identifying the article (pp. 802–809) and listing “LDL turnover” as a keyword, but no study results. Searches for hepatic LDL uptake, in vivo findings, and comparison with homozygous FH found no relevant passage, so the claim cannot be checked against this copy. (LLM, conf=0.76)
Experimental — accuracy not yet measuredIndividuals lacking ARH have severe hypercholesterolemia due to impaired hepatic clearance of LDL.
“Individuals lacking ARH (ARH ؊/؊ ) have severe hypercholesterolemia due to impaired hepatic clearance of LDL.”
LDLR-mediated uptake of LDL is impaired in the liver, but not in fibroblasts of subjects with autosomal recessive hypercholesterolemia.
“LDLR-mediated uptake of LDL is impaired in the liver, but not in fibroblasts of subjects with this disorder.”
The rate at which LDL particles are cleared from plasma by the liver of ARH patients is as low as in patients with no functional LDLRs.
“The rate at which LDL particles are cleared from the plasma by the liver of ARH patients is as low as that in patients with no functional LDLRs (3”
From ARH Is a Modular Adaptor Protein That Interacts with the LDL Receptor, Clathrin, and AP-2 (2002) · cites this paper as [3]
Individuals lacking ARH have severe hypercholesterolemia due to an impaired hepatic clearance of LDL.
“Individuals lacking ARH have severe hypercholesterolemia due to an impaired hepatic clearance of LDL.”
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Citations
Cites
Mutations at the lysosomal acid cholesteryl ester hydrolase gene locus in Wolman disease
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Cited by
Sorted by citations
Zhang, L., Hou, D., Chen, X., Li, D., Zhu, L., Zhang, Y., Li, J., Bian, Z., Liang, X., Cai, X., et al. (2012) · Cell Research · doi:10.1038/cr.2011.158 · Cited by 1,216
ARH Is a Modular Adaptor Protein That Interacts with the LDL Receptor, Clathrin, and AP-2
He, G., Gupta, S., Yi, M., Michaely, P., Hobbs, H. H., & Cohen, J. C. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m208539200 · Cited by 232
The adaptor protein Dab2 sorts LDL receptors into coated pits independently of AP-2 and ARH
Maurer, M. E., & Cooper, J. A. (2006) · Journal of Cell Science · doi:10.1242/jcs.03217 · Cited by 195
Keyel, P. A., Mishra, S. K., Roth, R., Heuser, J. E., Watkins, S. C., & Traub, L. M. (2006) · Molecular Biology of the Cell · doi:10.1091/mbc.e06-05-0421 · Cited by 134
Garuti, R., Jones, C., Li, W.-P., Michaely, P., Herz, J., Gerard, R. D., Cohen, J. C., & Hobbs, H. H. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m509394200 · Cited by 91
Michaely, P., Li, W.-P., Anderson, R. G. W., Cohen, J. C., & Hobbs, H. H. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m405242200 · Cited by 66
Sirinian, M. I., Belleudi, F., Campagna, F., Ceridono, M., Garofalo, T., Quagliarini, F., Verna, R., Calandra, S., Bertolini, S., Sorice, M., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m504343200 · Cited by 42
Self-citation
Metadata
- Authors
- Zuliani, G., Arca, M., Signore, A., Bader, G., Fazio, S., Chianelli, M., Bellosta, S., Campagna, F., Montali, A., Maioli, M., Pacifico, A., Ricci, G., & Fellin, R.
- Affiliations
- From the Department of Internal Medicine, University of Ferrara, Ferrara (G.Z., G.B., R.F.), and the Institute of Terapia Medica Sistematica (M.A., F.C., A.M., G.R.) and Service of Nuclear Medicine (A.S., M.C.), Department of Internal Medicine II, University of Rome “La Sapienza,” Rome, Italy; Vanderbilt University Medical School, Nashville, Tenn (S.F.); and the Institute of Pharmacological Science, University of Milan, Milan (S.B.), and the Department of Internal Medicine, University of Sassari,...
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 1999-03
- Volume
- 19
- Issue
- 3
- Pages
- 802-809
- ISSN
- 1079-5642
- 1524-4636
- Cited by
- 72
- References
- 1
- Language
- en
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