HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Krul, E. S. Articles by Schonfeld, G. Search for Related Content PubMed PubMed Citation Articles by Krul, E. S. Articles by Schonfeld, G. Social Bookmarking                      What's this?

Journal of Lipid Research, Vol 33, 1037-1050, Copyright © 1992 by Lipid Research, Inc.

ARTICLES

ApoB-75, a truncation of apolipoprotein B associated with familial hypobetalipoproteinemia: genetic and kinetic studies

ES Krul, KG Parhofer, PH Barrett, RD Wagner and G Schonfeld
Lipid Research Center, Washington University School of Medicine, St. Louis, MO 63110.

We have identified a mutation of apolipoprotein B (apoB) in a kindred with hypobetalipoproteinemia. Four affected members had plasma concentrations of total cholesterol of 115 +/- 14, low density lipoprotein (LDL)-C of 48 +/- 11, and apoB of 28 +/- 9 (mg/dl mean +/- SD). The values correspond to approximately 30% the values for unaffected relatives. Triglyceride and high density lipoprotein (HDL)-C concentrations were 92 +/- 50 and 49 +/- 4, respectively, neither significantly different from unaffected relatives. Western blots of plasma apoB of affected subjects showed two major bands: apoB-100 and an apoB-75 (mol wt of approximately 418,000). DNA sequencing of the appropriate polymerase chain reaction (PCR)-amplified genomic DNA segment revealed a deletion of the cytidine at nucleotide position 10366, resulting in a premature stop codon at amino acid residue 3387. In apoB-75/apoB-100 heterozygotes, two LDL populations containing either apoB-75 or apoB-100 could be distinguished from each other by gel permeation chromatography and by immunoblotting of nondenaturing gels using monoclonal antibodies B1B3 (epitope between apoB amino acid residues 3506-3635) and C1.4 (epitope between residues 97-526). ApoB-75 LDL were smaller and more dense than apoB-100 LDL. To determine whether the low concentration of apoB-75 was due to its enhanced LDL-receptor- mediated removal, apoB-75 LDL were isolated from the proband's d 1.063- 1.090 g/ml fraction (which contained most of the apoB-75 in his plasma) by chromatography on anti-apoB and anti-apoA-I immunoaffinity columns. The resulting pure apoB-75 LDL fraction interacted with the cells 1.5- fold more effectively than apoB-100 LDL (d 1.019-1.063 g/ml). To determine the physiologic mechanism responsible for the hypobetalipoproteinemia, in vivo kinetic studies were performed in two affected subjects, using endogenous labeling of apoB-75 and apoB-100 with [13C]leucine followed by multicompartmental kinetic analyses. Fractional catabolic rates of apoB-75 VLDL and LDL were 2- and 1.3-fold those of apoB-100 very low density lipoprotein (VLDL) and LDL, respectively. Production rates of apoB-75 were approximately 30% of those for apoB-100. This differs from the behavior of apoB-89, a previously described variant, whose FCRs were also increased approximately 1.5-fold relative to apoB-100, but whose production rates were nearly identical to those of apoB-100. Thus, in contrast to the apoB-89 mutation, the apoB-75 mutation imparts two physiologic defects to apoB-75 lipoproteins that account for the hypobetalipoproteinemia, diminished production and increased catabolism.
CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				K. G. Parhofer and P. H. R. Barrett Thematic review series: Patient-Oriented Research. What we have learned about VLDL and LDL metabolism from human kinetics studies J. Lipid Res., August 1, 2006; 47(8): 1620 - 1630. [Abstract] [Full Text] [PDF]

				A. J. Whitfield, P. H. R. Barrett, F. M. van Bockxmeer, and J. R. Burnett Lipid Disorders and Mutations in the APOB Gene Clin. Chem., October 1, 2004; 50(10): 1725 - 1732. [Abstract] [Full Text] [PDF]

				Z. Chen, R. L. Fitzgerald, G. Li, N. O. Davidson, and G. Schonfeld Hepatic secretion of apoB-100 is impaired in hypobetalipoproteinemic mice with an apoB-38.9-specifying allele J. Lipid Res., January 1, 2004; 45(1): 155 - 163. [Abstract] [Full Text] [PDF]

				G. Schonfeld Familial hypobetalipoproteinemia: a review J. Lipid Res., May 1, 2003; 44(5): 878 - 883. [Abstract] [Full Text] [PDF]

				Z. Chen, R. L. Fitzgerald, J. E. Saffitz, C. F. Semenkovich, and G. Schonfeld Amino Terminal 38.9% of Apolipoprotein B-100 Is Sufficient to Support Cholesterol-Rich Lipoprotein Production and Atherosclerosis Arterioscler. Thromb. Vasc. Biol., April 1, 2003; 23(4): 668 - 674. [Abstract] [Full Text] [PDF]

				G. Schonfeld, B. W. Patterson, D. A. Yablonskiy, T. S. K. Tanoli, M. Averna, N. Elias, P. Yue, and J. Ackerman Fatty liver in familial hypobetalipoproteinemia: triglyceride assembly into VLDL particles is affected by the extent of hepatic steatosis J. Lipid Res., March 1, 2003; 44(3): 470 - 478. [Abstract] [Full Text] [PDF]

				M. E. Hinsdale, P. M. Sullivan, H. Mezdour, and N. Maeda ApoB-48 and apoB-100 differentially influence the expression of type-III hyperlipoproteinemia in APOE*2 mice J. Lipid Res., September 1, 2002; 43(9): 1520 - 1528. [Abstract] [Full Text] [PDF]

				Z. Chen, R. L Fitzgerald, and G. Schonfeld Hypobetalipoproteinemic Mice with a Targeted Apolipoprotein (Apo) B-27.6-specifying Mutation. IN VIVO EVIDENCE FOR AN IMPORTANT ROLE OF AMINO ACIDS 1254-1744 OF ApoB IN LIPID TRANSPORT AND METABOLISM OF THE ApoB-CONTAINING LIPOPROTEIN J. Biol. Chem., April 12, 2002; 277(16): 14135 - 14145. [Abstract] [Full Text] [PDF]

				P. Tarugi, A. Lonardo, C. Gabelli, F. Sala, G. Ballarini, I. Cortella, L. Previato, S. Bertolini, R. Cordera, and S. Calandra Phenotypic expression of familial hypobetalipoproteinemia in three kindreds with mutations of apolipoprotein B gene J. Lipid Res., October 1, 2001; 42(10): 1552 - 1561. [Abstract] [Full Text] [PDF]

				J. P. Segrest, M. K. Jones, H. De Loof, and N. Dashti Structure of apolipoprotein B-100 in low density lipoproteins J. Lipid Res., September 1, 2001; 42(9): 1346 - 1367. [Abstract] [Full Text] [PDF]

				N. Elias, B. W. Patterson, and G. Schonfeld In Vivo Metabolism of ApoB, ApoA-I, and VLDL Triglycerides in a Form of Hypobetalipoproteinemia Not Linked to the ApoB Gene Arterioscler. Thromb. Vasc. Biol., May 1, 2000; 20(5): 1309 - 1315. [Abstract] [Full Text] [PDF]

				N. Elias, B. W. Patterson, and G. Schonfeld Decreased Production Rates of VLDL Triglycerides and ApoB-100 in Subjects Heterozygous for Familial Hypobetalipoproteinemia Arterioscler. Thromb. Vasc. Biol., November 1, 1999; 19(11): 2714 - 2721. [Abstract] [Full Text] [PDF]

				J.-P. Wang, M. Enjoji, M. Tiebel, S. Ochsner, L. Chan, and B.-B. Teng Hammerhead Ribozyme Cleavage of Apolipoprotein B mRNA Generates a Truncated Protein J. Biol. Chem., August 20, 1999; 274(34): 24161 - 24170. [Abstract] [Full Text] [PDF]

				J. Wu, J. Kim, Q. Li, P.-Y. Kwok, T. G. Cole, B. Cefalu, M. Averna, and G. Schonfeld Known mutations of apoB account for only a small minority of hypobetalipoproteinemia J. Lipid Res., May 1, 1999; 40(5): 955 - 959. [Abstract] [Full Text]

				F. Pont, L. Duvillard, B. Verges, and P. Gambert Development of Compartmental Models in Stable-Isotope Experiments : Application to Lipid Metabolism Arterioscler. Thromb. Vasc. Biol., June 1, 1998; 18(6): 853 - 860. [Abstract] [Full Text] [PDF]

				X.-F. Zhu, D. Noto, R. Seip, A. Shaish, and G. Schonfeld Organ Loci of Catabolism of Short Truncations of ApoB Arterioscler. Thromb. Vasc. Biol., June 1, 1997; 17(6): 1032 - 1038. [Abstract] [Full Text]

				F. K. Welty, A. H. Lichtenstein, P. H. R. Barrett, G. G. Dolnikowski, J. M. Ordovas, and E. J. Schaefer Decreased Production and Increased Catabolism of Apolipoprotein B-100 in Apolipoprotein B-67/B-100 Heterozygotes Arterioscler. Thromb. Vasc. Biol., May 1, 1997; 17(5): 881 - 888. [Abstract] [Full Text]

				M. Averna, S. M. Marcovina, D. Noto, T. G. Cole, E. S. Krul, and G. Schonfeld Familial Hypobetalipoproteinemia Is Not Associated With Low Levels of Lipoprotein(a) Arterioscler. Thromb. Vasc. Biol., December 1, 1995; 15(12): 2165 - 2175. [Abstract] [Full Text]

				C. A. Aguilar-Salinas, P. H. R. Barrett, K. G. Parhofer, S. G. Young, D. Tessereau, J. Bateman, C. Quinn, and G. Schonfeld Apoprotein B-100 Production Is Decreased in Subjects Heterozygous for Truncations of Apoprotein B Arterioscler. Thromb. Vasc. Biol., January 1, 1995; 15(1): 71 - 80. [Abstract] [Full Text]

				Z. Chen, R. L. Fitzgerald, M. R. Averna, and G. Schonfeld A Targeted Apolipoprotein B-38.9-producing Mutation Causes Fatty Livers in Mice Due to the Reduced Ability of Apolipoprotein B-38.9 to Transport Triglycerides J. Biol. Chem., October 13, 2000; 275(42): 32807 - 32815. [Abstract] [Full Text] [PDF]

				J. Boren, U. Ekstrom, B. Agren, P. Nilsson-Ehle, and T. L. Innerarity The Molecular Mechanism for the Genetic Disorder Familial Defective Apolipoprotein B100 J. Biol. Chem., March 16, 2001; 276(12): 9214 - 9218. [Abstract] [Full Text] [PDF]