Characterization of an abnormal species of apolipoprotein B, apolipoprotein B-37, associated with familial hypobetalipoproteinemia.

Young, Stephen G.; Bertics, S.J.; Curtiss, Linda K.; Witztum, J L

doi:10.1172/jci113025

Cited by 114 publications

(65 citation statements)

References 38 publications

(35 reference statements)

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“…Apo B-40 was the only detectable apo B species in the d>1.124 g/ml fraction. In this regard, the apo B-40 is similar to the apo B-37 species reported by Young et al 7 in that it is found in particles with HDL density; however, it should be noted that apo B-40 is found in much lower concentrations in plasma and HDL than apo B-37. Also, there was no evidence of a "peak" of apo B-40 in the HDL density range as was reported for apo B-37 by Young et al…”

Section: Characterization Of Upoprotelnssupporting

confidence: 82%

Two distinct truncated apolipoprotein B species in a kindred with hypobetalipoproteinemia.

et al. 1989

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Two novel, distinct truncated forms of apolipoprotein B (apo B) designated as apo B-90 and apo B-40 were found in five members of a kindred with hypobetalipoproteinemia. Sodium dodecyl sulfate gels and immunoblots of plasma or low density llpoproteln (LOL) (d=1.019 to 1.063 g/ml) of the affected members demonstrated the presence of one or both of the truncated apo B bands. Employing four monoclonal antl-LDL antibodies with defined regional specificities, we demonstrated that amlno terminal epttopes of the truncated apo Bs were Intact, but that 10% and 60%, respectively, of the carboxyl terminal regions were absent Tnrombln digestion of apo B-90 generated an abnormally small T2 fragment, confirming that approximately 550 amlno acids had been deleted from the carboxyl terminus of apo B-100. A polipoprotein B (apo B) is important in lipoprotein metabolism. Under normal conditions, human apo B is secreted in two forms, one with apparent A^=550 Kd (apo B-100) from liver in association with very low density lipoprotein (VLDL) and another with apparent M r =246 Kd (apo B-48) from intestine in association with chylomicrons. Hepatic VLDL are converted to intermediate density lipoprotein (IDL) and low density lipoprotein (LDL), which are removed from circulation via LDL receptormediated endocytosis, and apo B-100 serves as the ligand for lipoprotein recognition in this case.Familial hypobetalipoproteinemia (HBL), is characterized in the homozygous state by symptoms that resemble abetalipoproteinemia (ABL).

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Section: Characterization Of Upoprotelnssupporting

confidence: 82%

Two distinct truncated apolipoprotein B species in a kindred with hypobetalipoproteinemia.

et al. 1989

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“…Coomassie blue staining documented the presence of intact apolipoprotein B and of fragments resembling those seen after oxidative modification in vitro (6). That these lower molecular weight fragments were, indeed, derived from apolipoprotein B was confirmed by Western blot techniques, using a panel of apolipoprotein-B-specific mAbs (10). For example, both the intact apolipoprotein B-100 and a number of lower molecular weight fragments reacted with mAb MB-47 (Fig.…”

Section: Methodsmentioning

confidence: 76%

Low density lipoprotein undergoes oxidative modification in vivo.

Palinski

Rosenfeld

Ylä‐Herttuala

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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1,333

693

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It has been proposed that low density lipoprotein (LDL) must undergo oxidative modification before it can give rise to foam cells, the key component ofthe fatty streak lesion of atherosclerosis. Oxidation of LDL probably generates a broad spectrum of conjugates between fragments of oxidized fatty acids and apolipoprotein B. We now present three mutually supportive lines of evidence for oxidation of LDL in vivo: (i) Antibodies against oxidized LDL, malondialdehyde-lysine, or 4-hydroxynonenal-lysine recognize materials in the atherosclerotic lesions of LDL receptor-deficient rabbits; (ii) LDL gently extracted from lesions of these rabbits is recognized by an antiserum against malondialdehyde-conijugated LDL; (iii) autoantibodies against malondialdehyde-LDL (titers from 512 to >4096) can be demonstrated in rabbit and human sera.A growing body of evidence suggests that oxidative modification of low density lipoprotein (LDL) enhances its atherogenicity (for review see ref. 1). Monocyte-derived macrophages, the precursor of most foam cells in early atherosclerotic lesions, cannot take up native LDL rapidly enough to cause lipid loading (2). Oxidative modification converts LDL to a form recognized by the macrophage acetyl-LDL receptor (1, 2) and possibly by other receptors as well (3). This is true whether the oxidation is effected by incubation under appropriate conditions with cultured cells or by autooxidation catalyzed by Cu2+ ions in the absence of cells. Oxidative modification of LDL is accompanied by extensive degradation of its polyunsaturated fatty acids, generating a complex array of shorter chain-length fragments (4). During the oxidation, some of these fragments become covalently linked to apolipoprotein B (5), and much ofthis conjugation involves the E-amino groups of lysine residues. This chemically modified form of apolipoprotein is recognized by the acetyl-LDL receptor (6). Thus we can generate models for oxidized LDL by conjugating the apolipoprotein with single compounds generated during oxidation. Fogelman et al. (7) demonstrated that malondialdehyde (MDA)-conjugated LDL is so recognized. If oxidized LDL contains lysine residues conjugated with a variety of fatty acid fragments of different chain lengths, it should react with antibodies against a variety of such lysine derivatives. We previously showed that immunization of animals with autologous LDL modified by conjugation of lysine groups with glucose yields antisera directed specifically against glucitollysine (8) and that antibodies generated by injection of carbamoylated autologous LDL generates antisera that recognize the carbamoyllysine-not only in LDL but in other conjugated proteins as well (9). In other words, the specificity of these antisera is for very narrowly defined "X"-lysine adducts.The present studies, which use immunochemical methods, offer three lines of evidence that oxidation of LDL occurs in vivo.

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“…This finding is in agreement with our observation that apoB-38.7 was not present in the dϾ1.21 g/mL fraction. ApoB-37, 5 apoB-38.9, 17 apoB-40, 34 and apoB-46 35 were reported to be present in HDL, but apoB-39, 12 apoB-50, 21 and the other species larger than apoB-50 were not, indicating that a portion of the apoB between apoB-37 and apoB-46 is essential for distribution in HDL. This finding is consistent with our observation that apoB-38.7 was distributed in HDL.…”

Section: Discussionmentioning

confidence: 97%

“…Previous studies have shown that the buoyant density of the apoB-containing lipoproteins is largely proportional to the size of apoB between apoB-31 and apoB-37. It has been reported that apoB-31, 31 apoB-32, 32 and apoB-32.5 33 are present in the dϾ1.21 g/mL fraction, but apoB-37 is not, 5 suggesting that a portion of the apoB proteins between apoB-32.5 and apoB-37 is critical for the distribution to the dϾ1.21 g/mL fraction. This finding is in agreement with our observation that apoB-38.7 was not present in the dϾ1.21 g/mL fraction.…”

Section: Discussionmentioning

confidence: 99%

“…The clinical phenotype of HBLP homozygotes is highly variable, with severe cases presenting with fat malabsorption, acanthocytosis, retinitis pigmentosa, and neurological complications resulting from intestinal malabsorption of vitamin E. Symptoms observed in some patients with homozygous HBLP are indistinguishable from those of patients with abetalipoproteinemia, a recessive disease arising from mutations in microsomal triglyceride transfer protein (MTP). 3,4 Since Young and his colleagues 5,6 demonstrated that mutations in the apoB gene cause HBLP, Ϸ30 mutations have been reported. Most of these mutations are nonsense or frameshift mutations that prevent the translation of the full-length apoB-100 protein.…”

Section: F Amilial Hypobetalipoproteinemia (Hblp)mentioning

confidence: 99%

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A Truncated Species of Apolipoprotein B (B-38.7) in a Patient With Homozygous Hypobetalipoproteinemia Associated With Diabetes Mellitus

Ohashi

Ishibashi

Yamamoto

et al. 1998

ATVB

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Abstract-Familial hypobetalipoproteinemia is caused by mutations in the apolipoprotein (apo) B gene. We identified a 57-year-old woman whose plasma total cholesterol and apoB levels were 2.17 mmol/L and 0.03 g/L, respectively. Separation of plasma lipoproteins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed the absence of apoB-100 and the presence of a faster-migrating form of apoB with an apparent M r of 195 kDa. Direct sequencing of a polymerase chain reaction-amplified fragment of the patient's apoB gene DNA revealed a single C3 T transition at nucleotide 5472 that converts glutamine 1755 (CAA) to a stop codon (TAA). We predict this novel nonsense mutation of the apoB gene to produce a truncated protein that contains 1754 amino-terminal amino acid residues of apoB-100. We designated this mutant form of apoB apoB-38.7 by following the centile nomenclature of the apoB species. The same mutation was found in both of her children. The proband revealed clinical findings of retinitis pigmentosa, acanthocytosis, and loss of deep tendon reflexes that are characteristic of severe hypobetalipoproteinemia. In addition, the proband had type II diabetes mellitus with nephropathy, anemia, cholelithiasis, hepatic hemangioma, bronchiectasis, and extensive calcification of major arteries including, the celiac, splenic, and renal. In summary, we have found a novel truncated apoB, apoB-38.7, in a patient with an unusual presentation of hypobetalipoproteinemia that includes diabetes mellitus and extensive arterial calcification. (Arterioscler Thromb Vasc Biol. 1998;18:1330-1334.)

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Characterization of an abnormal species of apolipoprotein B, apolipoprotein B-37, associated with familial hypobetalipoproteinemia.

Cited by 114 publications

References 38 publications

Two distinct truncated apolipoprotein B species in a kindred with hypobetalipoproteinemia.

Two distinct truncated apolipoprotein B species in a kindred with hypobetalipoproteinemia.

Low density lipoprotein undergoes oxidative modification in vivo.

A Truncated Species of Apolipoprotein B (B-38.7) in a Patient With Homozygous Hypobetalipoproteinemia Associated With Diabetes Mellitus

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