Characterization of an unusual lipoprotein similar to human lipoprotein a isolated from the baboon, Papio sp

Rainwater, David L.; Manis, Georgios; Kushwaha, Rampratap S.

doi:10.1016/0005-2760(86)90120-7

Cited by 36 publications

(12 citation statements)

References 20 publications

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“…Given that the Lp(a) assay measures apoB levels, a consequence of such interactions (should they occur in the assay and be diet specific) might be to give spuriously high Lp(a) readings for some diet samples. Although we cannot rule out this possibility, we have not observed, in density gradient analyses, 13,17,21 apo(a) proteins in density fractions more buoyant than Lp(a). Furthermore, baboons tend to have relatively low plasma triglyceride concentrations (Ϸ52 mg/dL on the basal diet and Ϸ37 mg/dL on the HFHC diet 35 and, consequently, low levels of TRLs.…”

Section: Discussionmentioning

confidence: 79%

“…13,21,[27][28][29] We found that dietary fat and cholesterol significantly increased Lp(a) concentrations. This result confirms our earlier work in baboons 13,14 but appears to contradict results from studies in humans that suggest either a reduction in Lp(a) with increased dietary fat 30 or a lack of diet response.…”

Section: Discussionmentioning

confidence: 99%

“…Although it is possible that there is some variation in lipid amount per Lp(a) particle for different diets, the Lp(a) cholesterol concentration was estimated as 30% of Lp(a) mass. 21 This value was subtracted from ␤-lipoprotein cholesterol to estimate the non-Lp(a)/non-HDL cholesterol concentration (termed LDLC in this report) in each sample.…”

Section: Measurement Of Lp(a) and Ldl Cholesterol Concentrationsmentioning

confidence: 99%

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Evidence That Multiple Genes Influence Baseline Concentrations and Diet Response of Lp(a) in Baboons

Rainwater

Kammerer

VandeBerg

1999

ATVB

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Abstract-We investigated the response of lipoprotein(a) [Lp(a)] levels to dietary fat and cholesterol in 633 baboons fed a series of 3 diets: a basal diet low in cholesterol and fat, a high-fat diet, and a diet high in fat and cholesterol. Measurement of serum concentrations in samples taken while the baboons were sequentially fed the 3 diets allowed us to analyze 3 Lp(a) variables: Lp(a) Basal , Lp(a) RF (response to increased dietary fat), and Lp(a) RC (response to increased dietary cholesterol in the high-fat environment). On average, Lp(a) concentrations significantly increased 6% and 28%, respectively, when dietary fat and cholesterol were increased (PϽ0.001). As expected, most of the variation in Lp(a) Basal was influenced by genes (h 2 ϭ0.881). However, less than half of the variation in Lp(a) RC was influenced by genes (h 2 ϭ0.347, PϽ0.0001), whereas the increase due to dietary fat alone was not significantly heritable (h 2 ϭ0.043, Pϭ0.28). To determine whether Lp(a) phenotypic variation was due to variation in LPA, the locus encoding the apolipoprotein(a) [apo(a)] protein, we conducted linkage analyses by using LPA genotypes inferred from the apo(a) isoform phenotypes. All of the genetic variance in Lp(a) Basal concentration was linked to the LPA locus (log of the odds [LOD] score was 30.5). In contrast, linkage analyses revealed that genetic variance in Lp(a) RC was not linked to the LPA locus (LOD score was 0.036, PϾ0.5). To begin identifying the non-LPA genes that influence the Lp(a) response to dietary cholesterol, we tested, in bivariate quantitative genetic analyses, for correlation with low density lipoprotein cholesterol [LDLC; ie, non-high density lipoprotein cholesterol less the cholesterol contribution from Lp(a)]. LDLC Basal was weakly correlated with Lp(a) Basal ( P ϭ0.018). However, LDLC RC and Lp(a) RC were strongly correlated ( P ϭ0.382), and partitioning the correlations revealed significant genetic and environmental correlations ( G ϭ0.587 and E ϭ0.251, respectively). The results suggest that increasing both dietary fat and dietary cholesterol caused significant increases in Lp(a) concentrations and that the response to dietary cholesterol was mediated by a gene or suite of genes that appears to exert pleiotropic effects on LDLC levels as well. The gene(s) influencing Lp(a) response to dietary cholesterol is not linked to the LPA locus.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Measurement Of Lp(a) and Ldl Cholesterol Concentrationsmentioning

confidence: 99%

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Evidence That Multiple Genes Influence Baseline Concentrations and Diet Response of Lp(a) in Baboons

Rainwater

Kammerer

VandeBerg

1999

ATVB

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“…8 Recently, a striking homology between the human apo(a) and plasminogen was demonstrated in both amino acid 910 and DNA sequences. 11 Serum and liver samples from various species were analyzed for the presence of Lp(a), but only humans, primates, 12 and hedgehogs 13 were found to express apo (a). Lp(a) was first demonstrated in human plasma by Blumberg et al 14 and later by Berg and his associates.…”

Section: Ipoprotein(a) [Lp(a)mentioning

confidence: 99%

Detection and quantification of lipoprotein(a) in the arterial wall of 107 coronary bypass patients.

et al. 1989

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“…Baboons show very similar characteristics to humans in terms of plasma Lp(a) levels and apo(a) isoform sizes (40,41). We have established primary cultures of baboon hepatocytes as a model system for the analysis of Lp(a) biogenesis (34).…”

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Influence of Allelic Variation on Apolipoprotein(a) Folding in the Endoplasmic Reticulum

White

Guerra

Lanford

1997

Journal of Biological Chemistry

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Plasma levels of lipoprotein(a) (Lp(a)) vary over 1000-fold between individuals and are determined by the gene for its unique apolipoprotein, apo(a), which has greater than 100 alleles. Using primary baboon hepatocyte cultures, we previously demonstrated that differences in the ability of apo(a) allelic variants to escape the endoplasmic reticulum (ER) are a major determinant of Lp(a) production rate. To examine the reason for these differences, the folding of newly synthesized apo(a) was analyzed in pulse-chase experiments. Samples were harvested in the presence of N-ethylmaleimide to preserve disulfide-bonded folding intermediates, and apo(a) was analyzed by immunoprecipitation and SDS-polyacrylamide gel electrophoresis. Apo(a) required a prolonged period (30 -60 min) to reach its fully oxidized form. Multiple folding intermediates were resolved, including a disulfide-linked, apo(a)-containing complex. Unexpectedly, all allelic variants examined showed similar patterns and kinetics of folding. Even "null" apo(a) proteins, which are unable to exit the ER, appeared to fold normally. The ER glucosidase inhibitor, castanospermine, prevented apo(a) secretion, but did not inhibit folding. This suggests that an event which is dependent on trimming of N-linked glucoses, and which occurs after the folding events detectable in our assay, is required for apo(a) secretion. Differences in the ability to undergo this event may explain the variable efficiency with which apo(a) allelic variants exit the ER. Apolipoprotein(a) (apo(a))1 is a highly polymorphic, high molecular weight glycoprotein that circulates in plasma as a component of lipoprotein(a) (Lp(a)). Lp(a) is composed of low density lipoprotein in which apoB is attached to apo(a) by disulfide linkage (1, 2). As many as 34 different isoforms of apo(a) have been identified in human plasma, which vary in size from Ͻ300 to Ͼ800 kDa (3-6). Apo(a) has a highly complex, repetitive structure and is homologous with plasminogen (7). Apo(a) contains an inactive copy of the plasminogen protease domain and a single plasminogen kringle 5 (K5) domain, preceded by multiple domains with homology to plasminogen K4 (7). The size variation of apo(a) is due to differences in the number of K4 domains encoded in the apo(a) gene (8 -11), which varies from approximately 12 to 51 (3). Each K4 repeat contains 3 internal disulfide bonds, 1 N-linked, and 6 potential O-linked glycosylation sites (7). Thus, a large apo(a) isoform may contain in excess of 150 disulfide bonds, 50 N-linked and 300 O-linked carbohydrate side chains.Lp(a) is only found in the plasma of primates (12) and the hedgehog (13,14). In humans, plasma levels of Lp(a) vary from Ͻ1 to Ͼ100 mg/dl and are highly heritable (15). High plasma levels of Lp(a) are associated with an increased incidence of cardiovascular diseases (for review, see Ref. 16). Greater than 90% of the inter-individual variation in Lp(a) concentration is attributable to the apo(a) gene locus (17). There is an inverse correlation between apo(a) size and plasma...

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Characterization of an unusual lipoprotein similar to human lipoprotein a isolated from the baboon, Papio sp

Cited by 36 publications

References 20 publications

Evidence That Multiple Genes Influence Baseline Concentrations and Diet Response of Lp(a) in Baboons

Evidence That Multiple Genes Influence Baseline Concentrations and Diet Response of Lp(a) in Baboons

Detection and quantification of lipoprotein(a) in the arterial wall of 107 coronary bypass patients.

Influence of Allelic Variation on Apolipoprotein(a) Folding in the Endoplasmic Reticulum

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