The assembly of lipoprotein Lp(a)

Frank, Saša; Durovic, S.; Kostner, Gert M.

doi:10.1046/j.1365-2362.1996.112255.x

Cited by 32 publications

(38 citation statements)

References 42 publications

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“…The relationship with LDL persisted and was little changed after correcting the LDL concentrations for its Lp(a) content, and is not surprising, since Lp(a) is structurally related to LDL cholesterol. 10,11 The link with BMI, although relatively weak (with LDL, 8.0%, on multiple regression analysis) offers at least one avenue for non-pharmacological reduction of elevated Lp(a) levels by the encouragement of healthy diet, physical activity and similar lifestyle changes in the obese. 9 …”

Section: Lp(a) and Anthropometric Demographic And Biochemical Paramementioning

confidence: 99%

“…Nonetheless, these non-genetic parameters could be subject to therapeutic intervention in attempts to modify Lp(a) concentrations. 9 Suggested mechanisms for the effects of Lp(a) in modulating vascular disease risk include: (1) anti®brinolytic and prothrombotic effects based on the structural similarity between Lp(a) and plasminogen 10,11 and the described in¯uence of Lp(a) in regulating the endothelial cell synthesis of tissue plasminogen activator inhibitor PAI-1; 12 (2) signi®-cant uptake of Lp(a) with low-density lipoprotein (LDL) by the LDL native and scavenger receptorsÐ indeed, both lipoproteins co-determine atherosclerotic disease risk. However, these different mechanisms remain controversial 13 and do not always satisfactorily account for the striking atherogenicity of Lp(a).…”

Section: Introductionmentioning

confidence: 99%

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Metabolic and anthropometric determinants of serum Lp(a) concentrations and Apo(a) polymorphism in a healthy Arab population

1999

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BACKGROUND: Blood lipoprotein(a) Lp(a) concentrations are an important risk factor for atherosclerosis. The basis for this atherogenic property of Lp(a) and the factors that in¯uence its cross-population levels, however, remain poorly understood. OBJECTIVES: To investigate the relationship between serum Lp(a) and metabolic and anthropometric parameters in a healthy Kuwaiti population. DESIGN: Cross-sectional study. SUBJECTS: 177 (72 male, 105 female) randomly recruited healthy Kuwait Arabs aged 17 ± 60 y MEASUREMENTS: Metabolic parameters in serum: Lp(a), apo(a) phenotypes, lipids and lipoproteins, glucose and urate. Anthropometric parameters: body mass index (BMI) and waist:hip-ratio (WHR). RESULTS: The distribution of Lp(a) concentrations was positively skewed (median 153 mgal, range 0 ± 1086). Women had higher concentrations ± (194, 0 ± 1086) than men (117, 0 ± 779), P 0.069. Lp(a) and insulin concentrations were signi®cantly higher when the men and women were obese. In all subjects, there were signi®cant correlations between Lp(a) and BMI (r 0.23), total cholesterol (TC) (r 0. Multivariate analyses con®rmed BMI and low-density lipoprotein (LDL) as the signi®cant determinants of serum Lp(a).On apo (a) phenotyping, 114 (67%), 51 (30%) and 6 (4%) had single, double and null phenotypes respectively. The isoforms and their corresponding kringle IV repeat numbers were: F (14 repeats in 3%, mean Lp(a) 497 mgal); S1 (19 repeats in 14%, mean 245 mgal); S2 (23 repeats in 16%, mean 264 mgal); S3 (27 repeats in 35%, mean 236 mgal); and S4 (35 repeats in 28%, mean 235 mgal). DISCUSSION AND CONCLUSION: The results from the Kuwaiti population studied suggest that: (1) serum Lp(a) concentrations and distribution are similar to the pattern in Caucasians and Asians but not African ± Americans or Africans; (2) serum Lp(a) is variably in¯uenced by BMI and LDL ± the impact of either factor differs between the sexes; (3) there is a high frequency of the single-banded phenotype; (4) contrary to reports in some Caucasian and Asian populations, there is no simple relationship between kringle IV repeat numbers and plasma Lp(a) concentrations.

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Section: Lp(a) and Anthropometric Demographic And Biochemical Paramementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metabolic and anthropometric determinants of serum Lp(a) concentrations and Apo(a) polymorphism in a healthy Arab population

1999

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“…A widely accepted two-step model of Lp[a] assembly depicts a noncovalent association between apoB and apo[a] preceding the formation of the disulphide bond (5,6). The exact amino acids required for the noncovalent association between apo[a] and apoB are not well characterized, although a growing body of evidence suggests that apoB lysine residues may be important (11)(12)(13)(14)(15)(16).…”

Section: Discussionmentioning

confidence: 99%

Mutation of lysine residues in apolipoprotein B-100 causes defective lipoprotein[a] formation

Liu

Broadhurst

Marcovina

et al. 2004

Journal of Lipid Research

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Recent studies have focused on characterizing the apoB sequences involved in the initial binding to apo [a]. Experiments with a series of truncated apoB proteins expressed in cell culture have identified an N-terminal region between apoB15 and apoB18 that is important for apo [a] binding (17). A subsequent study identified an apoB lysine residue within this region (apoBLys680) that was required for the binding of the apoB18 molecule to apo [a] (18). The importance of the apoBLys680 residue for binding to apo [a] in the context of a full-length apoB-100, however, remains to be shown.Carboxyl-terminal sequences of apoB have been implicated in apo [a] binding by a study of two truncated apoB proteins expressed in transgenic mice, apoB95 (4,330 amino acids), and apoB-97 (4,397 amino acids) (19). In that study, apoB-97 formed Lp[a] with an efficiency similar to that of full-length apoB-100, whereas apoB95 formed Lp[a] very poorly, suggesting that the region between apoB-100 amino acids 4,330 and 4,397 is important for apo [a]

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“…Lysine residues on apoB have been implicated in the noncovalent interaction with apo(a), because lysine analogues disrupt Lp(a) assembly in vitro (19)(20)(21) and deletion of lysine-binding sites in apo(a) kringle IV domains interfere with Lp(a) formation (22)(23)(24). A number of apoB sequences that noncovalently bind apo(a) have been reported.…”

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confidence: 99%

Structural features of apolipoprotein B synthetic peptides that inhibit lipoprotein(a) assembly

Sharp

Perugini

Marcovina

et al. 2004

Journal of Lipid Research

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Lipoprotein(a) [Lp(a)] is an atherogenic lipoprotein comprised of apolipoprotein(a) [apo(a)] attached to the apolipoprotein B100 (apoB) of a LDL (1). Large clinical trials have identified high plasma levels of Lp(a) as a risk factor for developing heart disease (2-4). The deposition of Lp(a) in vascular lesions has been well documented in humans (5, 6) and in animal models (7). Unfortunately, Lp(a) has proven resistant to traditional lipid-lowering therapies (8, 9), except high doses of niacin (10). Estrogen dramatically reduces Lp(a) levels (11), but a safe and effective agent for lowering Lp(a) levels has yet to be developed.The majority of evidence suggests that Lp(a) assembly occurs in circulation (12) after secretion of apo(a) from the liver and metabolism of VLDL to LDL in the circulation. Lp(a) assembly is thought to be a two-step process (13,14) with noncovalent interactions between apo(a) and apoB preceding the formation of the disulfide bond between apo(a) Cys4057 (13, 15) and apoB Cys4326 (16, 17). The two-step model of Lp(a) assembly was confirmed in a study of a human apoB100 mutant lacking Cys4326, which still showed binding to apo(a), despite being unable to form the disulfide bond (18).Recent research has focused on characterizing the apoB residues involved in the noncovalent interaction with apo(a). Lysine residues on apoB have been implicated in the noncovalent interaction with apo(a), because lysine analogues disrupt Lp(a) assembly in vitro (19-21) and deletion of lysine-binding sites in apo(a) kringle IV domains interfere with Lp(a) formation (22)(23)(24). A number of apoB sequences that noncovalently bind apo(a) have been reported. Becker et al. (25) identified an apoB lysine residue in the N terminus, apoBLys680, that mediates the noncovalent binding of an apoB18 fragment to apo(a); in their study, a synthetic peptide spanning the Lys680 residue was shown to inhibit Lp(a) formation at similar concentrations to lysine analogues.Sequences in the carboxyl terminus of apoB have also been implicated in the noncovalent interaction with apo(a).Abbreviations: apo(a), apolipoprotein(a); apoB, apolipoprotein B100; CD, circular dichroism; DMPC, dimyristoylphosphatidylcholine; Lp(a), lipoprotein(a).

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The assembly of lipoprotein Lp(a)

Cited by 32 publications

References 42 publications

Metabolic and anthropometric determinants of serum Lp(a) concentrations and Apo(a) polymorphism in a healthy Arab population

Metabolic and anthropometric determinants of serum Lp(a) concentrations and Apo(a) polymorphism in a healthy Arab population

Mutation of lysine residues in apolipoprotein B-100 causes defective lipoprotein[a] formation

Structural features of apolipoprotein B synthetic peptides that inhibit lipoprotein(a) assembly

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