Metabolism of apolipoprotein B in large triglyceride-rich very low density lipoproteins of normal and hypertriglyceridemic subjects.

Packard, C.J.; Munro, Alison F.; Lorimer, A. R.; Gotto, Antonio M.; Shepherd, James

doi:10.1172/jci111644

Cited by 289 publications

(115 citation statements)

References 26 publications

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“…Original studies showed that a precursor-product relationship existed between VLDL and LDL in normolipidemic individuals (26-28) (i.e., all VLDL was converted to LDL, and all LDL was derived from VLDL). In more recent studies (30)(31)(32)(33), however, it has been shown that a significant proportion of VLDL apo B can be cleared from the plasma by receptor-mediated uptake (presumably in the liver) (arrow 2, Fig. 8) and is therefore not converted to LDL.…”

Section: Discussionmentioning

confidence: 99%

“…Subjects have therefore been studied during periods of both fasting and feeding. In previous VLDL apo B kinetic studies (26)(27)(28)(29)(30), fat-and calorie-restricted diets have been given to minimize the secretion of chylomicrons and VLDL from the intestine. This rather artificial situation, however, represents neither a fasted nor fed state.…”

Section: Discussionmentioning

confidence: 99%

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Measurement of very low density and low density lipoprotein apolipoprotein (Apo) B-100 and high density lipoprotein Apo A-I production in human subjects using deuterated leucine. Effect of fasting and feeding.

Cohn¹,

Wagner²,

Cohn³

et al. 1990

J. Clin. Invest.

185

128

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Six normolipidemic male subjects, after an 8-h overnight fast, were given a bolus injection and then a 15-h constant intravenous infusion of [D3AL-leucine. Subjects were studied in the fasted state and on a second occasion in the fed state (small, physiological meals were given every hour for 15 h). Apolipoproteins were isolated by preparative gradient gel electrophoresis from plasma lipoproteins separated by sequential ultracentrifugation. Incorporation of [D3jL-leucine into apolipoproteins was monitored by negative ionization, gas chromatography-mass spectrometry. Production rates were determined by multiplying plasma apolipoprotein pool sizes by fractional production rates (calculated as the rate of isotopic enrichment IIEI of each protein as a fraction of IE achieved by VLDL (d < 1.006 g/ml) apo B-100 at plateau. VLDL apo B-100 production was greater, and LDL (1.019 < d < 1.063 g/ml) apo B-100 production was less in the fed compared with the fasted state (9.9±1.7 vs. 6.4±1.7 mg/kg per d, P < 0.01, and 8.9±1.2 vs. 13.1±1.2 mg/kg per d, P < 0.05, respectively). No mean change was observed in high density lipoprotein apo A-I production. We conclude that: (a) this stable isotope, endogenous-labeling technique, for the first time allows for the in vivo measurement of apolipoprotein production in the fasted and fed state; and (b) since LDL apo B-100 production was greater than VLDL apo B-100 production in the fasted state, this study provides in vivo evidence that LDL apo B-100 can be produced independently of VLDL apo B-100 in normolipidemic subjects. (J. Clin. Invest. 1990. 85:804-811.) stable isotope * postprandial triglyceridemia * apolipoprotein kinetics

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Measurement of very low density and low density lipoprotein apolipoprotein (Apo) B-100 and high density lipoprotein Apo A-I production in human subjects using deuterated leucine. Effect of fasting and feeding.

Cohn¹,

Wagner²,

Cohn³

et al. 1990

J. Clin. Invest.

185

128

View full text Add to dashboard Cite

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“…23 Once in the circulation, the larger VLDL species are lipolyzed by lipoprotein lipase, and most of the remnant particles formed in this process are removed from the circulation before reaching a particle size or density corresponding to LDL. 26 Small VLDL particles, on the other hand, seem to be direct precursors of LDL, as the secretion rate of small VLDL is tightly linked to the LDL cholesterol concentration in plasma. 27 It could thus be speculated that enhanced function of MTP, as would occur with the rare MTP Ϫ493 T promoter variant we have described, acts by shifting the balance between secretion of large and small VLDLs.…”

Section: Discussionmentioning

confidence: 99%

A Common Functional Polymorphism in the Promoter Region of the Microsomal Triglyceride Transfer Protein Gene Influences Plasma LDL Levels

Karpe¹,

Lundahl²,

Ehrenborg³

et al. 1998

ATVB

131

140

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Abstract-Microsomal triglyceride transfer protein (MTP) is required for the assembly and cellular secretion of apolipoprotein B (apoB) -containing lipoproteins from the liver and intestine. The secretion pattern of apoB-containing lipoproteins is likely to influence the VLDL and LDL levels in plasma. By initial opportunistic screening for polymorphic sites in the regulatory region of the MTP gene by gene sequencing in 20 healthy male subjects, a common functional G/T polymorphism was detected 493 bp upstream from the transcriptional start point. There was differential binding of unique nuclear proteins at this site, as shown by electrophoretic mobility shift assay. The G variant seemed to bind two or three nuclear proteins that do not bind to the T variant. Expression studies with minimal promoter constructs linked to the chloramphenicol acetyltransferase reporter and transfected into HepG2 cells revealed marked enhancement of transcriptional activity with the T variant. The prevalence of the MTP promoter genotypes was investigated in a group of 184 healthy, middle-aged white men; the frequency of homozygosity for the MTP Ϫ493 T variant was .06 and the allele frequency of MTP Ϫ493T was .25 in the population. These homozygous subjects had a 22% lower LDL cholesterol concentration than did heterozygotes or subjects homozygous for the MTP Ϫ493 1 Functional MTP is an absolute requirement for the assembly and cellular secretion of apoB-containing lipoproteins. Cells that normally do not secrete apoB can acquire this competence if the genes encoding apoB and MTP are provided by gene transfection, as shown in HeLa cells and COS-1 cells.2,3 Conversely, if MTP activity is inhibited in cells that normally do secrete apoB-containing lipoproteins, the secretion of apoB is drastically reduced.4,5 A complete lack of MTP activity leads to abetalipoproteinemia, 6 a disease caused by mutations in the coding region of the MTP gene. 7-9The promoter region of the MTP gene is highly conserved between species and shows signs of both cell type-specific expression and response to metabolic regulators. The activity of the human MTP promoter is suppressed by insulin and enhanced by cholesterol. 10 The insulin response has been confirmed in HepG2 cells.11 It has also been shown that hamsters fed either a high-fat or a cholesterol-enriched diet have higher concentrations of MTP mRNA.Against this background we hypothesized that genetic variation in MTP expression might influence the plasma concentrations of apoB-containing lipoproteins in humans. We report herein a common functional polymorphism in the promoter region of the MTP gene, of which the rarer allele is linked to low plasma LDL cholesterol concentrations. Methods Human SubjectsA total of 184 healthy white men, aged 30 to 45 years, were recruited at random from a register containing all permanent residents of the Stockholm metropolitan area (response rate of 70%). Men with documented coronary heart disease or any other chronic disease were excluded. The mean age of the study group ...

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“…34 -36 In both normal and hypertriglyceridemic subjects, the VLDL 3 density subclass contains at least two metabolically distinct particle populations. 35 One of these is derived from large triglyceride-rich VLDL, S f >60, and its turnover within the interval S f 12-100 is slow, with little reaching LDL (S f 0-12). The other particle within the VLDL 3 subclass is rapidly turned over into LDL and represents a major precursor.…”

Section: Discussionmentioning

confidence: 99%

“…The other particle within the VLDL 3 subclass is rapidly turned over into LDL and represents a major precursor. 35 VLDL 3 is also the subclass in which LDL receptor binding can be mediated by either apoE or apoB in hypertriglyceridemic subjects, 32 -37 further indicating metabolic heterogeneity and at least two subpopulations within this subclass. Although the average K A of binding of VLDL 3 to the LDL receptor did not change after treatment, as measured in vitro (Table 5), there may be changes in the metabolism of this subclass in vivo (i.e., increased transport into this subclass from VLDL!…”

Section: Discussionmentioning

confidence: 99%

Effects of lovastatin on the levels, structure, and atherogenicity of VLDL in patients with moderate hypertriglyceridemia.

Gianturco

Bradley

Nozaki

et al. 1993

Arterioscler Thromb

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The purpose of this study was to determine whether lovastatin treatment reduced very low density lipoprotein (VLDL) abnormalities in hypertriglyceridemic subjects. Lovastatin reduced plasma triglyceride levels and the levels of total VLDL, intermediate density lipoprotein (IDL), and low density lipoprotein (LDL) cholesterol. The numbers of VLDL particles of S, 100-400 and S r 60-100 but not S r 20-60 particles were reduced by lovastatin, as was the amount of cholesteryl ester per particle. All VLDL subspecies bound to the LDL receptor of cultured human fibroblasts with similar, high affinities on both placebo and lovastatin, but VLDL S f 100-400 and VLDL S f 60-100 caused less suppression of 3-hydroxy-3-methyl glutaryl coenzyme A reductase activity after lovastatin therapy, indicating reduced LDL receptor-mediated cholesterol delivery. The average decrease in reductase suppression by VLDL S r 100-400 after lovastatin was 32%, similar to the 34% average decrease in cholesteryl ester content of VLDL S r 100-400 after lovastatin. Although statistical significance was not achieved, there was a trend toward decreased VLDL S r 100-400-induced rapid, receptor-mediated triglyceride accumulation in P388D, macrophages after lovastatin. Taken together, these observations suggest that lovastatin may be of potential benefit in decreasing the atherosclerotic complications of hypertriglyceridemia. There is growing evidence, however, that hypertriglyceridemia may be associated with increased risk for CHD.2 -4 -6 The mechanism(s) for a connection between hypertriglyceridemia and CHD has not been determined with certainty, but two general possibilities must be considered. These two potential mechanisms are not mutually exclusive, and both may play a role in CHD. First, triglyceride-rich lipoproteins (TGRLPs) could be directly atherogenic, and abnormally high levels could promote the development of coronary atherosclerosis. Alternatively, the metabolic consequences of hypertriglyceridemia, i.e., low levels of high density lipoprotein (HDL), the presence of small, dense low density lipoprotein (LDL), or a tendency for thrombogenesis, could account for the increased risk for CHD. Although the

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Metabolism of apolipoprotein B in large triglyceride-rich very low density lipoproteins of normal and hypertriglyceridemic subjects.

Abstract: Abstract. The

Cited by 289 publications

References 26 publications

Measurement of very low density and low density lipoprotein apolipoprotein (Apo) B-100 and high density lipoprotein Apo A-I production in human subjects using deuterated leucine. Effect of fasting and feeding.

Measurement of very low density and low density lipoprotein apolipoprotein (Apo) B-100 and high density lipoprotein Apo A-I production in human subjects using deuterated leucine. Effect of fasting and feeding.

A Common Functional Polymorphism in the Promoter Region of the Microsomal Triglyceride Transfer Protein Gene Influences Plasma LDL Levels

Effects of lovastatin on the levels, structure, and atherogenicity of VLDL in patients with moderate hypertriglyceridemia.

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