Apolipoprotein E kinetics: influence of insulin resistance and type 2 diabetes

Bach-Ngohou, Kalyane; Ouguerram, Khadija; Nazih, Hassan; Maugère, Pascale; Ripolles-Piquer, B; Zaïr, Yassine; Frénais, R.; Krempf, Michel; Bard, Jean‐Marie

doi:10.1038/sj.ijo.0802149

Cited by 20 publications

(23 citation statements)

References 50 publications

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“…Previous studies demonstrated that overproduction and slower catabolism of VLDL apoE explained the high concentration of VLDL apoE in hypertriglyceridemic subjects ( 25,27 ). Higher VLDL apoE concentration and PR were associated with elevated plasma and VLDL triglycerides ( 25,27 ). Our subjects exhibited overproduction of VLDL apoE, with concentrations of plasma and VLDL apoE within range of those previously reported in hypertriglyceridemic subjects ( 20,21,25,27 ).…”

Section: Data Interpretationsupporting

confidence: 63%

“…Higher VLDL apoE concentration and PR were associated with elevated plasma and VLDL triglycerides ( 25,27 ). Our subjects exhibited overproduction of VLDL apoE, with concentrations of plasma and VLDL apoE within range of those previously reported in hypertriglyceridemic subjects ( 20,21,25,27 ). It is, however, important to acknowledge that, in this study, VLDL apoE PR represents the transport of apoE through the VLDL pool.…”

Section: Data Interpretationmentioning

confidence: 47%

“…These kinetic aberrations may be related to altered VLDL apoE metabolism. Previous studies demonstrated that overproduction and slower catabolism of VLDL apoE explained the high concentration of VLDL apoE in hypertriglyceridemic subjects ( 25,27 ). Higher VLDL apoE concentration and PR were associated with elevated plasma and VLDL triglycerides ( 25,27 ).…”

Section: Data Interpretationmentioning

confidence: 99%

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Effect of fenofibrate and atorvastatin on VLDL apoE metabolism in men with the metabolic syndrome

Ooi

Watts

et al. 2012

Journal of Lipid Research

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Hypertriglyceridemia, a key feature of the metabolic syndrome (MetS), is associated with increased risk of cardiovascular disease (CVD) ( 1 ). It is the most consistent lipid disorder in subjects with obesity and type 2 diabetes. Hypertriglyceridemia is primarily related to dysregulated triglyceride-rich lipoprotein (TRL) metabolism, including overproduction of very low-density lipoprotein (VLDL) particles and delayed catabolism of TRL and their remnants ( 2 ). These abnormalities are a collective consequence of insulin resistance and increased lipid substrate availability in the liver, as well as depressed activities of lipoprotein lipase (LPL) and hepatic receptors ( 3 ).Apolipoprotein (apo)E is a 34.2 kDa glycoprotein synthesized by the liver and, to a lesser extent, by peripheral tissues ( 4 ). Clinical studies show that plasma apoE concentration explains 20-40% of the variation in plasma trig lyceride concentrations. A key role of apoE is to act as a high-affi nity ligand for members of the low-density lipoprotein (LDL) receptor family, including the LDL receptor, LDL receptor-related protein (LRP), the VLDL receptor, GP330/Megalin, and ApoER-2. ApoE is also a ligand for heparin sulfate proteoglycans (HSPG). By binding to these hepatic and extrahepactic receptors, apoE mediates the clearance of TRL and their remnants from the circulation ( 5 ). The role of apoE is not confi ned only to the clearance of lipoprotein particles, however. ApoE inhibits LPL-mediated lipolysis of lipoproteins by displacing LPL cofactor apoC-II ( 6, 7 ). ApoE has also been shown to stimulate hepatic secretion VLDL particles; apoEdefi cient mice showed a 50% reduction in VLDL secretion ( 8 ), and hepatic expression of human apoE2, apoE3, and apoE4 stimulated VLDL production in vivo ( 9-12 ). Therefore, apoE is an important determinant of in vivo TRL Abstract We examined the effects of fenofi brate and atorvastatin on very low density lipoprotein (VLDL) apolipoprotein (apo)E metabolism in the metabolic syndrome (MetS). We studied 11 MetS men in a randomized, double-blind, crossover trial. VLDL-apoE kinetics were examined using stable isotope methods and compartmental modeling. Compared with placebo, fenofi brate (200 mg/day) and atorvastatin (40 mg/day) decreased plasma apoE concentrations ( P < 0.05). Fenofi brate decreased VLDL-apoE concentration and production rate (PR) and increased VLDL-apoE fractional catabolic rate (FCR) compared with placebo ( P < 0.05). Compared with placebo, atorvastatin decreased VLDL-apoE concentration and increased VLDL-apoE FCR ( P < 0.05). Fenofi brate and atorvastatin had comparable effects on VLDL-apoE concentration. The increase in VLDL-apoE FCR with fenofi brate was 22% less than that with atorvastatin ( P < 0.01). With fenofi brate, the change in VLDL-apoE concentration was positively correlated with change in VLDL-apoB concentration, and negatively correlated with change in VLDL-apoB FCR. In MetS, fenofibrate and atorvastatin decreased plasma apoE concentrations. Fenofi brate decreased VLDL-apoE ...

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Section: Data Interpretationsupporting

confidence: 63%

Section: Data Interpretationmentioning

confidence: 47%

Section: Data Interpretationmentioning

confidence: 99%

See 1 more Smart Citation

Effect of fenofibrate and atorvastatin on VLDL apoE metabolism in men with the metabolic syndrome

Ooi

Watts

et al. 2012

Journal of Lipid Research

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“…Kinetic studies of apoE (Bach-Ngohou et al, 2002) and apoAI (Frénais et al, 1997) have been previously described. Briefly, endogenous labeling of these apolipoproteins was performed by administration of L-[5,5,5-2 H 3 ]leucine (99.8 atom % 2 H 3 ; Cambridge Isotope Laboratories, Andover, MA) dissolved in a 0.9% saline solution and tested for sterility and the absence of pyrogens before the study.…”

Section: Subjects and Study Protocolmentioning

confidence: 99%

Influence of Atorvastatin on Apolipoprotein E and AI Kinetics in Patients with Type 2 Diabetes

Bach-Ngohou

Ouguerram²,

Frénais³

et al. 2005

J Pharmacol Exp Ther

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Atorvastatin reduces both plasma cholesterol and triglyceride concentrations in patients with type 2 diabetes, but mechanisms underlying triglyceride decrease and the effect of atorvastatin on high density lipoprotein (HDL) still remain unclear. Apolipoprotein (apo) E plays a crucial role in modulating production and clearance of triglyceride-rich very low density lipoprotein (VLDL). The main effect of apoAI is to modulate HDL metabolism. The aim of this work was to study the influence of atorvastatin on apoAI and apoE kinetics and to determine whether its hypocholesterolemic and hypotriglyceridemic effects could be related to changes in this apolipoprotein metabolism. Plasma VLDL-apoE, HDL-apoE, and HDL-apoAI were studied in seven patients with diabetes with mixed hyperlipidemia using a stable isotope labeling technique ([ 2 H 3 ]leucineprimed constant infusion) and monocompartmental model before and after 2 months of treatment with 40 mg/day of atorvastatin. Plasma apoE concentration was significantly reduced (44.1 Ϯ 19.1 versus 32 Ϯ 11.6 mg/l, p Ͻ 0.05) after treatment. This decrease was associated with a diminution of HDL-apoE concentration (17.46 Ϯ 6.71 versus 13.37 Ϯ 6.05 mg/l, p Ͻ 0.05) and production rate (0.202 Ϯ 0.085 versus 0.119 Ϯ 0.047 mg/kg/day, p Ͻ 0.05), whereas an increase in VLDL-apoE concentration (6.44 Ϯ 2.16 before versus 9.23 Ϯ 4.02 mg/l after, p Ͻ 0.05) and production rate (0.827 Ϯ 0.367 versus 1.524 Ϯ 0.664 mg/kg/day, p Ͻ 0.05) was observed. No significant difference was observed after treatment for apoAI parameters. We conclude that atorvastatin treatment promotes different apoE distribution between HDL and VLDL, favoring VLDL apoE content. The increased number of apoE per VLDL particle suggests that atorvastatin could enhance the direct catabolism of triglyceride-rich VLDL through apoE receptor pathways.

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“…Most lipoprotein turnover studies with mass isotopes have used primed constant infusions (27,29,41,50,68,70,(99)(100)(101)(102)(103). Our results suggest that the reported FSRs and production rates are underestimates, with the percent error roughly equal to the plateau enrichment percent.…”

Section: Discussionmentioning

confidence: 52%

Studying apolipoprotein turnover with stable isotope tracers: correct analysis is by modeling enrichments

Ramakrishnan

2006

Journal of Lipid Research

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Lipoprotein kinetic parameters are determined from mass spectrometry data after administering mass isotopes of amino acids, which label proteins endogenously. The standard procedure is to model the isotopic content of the labeled precursor amino acid and of proteins of interest as tracer-to-tracee ratio (TTR). It is shown here that even though the administered tracer alters amino acid mass and turnover, apolipoprotein synthesis is unaltered and hence the apolipoprotein system is in a steady state, with the total (labeled plus unlabeled) masses and fluxes remaining constant. The correct model formulation for apolipoprotein kinetics is shown to be in terms of tracer enrichment, not of TTR. The needed mathematical equations are derived. A theoretical error analysis is carried out to calculate the magnitude of error in published results using TTR modeling. It is shown that TTR modeling leads to a consistent underestimation of the fractional synthetic rate. In constant-infusion studies, the bias error percent is shown to equal approximately the plateau enrichment, generally ,10%. It is shown that, in bolus studies, the underestimation error can be larger. Thus, for mass isotope studies with endogenous tracers, apolipoproteins are in a steady state and the data should be fitted by modeling enrichments.-Ramakrishnan, R. Studying apolipoprotein turnover with stable isotope tracers: correct analysis is by modeling enrichments. Beginning in the 1970s, apolipoprotein kinetics were routinely studied with exogenous tracers, for instance by isolating VLDL or LDL from a subject, radioiodinating it, and injecting it back into the subject (1-4). Endogenous labeling, with a labeled precursor of the metabolite of interest, has the virtue of labeling the synthetic pathways and not altering tracer metabolic properties, as might happen with exogenous labeling. Whole body cholesterol metabolism was studied with tritiated water (5), and tritiated leucine has been used to study lipoprotein kinetics (6-8). Highly sensitive gas chromatography-mass spectrometry and refinements thereof, and the availability of synthetic amino acids and other molecules that are multiply labeled with mass isotopes, have altered the field to the point that endogenous labeling with mass isotopes is now the norm in human turnover studies (9).An important aspect of mass isotopes is that the amount of tracer introduced is not negligible in relation to the amount in plasma of the tracee. Cobelli, Toffolo, and Foster (10) and Foster et al. (11) considered this problem and advocated the use of tracer-to-tracee ratio (TTR) in place of the previously standard use of tracer enrichment in atoms percent excess or moles percent excess (12-15). Since then, nearly all investigators have used TTR in analyzing mass isotope data to calculate lipoprotein turnover parameters. In what follows, we revisit this issue and derive the mathematical relationships needed for the analysis of tracer data from endogenous labeling. In particular, we show that the apolipoprotein syste...

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Apolipoprotein E kinetics: influence of insulin resistance and type 2 diabetes

Cited by 20 publications

References 50 publications

Effect of fenofibrate and atorvastatin on VLDL apoE metabolism in men with the metabolic syndrome

Effect of fenofibrate and atorvastatin on VLDL apoE metabolism in men with the metabolic syndrome

Influence of Atorvastatin on Apolipoprotein E and AI Kinetics in Patients with Type 2 Diabetes

Studying apolipoprotein turnover with stable isotope tracers: correct analysis is by modeling enrichments

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