Published online before print June 12, 2008, doi: 10.1161/ATVBAHA.108.169383
© 2008 American Heart Association, Inc.
Clinical and Population Studies |
Triglyceride-Rich Lipoprotein-Associated Apolipoprotein C-III Production Is Stimulated by Plasma Free Fatty Acids in Humans
From the Departments of Medicine and Physiology, Division of Endocrinology and Metabolism (M.P., R.V., H.D., C.X., L.S., G.F.L.), University of Toronto, Canada; and the Washington University School of Medicine (B.W.P.), St. Louis, Mo.
Correspondence to Dr Gary F. Lewis, Toronto General Hospital, 200 Elizabeth Street, EN12-218, Toronto, Ontario, M5G 2C4. E-mail gary.lewis{at}uhn.on.ca
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Objective— Insulin resistant states are associated with increased fatty acid flux to liver and intestine, which stimulates the production of triglyceride-rich lipoproteins (TRL). ApoC-III production and plasma and TRL concentrations are increased in insulin resistance and may contribute to the hypertriglyceridemia of these conditions. The mechanism underlying that increase is not known, but because apoC-III and VLDL production are closely linked we hypothesized that FFAs may stimulate TRL apoC-III production.
Methods and Results— We used Intralipid/heparin (IH) to raise plasma FFA in 12 healthy men in the fed state, and stable isotopes to examine apoC-III metabolism. TRL apoC-III concentration was significantly higher in the IH study, and this increase was associated with higher production (PR) and fractional catabolic rate (FCR). The increase in production was greater than in FCR (90% versus 30%, respectively), accounting for the elevated concentration. Glycerol infusion had no effect on apoC-III concentration, PR, or FCR compared to saline, indicating that the effect was not attributable to glycerol released from intralipid.
Conclusion— These findings confirm that TRL apoC-III production is stimulated by an acute elevation of plasma FFAs, suggesting a novel regulatory pathway that may play a role in the overproduction of TRL apoC-III in insulin resistant states.
The mechanism of the increase in triglyceride-rich lipoprotein (TRL) apoC-III concentration and production in insulin resistant states is not known. We investigated this phenomenon in healthy men using stable isotope enrichment methodology, and demonstrated that TRL apoC-III production is stimulated by an acute elevation of plasma FFAs.
Key Words: apolipoprotein C3 • free fatty acids • insulin resistance • lipoprotein
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Hypertriglyceridemia is a well described feature of insulin resistance and type 2 diabetes and is commonly associated with other lipid abnormalities such as low plasma HDL concentration and a shift toward smaller and denser LDL particles, as well as an increased risk of atherosclerotic cardiovascular disease.1 This hypertriglyceridemia is attributable predominantly to an increased rate of production of triglyceride rich lipoproteins (TRL) by both the liver (reviewed in2) and intestine.3,4 Several factors contribute to the overproduction of TRL particles in these conditions; including increased flux of fatty acids to liver and intestine, increased de novo lipogenesis, increased stability of apoB, and overexpression of microsomal transfer protein (MTP), the latter contributing to the increased efficiency of lipoprotein assembly and secretion.5,6
Reduced clearance of the triglyceride moiety of TRL and of the particles themselves also contributes to the hypertriglyceridemia (reviewed in2), particularly when the metabolic control of type 2 diabetes is poor and in the postprandial state, when there is a large influx of intestinally-derived TRL particles. Functional deficiency of lipoprotein lipase (LPL) or competition for a common, saturable, lipolytic pathway has been shown to play an important contributing role in this impaired TRL clearance.7 Additionally, elevated apoC-III in insulin resistance and in type 2 diabetes8–14 has also been postulated to contribute to the impairment of TRL particle clearance, possibly by inhibiting the activity of LPL15 or by interfering with the interaction between TRL particles and hepatic lipoprotein receptors.16,17 Major insight into the function of apoC-III has been obtained from genetically modified mouse models, with overexpression of apoC-III resulting in severe hypertriglyceridemia18 and apoC-III deficiency resulting in hypotriglyceridemia.19
ApoC-III is synthesized mainly by the liver and to a lesser extent by the intestine (reviewed in20,21). Mature apoC-III is a 79 amino-acid glycoprotein present in VLDL, chylomicrons, and HDL, and has the ability to exchange between TG-rich lipoproteins and HDL.22 In normolipidemic subjects the majority of plasma apoC-III is bound to HDL whereas in hypertriglyceridemic subjects the majority is bound to TRL.21 Although apoC-III is a relatively minor component of HDL protein, approximately 50% of total plasma apoC-III may be in the HDL fraction.21 In humans, the APOA1/C3/A4/A5 gene cluster is located on chromosome 11q23.23 ApoC-III gene expression is normally downregulated by insulin24 via Foxo1.25 A variant promoter that is defective in its response to insulin results in overexpression of the apoC-III gene, contributing to the development of hypertriglyceridemia.26 These observations have led some to hypothesize that overexpression of apoC-III in insulin resistant states leads to an elevation of TRL apoC-III concentration and that this phenomenon is an important contributor to the highly prevalent hypertriglyceridemia that occurs in insulin resistance.26 In support of this notion, insulin sensitizing therapy with the PPAR
agonist pioglitazone in patients with type 2 diabetes reduced apoC-III production, plasma apoC-III concentration, and lowered plasma triglycerides,27 although it should be noted that pioglitazone also has some PPAR
agonist activity and the drug may have mediated its effect on apoC-III production and triglyceride metabolism by a mechanism that is not dependent on insulin sensitization. Insulin resistance and apoC-III production are correlated in humans,11 and increased VLDL apoC-III concentration resulting from its overproduction is strongly associated with the delayed catabolism of triglycerides and apoB in VLDL.28
Fatty acid flux from adipose tissue is increased in insulin resistant states and plays an important role in stimulating the production of TRL particles by the liver.6,29 More recently we have made the observation that acute elevation of plasma FFAs by Intralipid/heparin increased intestinal lipoprotein production in the Syrian Golden hamster30 and in humans.31 Because increased apoC-III production is closely linked with VLDL-triglyceride production,32 we hypothesized that TRL apoC-III production may also be stimulated by elevated plasma FFAs, providing an alternative mechanism explaining the increased rate of production of TRL apoC-III in insulin resistance. In the present study we examined the effect of an acute elevation of plasma FFAs on TRL apoC-III production in healthy men and found that TRL apoC-III production rate is indeed increased by an acute elevation of plasma FFAs.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Subjects
The subjects participating in the present study and the study protocol have been reported previously.31 The previous report of these subjects focused exclusively on the kinetics of TRL-apoB100 and TRL-apoB48 in response to an acute elevation of plasma FFA.31 The demographic characteristics and fasting biochemical profiles of the 12 study participants were described in detail in that publication,31 and only mean values are presented in Table 1 of the present article. All were healthy male subjects with no previous history of cardiovascular, gastrointestinal, or systemic illness, or surgical intervention within 6 months before the studies. No subject was taking medications, and they were all normoglycemic. To exclude those with gross dyslipidemia from the study, individuals whose total cholesterol was >5.3 mmol/L, TG >3 mmol/L, HDL-c <0.9 mmol/L, LDL-c >3.2 mmol/L were excluded.
|
The Research Ethics Board of the University Health Network, University of Toronto, approved the study and all subjects gave written informed consent prior to their participation.
Experimental Protocol for Lipoprotein Kinetic Studies
The experimental protocol has previously been described in detail.31 Briefly, 12 subjects underwent 2 separate 12-hour lipoprotein turnover studies, both conducted during a constant fed state, in random order, 4 to 6 weeks apart. One study was performed during intravenous infusion of Intralipid (a synthetic triglyceride emulsion, suitable for intravenous infusion, that provides a source of mainly polyunsaturated FFAs) and heparin (to activate lipoprotein lipase, which stimulates intravascular lipolysis of the intralipid triglycerides), and the other during intravenous saline infusion as a control study. Because the infusion of Intralipid raises both FFAs and glycerol, a subset of 5 subjects also underwent a third kinetics study during i.v. infusion of glycerol as an additional control study to differentiate the effects of FFA from potential effects of glycerol released by intravascular lipolysis of Intralipid. In this case, all 3 studies were performed in random order, 4 to 6 weeks apart.
After an overnight fast, an intravenous catheter was inserted into a superficial vein in each forearm, one for infusion and one for blood sampling. At 4 AM the subject was instructed to start ingesting the first aliquot of a liquid food supplement, hourly for the first 3 hours (Hormel Great Shake Plus, Hormel Health Labs, 49% calories from fat, 38% from carbohydrates, 13% from proteins), each hourly aliquot equivalent to 1/17th of their total daily caloric needs. After the first 3 hours (after 7 AM), the subjects ingested the same formula every half hour for the remainder of the study, ie, 1/34th of their daily caloric intake every half hour. Total energy requirements to achieve a constant fed state were determined using the Harris Benedict Equation. At 4 AM, at the same time as the start of the hourly formula ingestion, an i.v. infusion with either Intralipid/heparin (IH; Baxter; Intralipid 20% at 20 mL/h plus heparin 250U/h) or saline (65 mL/h) or glycerol (2.25 g/h) was started and was constantly infused for the full 17-hour duration of the study. Five hours after starting the liquid formula ingestion (at 9 AM), a primed constant infusion of deuterium-labeled leucine33 ([D3]L-leucine 98%, Cambridge Isotope Laboratories) was administered (10 µmol/kg bolus followed by 10 µmol/kg.hr for 12 hours) to enrich apoC-III to calculate production and clearance rates, as previously described.34 Blood samples were collected at regular intervals as previously described.31 The total blood volume drawn during the entire study was <350 mL. The hematocrit does not change appreciably after removal of this amount of blood.
For details on laboratory methods, calculation of lipoprotein clearance and production rates by multicompartmental modeling, and statistical analysis, please see the data supplement (available online at http://atvb.ahajournals.org).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Glycerol Control Study
We have recently demonstrated that glycerol infusion has no effect on plasma FFA, TG, TRL-apoB100, or TRL apoB48 levels, production and clearance rates compared to saline.31 Here we found no difference between glycerol and saline infusion on TRL apoC-III concentration (saline 5.52±0.9 versus glycerol 6.0±0.46 mg/dL, P=0.464), production (saline 2.54±0.63 versus glycerol 2.14±0.20 mg/kg · d, P=0.617), and clearance (saline 0.99±0.11 versus glycerol 0.80±0.06 pool/d, P=0.300). For clarity, and because power calculation estimated n=64 subjects would be needed to detect a significant difference between the kinetics parameters for TRL apoC-III in the saline and glycerol studies at P=0.05 with 80% power, the following results and illustration will therefore compare only the Intralipid/heparin and saline studies.
Effect of Acute Elevation of FFAs on Plasma and TRL Lipid and TRL and HDL Apolipoprotein Concentrations in the Constant Fed State
We have previously shown that plasma FFA, plasma TG levels, and TRL-TG increased during feeding, to a greater extent with Intralipid/heparin infusion compared to saline and plasma concentrations, remained stable in both the saline and IH studies for the duration of the 12-hour kinetics study (illustrated in31). Similary, TRL apoC-III concentrations increased with feeding, remained stable during the 12-hour kinetics study, and were significantly higher in the IH study compared to saline (IH 8.37±2.41 mg/dL versus Saline 5.65±0.75 mg/dL, P=0.002) (Table 2 and Figure 1). HDL apoC-III concentration decreased with feeding, remained stable during the kinetics study, and was significantly lower in IH compared to saline control (IH 2.50±0.48 mg/dL versus Saline 3.17±0.48, P=0.012; Figure 1).
|
|
Effects of Acute Elevation of FFAs on TRL ApoC-III Lipoprotein Production and Clearance Rates
Individual subject’s TRL apoC-III pool sizes, production rates, and FCRs for the IH and the saline infusion studies are provided in Table 2, and mean production rate and FCR results are depicted graphically in Figure 2. The mean TRL apoC-III fractional catabolic rate was 30% higher in the IH compared to the saline control study (IH 1.14±0.12 versus saline 0.86±0.08 pool/d, P=0.001; Figure 2A). The production rate of TRL apoC-III increased by 90% in subjects infused with IH compared to saline (IH 4.31±0.77 versus saline 2.26±0.36 mg/kg · d, P=0.003; Figure 2B).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
There is a positive association between TRL apoC-III and TRL triglyceride concentrations and production rates2,11 and also TRL apo-B concentrations and production rates,28,32,35 which are increased in insulin resistant states. Elevated FFA flux from extrahepatic tissues is one important cause of the overproduction of VLDL in insulin resistance,6,29,31,36,37 and we have recently shown in the Syrian Golden hamster30 and in humans31 that intestinal lipoprotein production is also stimulated by an acute elevation of plasma FFAs. Here, we examined whether an acute elevation of FFAs also stimulates TRL apoC-III production in healthy humans. Our findings confirm that TRL-associated apoC-III production is stimulated by an acute elevation of plasma FFAs, suggesting a novel regulatory pathway that may play a role in the overproduction of TRL apoC-III in insulin resistant states.
Kinetics studies in human subjects have shown that increased production rather than decreased clearance of apoC-III is the most important determinant of the elevated plasma apoC-III levels that characterize patients with hypertriglyceridemia and features of insulin resistance.11,32 We used Intralipid/heparin infusion to raise plasma FFA concentration in the fed state and well established stable isotope enrichment techniques to examine TRL apoC-III metabolism. The TRL apoC-III concentration was significantly higher in the IH infusion study compared with saline control study, and this increase was associated with both higher production rates of TRL apoC-III as well as higher FCR, with the increase in production rate being of greater relative magnitude (90% higher production rate in IH versus saline) than the increase in FCR (30% higher FCR in IH versus saline), providing an explanation for the increase in concentrations. Glycerol had no effect on apoC-III concentration, production or clearance rates when compared to saline infusion, indicating that the effect of IH was attributable to the FFAs released from the synthetic TG emulsion by the action of heparin-stimulated LPL, and not attributable to the release of glycerol.
Unlike apoB, apoC-III and other apolipoproteins are able to exchange actively between lipid surfaces, and apoC-III redistribution to intralipid particles must be considered in the interpretation of our findings. Larger intralipid particles would be expected to contain apoC-III and other exchangeable apolipoproteins, as has been demonstrated by others in the past.38,39 Whereas newly secreted apoC-III is very likely to be rapidly transferred to intralipid particles, there is no known mechanism for apolipoprotein feeding back on its own gene transcription, and therefore by far the most likely culprit responsible for enhancing apoC-III production by 90% in our studies is still the FFA released by intravascular lipolysis of intralipid. As shown in Figure 1, there was a slight decline in HDL apoC-III during the Intralipid/heparin infusion experiment. This decline likely reflects the transfer of HDL apoC-III to the increased pool of TRL and intralipid particles. Because the residence time of HDL apoC-III has been shown to be 3 times longer than VLDL apoC-III,34 and if intralipid particle-associated apoC-III is also cleared faster than HDL apoC-III because of enhanced lipolysis of intralipid by heparin-stimulated LPL, this transfer of apoC-III from HDL to TRL could account for the 30% higher FCR that we documented during Intralipid/heparin versus saline infusion.
Limitations of the present study must be addressed. First, for practical reasons the study was designed to examine the effect of a short-term elevation of plasma FFAs on lipoprotein metabolism. It is not feasible nor is it technically possible, considering issues of stable isotope recycling that complicate interpretation of data with prolonged infusion, to examine longer term elevations of plasma FFAs on lipoprotein-associated apolipoprotein kinetics. Extrapolation of our findings to clinical conditions that are associated with chronic elevations of plasma FFAs, such as insulin resistance and type 2 diabetes, should therefore be made with appropriate caution. The levels of FFA achieved in the present study were well within the physiological range that occurs in those with insulin resistance or type 2 diabetes. Second, our study was conducted in the fed state to facilitate the assessment of TRL apoB48 kinetics (reported in31). This was necessary because of the technical challenge of measuring very low concentrations of apoB-48-containing particles. Our finding that TRL apoC-III production rates were increased in the IH study and stimulated by acute elevation of plasma FFA were made in the setting of high-fat feeding and ongoing fat absorption. We cannot say with certainty that the same would have been observed in the fasted state. This would have to be specifically examined in future studies. Third, because apoC-III is produced in both liver and intestine, we were unable to determine whether the increase in production occurred primarily in the liver, primarily in the intestine, or in both organs to a relatively similar extent. Fourth, an in vivo human study of this nature cannot examine the molecular mechanisms of the increased apoC-III production and cannot determine whether the increase occurred as a result of upregulation of apoC-III gene transcription or whether the effect occurred at the posttranslational level. In addition we cannot determine whether the increase in production of TRL apoC-III occurred as a direct result of fatty acids stimulating the hepatocyte or intestinal enterocyte, was mediated through one or a number of intermediary regulators of apoC-III secretion, or whether the effect occurred secondary to the well described insulin resistance that occurs with elevation of plasma FFAs.40 Given our findings of a simultaneous upregulation of TRL apoB48, apoB100,31 and apoC-III production in response to the elevation of plasma FFAs, and because the regulation of apoB48 and apoB100 by fatty acids has been shown to occur primarily at the posttranslational level by inhibition of apoB degradation and enhancement of lipoprotein assembly,41 it is quite possible that the increase in apoC-III production seen in the present study also occurred posttranslationally. This interesting issue remains to be determined in future in vitro or ex vivo mechanistic studies.
As can be seen in Figure 1, TRL apoC-III concentration (pool size, on which our kinetic modeling was based) was not in perfect steady state during the 12-hour kinetics study (5 to 17 hours). We turned to model simulations to assess the potential impact of a nonsteady state on the analysis of apoC-III turnover kinetics, as we have described and illustrated in the online Data Supplement. Based on these model simulations and for the reasons described in the online Data Supplement, we are confident that our calculated production rates are valid and are not affected by the small perturbations of steady state that occurred in this study.
In conclusion, the present report provides evidence that TRL apo-CIII production is stimulated by a short-term elevation of plasma FFAs in healthy men. It is reasonable to assume that chronic elevation of plasma FFAs seen in type 2 diabetes and insulin resistance could play an important role in TRL apoC-III overproduction, which in turn could aggravate the hypertriglyceridemia of insulin resistant states and type 2 diabetes. Given the complexity of the mechanisms that have been shown to contribute to the overproduction of intestinal and hepatic lipoproteins in these conditions, it is unlikely that TRL apoC-III overproduction is the sole or even the dominant mechanism accounting for the hypertriglyceridemia, but it certainly could contribute and should be considered a potential therapeutic target for ameliorating this atherogenic condition.
|
Acknowledgments |
|---|
We are indebted to Patricia Harley, RN for her assistance with subject recruitment and conducting the clinical protocol.
Sources of Funding
This work was supported by funding from the Canadian Institutes for Health Research (MOP-43839). G.F.L. holds a Canada Research Chair in Diabetes and is a Career Investigator of the Heart and Stroke Foundation of Canada. H.D. is the recipient of a Postdoctoral Fellowship Award from the Heart and Stroke Foundation of Canada. B.W.P. was supported by NIH P30 DK56341 (Clinical Nutrition Research Unit). C.X. is supported by a Postdoctoral Fellowship Award from Canadian Diabetes Association.
Disclosures
None.
|
Footnotes |
|---|
M.P. and R.V. contributed equally to this study.
Original received March 20, 2008; final version accepted June 5, 2008.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Ginsberg HN. Insulin resistance and cardiovascular disease. J Clin Invest. 2000; 106: 453–458.[Medline] [Order article via Infotrieve]
2. Chan DC, Barrett PH, Watts GF. Recent studies of lipoprotein kinetics in the metabolic syndrome and related disorders. Curr Opin Lipidol. 2006; 17: 28–36.[Medline] [Order article via Infotrieve]
3. Duez H, Lamarche B, Uffelman KD, Valero R, Cohn JS, Lewis GF. Hyperinsulinemia is associated with increased production rate of intestinal apolipoprotein B-48-containing lipoproteins in humans. Arterioscler Thromb Vasc Biol. 2006; 26: 1357–1363.
4. Hogue JC, Lamarche B, Tremblay AJ, Bergeron J, Gagne C, Couture P. Evidence of increased secretion of apolipoprotein B-48-containing lipoproteins in subjects with type 2 diabetes. J Lipid Res. 2007; 48: 1336–1342.
5. Adeli K, Lewis GF. Intestinal lipoprotein overproduction in insulin-resistant states. Curr Opin Lipidol. 2008; 19: 221–228.[CrossRef][Medline] [Order article via Infotrieve]
6. Lewis GF, Carpentier A, Adeli K, Giacca A. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev. 2002; 23: 201–229.
7. Brunzell JD, Hazzard WR, Porte D Jr, Bierman EL. Evidence for a common, saturable, triglyceride removal mechanism for chylomicrons and very low density lipoproteins in man. J Clin Invest. 1973; 52: 1578–1585.[Medline] [Order article via Infotrieve]
8. Gervaise N, Garrigue MA, Lasfargues G, Lecomte P. Triglycerides, apo C3 and Lp B:C3 and cardiovascular risk in type II diabetes. Diabetologia. 2000; 43: 703–708.[CrossRef][Medline] [Order article via Infotrieve]
9. Chan DC, Watts GF, Redgrave TG, Mori TA, Barrett PH. Apolipoprotein B-100 kinetics in visceral obesity: associations with plasma apolipoprotein C-III concentration. Metabolism. 2002; 51: 1041–1046.[CrossRef][Medline] [Order article via Infotrieve]
10. Onat A, Hergenc G, Sansoy V, Fobker M, Ceyhan K, Toprak S, Assmann G. Apolipoprotein C-III, a strong discriminant of coronary risk in men and a determinant of the metabolic syndrome in both genders. Atherosclerosis. 2003; 168: 81–89.[CrossRef][Medline] [Order article via Infotrieve]
11. Cohn JS, Patterson BW, Uffelman KD, Davignon J, Steiner G. Rate of production of plasma and very-low-density lipoprotein (VLDL) apolipoprotein C-III is strongly related to the concentration and level of production of VLDL triglyceride in male subjects with different body weights and levels of insulin sensitivity. J Clin Endocrinol Metab. 2004; 89: 3949–3955.
12. Olivieri O, Bassi A, Stranieri C, Trabetti E, Martinelli N, Pizzolo F, Girelli D, Friso S, Pignatti PF, Corrocher R. Apolipoprotein C-III metabolic syndrome, and risk of coronary artery disease. J Lipid Res. 2003; 44: 2374–2381.
13. Florez H, Mendez A, Casanova-Romero P, Larreal-Urdaneta C, Castillo-Florez S, Lee D, Goldberg R. Increased apolipoprotein C-III levels associated with insulin resistance contribute to dyslipidemia in normoglycemic and diabetic subjects from a triethnic population. Atherosclerosis. 2006; 188: 134–141.[CrossRef][Medline] [Order article via Infotrieve]
14. Hernandez-Mijares A, Jarabo-Bueno MM, Lopez-Ruiz A, Sola-Izquierdo E, Morillas-Arino C, Martinez-Triguero ML. Levels of C3 in patients with severe, morbid and extreme obesity: its relationship to insulin resistance and different cardiovascular risk factors. Int J Obes (Lond). 2007; 31: 927–932.[CrossRef][Medline] [Order article via Infotrieve]
15. Ginsberg HN, Le NA, Goldberg IJ, Gibson JC, Rubinstein A, Wang-Iverson P, Norum R, Brown WV. Apolipoprotein B metabolism in subjects with deficiency of apolipoproteins CIII and AI. Evidence that apolipoprotein CIII inhibits catabolism of triglyceride-rich lipoproteins by lipoprotein lipase in vivo. J Clin Invest. 1986; 78: 1287–1295.[Medline] [Order article via Infotrieve]
16. Sehayek E, Eisenberg S. Mechanisms of inhibition by apolipoprotein C of apolipoprotein E-dependent cellular metabolism of human triglyceride-rich lipoproteins through the low density lipoprotein receptor pathway. J Biol Chem. 1991; 266: 18259–18267.
17. Ebara T, Ramakrishnan R, Steiner G, Shachter NS. Chylomicronemia due to apolipoprotein CIII overexpression in apolipoprotein E-null mice. Apolipoprotein CIII-induced hypertriglyceridemia is not mediated by effects on apolipoprotein E. J Clin Invest. 1997; 99: 2672–2681.[Medline] [Order article via Infotrieve]
18. Ito Y, Azrolan N, O'Connell A, Walsh A, Breslow JL. Hypertriglyceridemia as a result of human apo CIII gene expression in transgenic mice. Science. 1990; 249: 790–793.
19. Maeda N, Li H, Lee D, Oliver P, Quarfordt SH, Osada J. Targeted disruption of the apolipoprotein C-III gene in mice results in hypotriglyceridemia and protection from postprandial hypertriglyceridemia. J Biol Chem. 1994; 269: 23610–23616.
20. Shachter NS. Apolipoproteins C-I and C-III as important modulators of lipoprotein metabolism. Curr Opin Lipidol. 2001; 12: 297–304.[CrossRef][Medline] [Order article via Infotrieve]
21. van Dijk KW, Rensen PC, Voshol PJ, Havekes LM. The role and mode of action of apolipoproteins CIII and AV: synergistic actors in triglyceride metabolism? Curr Opin Lipidol. 2004; 15: 239–246.[CrossRef][Medline] [Order article via Infotrieve]
22. Jong MC, Hofker MH, Havekes LM. Role of ApoCs in lipoprotein metabolism: functional differences between ApoC1, ApoC2, and ApoC3. Arterioscler Thromb Vasc Biol. 1999; 19: 472–484.
23. Zannis VI, Kan HY, Kritis A, Zanni EE, Kardassis D. Transcriptional regulatory mechanisms of the human apolipoprotein genes in vitro and in vivo. Curr Opin Lipidol. 2001; 12: 181–207.[CrossRef][Medline] [Order article via Infotrieve]
24. Chen M, Breslow JL, Li W, Leff T. Transcriptional regulation of the apoC-III gene by insulin in diabetic mice: correlation with changes in plasma triglyceride levels. J Lipid Res. 1994; 35: 1918–1924.[Abstract]
25. Altomonte J, Cong L, Harbaran S, Richter A, Xu J, Meseck M, Dong HH. Foxo1 mediates insulin action on apoC-III and triglyceride metabolism. J Clin Invest. 2004; 114: 1493–1503.[CrossRef][Medline] [Order article via Infotrieve]
26. Li WW, Dammerman MM, Smith JD, Metzger S, Breslow JL, Leff T. Common genetic variation in the promoter of the human apo CIII gene abolishes regulation by insulin and may contribute to hypertriglyceridemia. J Clin Invest. 1995; 96: 2601–2605.[Medline] [Order article via Infotrieve]
27. Nagashima K, Lopez C, Donovan D, Ngai C, Fontanez N, Bensadoun A, Fruchart-Najib J, Holleran S, Cohn JS, Ramakrishnan R, Ginsberg HN. Effects of the PPARgamma agonist pioglitazone on lipoprotein metabolism in patients with type 2 diabetes mellitus. J Clin Invest. 2005; 115: 1323–1332.[CrossRef][Medline] [Order article via Infotrieve]
28. Chan DC, Watts GF, Nguyen MN, Barrett PH. Apolipoproteins C-III and A-V as predictors of very-low-density lipoprotein triglyceride and apolipoprotein B-100 kinetics. Arterioscler Thromb Vasc Biol. 2006; 26: 590–596.
29. Lewis GF, Uffelman KD, Szeto LW, Weller B, Steiner G. Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans. J Clin Invest. 1995; 95: 158–166.[Medline] [Order article via Infotrieve]
30. Lewis GF, Uffelman K, Naples M, Szeto L, Haidari M, Adeli K. Intestinal lipoprotein overproduction, a newly recognized component of insulin resistance, is ameliorated by the insulin sensitizer rosiglitazone: studies in the fructose-fed Syrian golden hamster. Endocrinology. 2005; 146: 247–255.
31. Duez H, Lamarche B, Valero R, Pavlic M, Proctor S, Xiao C, Szeto L, Patterson BW, Lewis GF. Both intestinal and hepatic lipoprotein production are stimulated by an acute elevation of plasma free fatty acids in humans. Circulation. 2008; 117: 2369–2376.
32. Cohn JS, Tremblay M, Batal R, Jacques H, Rodriguez C, Steiner G, Mamer O, Davignon J. Increased apoC-III production is a characteristic feature of patients with hypertriglyceridemia. Atherosclerosis. 2004; 177: 137–145.[CrossRef][Medline] [Order article via Infotrieve]
33. Cohn JS, Wagner DA, Cohn SD, Millar JS, Schaefer EJ. 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. J Clin Invest. 1990; 85: 804–811.[Medline] [Order article via Infotrieve]
34. Batal R, Tremblay M, Barrett PH, Jacques H, Fredenrich A, Mamer O, Davignon J, Cohn JS. Plasma kinetics of apoC-III and apoE in normolipidemic and hypertriglyceridemic subjects. J Lipid Res. 2000; 41: 706–718.
35. Chan DC, Nguyen MN, Watts GF, Barrett PH. Plasma apolipoprotein C-III transport in centrally obese men: associations with very low-density lipoprotein apolipoprotein B and high-density lipoprotein apolipoprotein A-I metabolism. J Clin Endocrinol Metab. 2008; 93: 557–564.
36. Lewis GF. Fatty acid regulation of very low density lipoprotein production. Curr Opin Lipidol. 1997; 8: 146–153.[Medline] [Order article via Infotrieve]
37. Steiner G, Poapst M, Davidson JK. Production of chylomicron-like lipoproteins from endogenous lipid by the intestine and liver of diabetic dogs. Diabetes. 1975; 24: 263–271.[CrossRef][Medline] [Order article via Infotrieve]
38. Connelly PW, Kuksis A. Effect of core composition and particle size of lipid emulsions on apolipoprotein transfer of plasma lipoproteins in vivo. Biochim Biophys Acta. 1981; 666: 80–89.[Medline] [Order article via Infotrieve]
39. Tajima S, Yokoyama S, Yamamoto A. Effect of lipid particle size on association of apolipoproteins with lipid. J Biol Chem. 1983; 258: 10073–10082.
40. Boden G, Chen X, Ruiz J, White JV, Rossetti L. Mechanisms of fatty acid-induced inhibition of glucose uptake. J Clin Invest. 1994; 93: 2438–2446.[Medline] [Order article via Infotrieve]
41. Adeli K, Taghibiglou C, Van Iderstine SC, Lewis GF. Mechanisms of hepatic very low-density lipoprotein overproduction in insulin resistance. Trends Cardiovasc Med. 2001; 11: 170–176.[CrossRef][Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  H. N. Ginsberg and R. Ramakrishnan Kinetic Studies of the Metabolism of Rapidly Exchangeable Apolipoproteins May Leave Investigators and Readers With Exchangeable Results Arterioscler Thromb Vasc Biol, October 1, 2008; 28(10): 1685 - 1686. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||