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Journal of Lipid Research, Vol. 47, 975-981, May 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Mass kinetics of apolipoprotein A-I in interstitial fluid after administration of intravenous apolipoprotein A-I/lecithin discs in humans

Roman Hovorka^*, M. Nazeem Nanjee, C. Justin Cooke, Irina P. Miller, Waldemar L. Olszewski^** and Norman E. Miller^1,

^* Diabetes Modeling Group, Department of Paediatrics, University of Cambridge, Cambridge, UK
Cardiovascular Genetics Division, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT
Chesterfield Royal Infirmary, Chesterfield, UK
^** Medical Research Center, Polish Academy of Sciences, Warsaw, Poland

¹ To whom correspondence should be addressed. e-mail: n.e.miller{at}btinternet.com

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Apolipoprotein kinetics are customarily determined by modeling time curves of specific radioactivity or isotopic enrichment in plasma after intravenous infusion of radiolabeled lipoproteins or stable isotope-enriched amino acids. However, this provides no information on the fractional rate of transfer of the apolipoprotein from plasma to interstitial fluid (k_p-if) or its mean residence time in interstitial fluid (MRT_if). To determine these parameters for a pharmacologic dose of exogenous apolipoprotein A-I (apoA-I) given intravenously as apoA-I/lecithin discs, we measured apoA-I in plasma and prenodal leg lymph in five healthy men before, during, and after a 4 h infusion at 10 mg/kg/h. ApoA-I concentrations in plasma and lymph were modeled by linear compartmental models (SAAM II version 1.1), using lymph albumin to adjust for the effects of variations in lymph flow rate. k_p-if averaged 0.75%/h (range, 0.33–1.32), and MRT_if averaged 29.1 h (14.1–40.0). Neither parameter was correlated with the distribution volume (57–105 ml/kg) or the fractional elimination rate (1.44–2.91%/h) of apoA-I, determined by modeling plasma apoA-I concentration alone. Although used here to study the mass kinetics of apoA-I, if combined with infusion of a tracer, analysis of lymph could also expand the modeling of endogenous apolipoprotein kinetics.

Supplementary key words high density lipoprotein • interstitium • lipoprotein • lymph • tissue fluid

Abbreviations: apoA-I, apolipoprotein A-I; IF, interstitial fluid; k_p-if, fractional rate constant for transfer from plasma to interstitial fluid; MRT_if, mean residence time in interstitial fluid

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Apolipoprotein kinetics are customarily determined either by modeling the plasma specific radioactivity-time curve after intravenous injection of radioiodinated lipoprotein or by infusing a stable isotope-enriched amino acid and modeling its appearance in the apolipoprotein in plasma by mass spectrometry. Both procedures have provided much valuable information (1–5). However, a limitation of methods that rely on plasma measurements alone is their inability to provide information on either the fractional rate of transfer of the apolipoprotein across the endothelium from plasma to the interstitial fluid (IF) or its residence time in IF. Such data might improve our understanding of lipoprotein metabolism in the interstitium, such as the oxidative modification of low density lipoproteins (6) and reverse cholesterol transport by HDLs (7). To obtain such information, it is necessary to model changes in both plasma and IF.

We have previously shown that IF can be collected continuously for several days from ambulant humans via a cannula placed in an afferent (prenodal) lymph vessel of the leg (8). We have now applied this technique to study the pharmacokinetics of exogenous apolipoprotein A-I (apoA-I) in IF after intravenous infusion of apoA-I/lecithin discs, a procedure of current interest as a potential new therapy for coronary heart disease (9, 10).

	METHODS

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Subjects
Five healthy men with low-normal plasma total and HDL cholesterol concentrations were studied (Table 1 ). All had undergone physical examination, electrocardiography, routine clinical chemistry and hematology, and screening for recreational drugs. None had evidence of renal, hepatic, endocrine, or cardiovascular disease or of drug abuse. None was taking a special diet or medication. The study had been approved by the relevant ethics committee. All subjects had given written informed consent.

On day 7, at 9:00 AM, a cannula was placed in an antecubital vein for blood sampling and kept patent by intermittent flushing with sterile 0.15 mol/l NaCl. Commencing 1 h later, a 4 h intravenous infusion of apoA-I/lecithin discs (ZLB Behring, Bern, Switzerland) was given via an antecubital vein of the other arm (10 mg apoA-I/kg/h, 0.4 ml/kg/h; total dose, 40 mg/kg) (11). The physical and chemical properties of the discs have been described (11). Every 3 or 4 h thereafter, a 5 ml blood sample was collected into Na₂EDTA (final concentration, 1 mg/ml), and the lymph collection tube was replaced with a new one. This was continued for 72–144 h from the start of the infusion.

Body weights were measured daily and remained essentially constant. No clinical complications developed, and no abnormalities of clinical chemistry or hematology were recorded.

Laboratory procedures
Blood and lymph tubes were kept on ice before centrifugation at 4°C (2,500 g, 20 min). Multiple aliquots of plasma and supernatant lymph were transferred to polypropylene tubes, which were kept at –80°C until analysis. Total lymph volume in each tube was determined by weighing before and after removal of lymph.

Plasma cholesterol and triglycerides were quantified using commercial enzymes (Sigma, Poole, UK) and Trinder-type reagents (Research Organics) in a microtiter plate spectrophotometer (11). Precinorm L® (Boehringer-Mannheim GmBH, Mannheim, Germany) was used as a calibrator. Plasma HDL cholesterol was quantified after precipitation of apoB-containing lipoproteins with polyethylene glycol 6000 [8%, w/v (final concentration)] (11). ApoA-I in plasma and lymph was quantified by rocket immunoelectrophoresis in the presence of polyethylene glycol 6000 (3%, w/v) and Tween 20 (0.2%, w/v) (11). The primary antiserum was goat polyclonal IgGs raised against delipidated human apoA-I (International Immunology Corp.). ApoA-I assays were standardized using dilutions of Precinorm L. Albumin concentrations in plasma and lymph were quantified by immunoelectrophoresis (11). Coefficients of variation for all immunoassays were <10%. Plasma and lymph samples from the same subject were processed together. All assays were done in duplicate, and mean values were calculated.

Data analysis and modeling
The durations of the experiments used for modeling were 192, 124, 156, 192, and 120 h for subjects 1–5, respectively. All modeling was done using the SAAM II program version 1.1 (SAAM Institute, Seattle, WA). It was assumed that the infusion of apoA-I had no effect on endogenous apoA-I synthesis or catabolism and that the kinetics of apoA-I were time-invariant during the study.

First, the changes in plasma apoA-I concentration alone were modeled, as described previously (12), to provide the distribution volume of the infused apoA-I (V) and the fractional rate constant for elimination (k_el). The model is described by the following equations:

where c_P(t) is the plasma apoA-I concentration, c_P0 is the plasma apoA-I concentration before the start of the apoA-I infusion (calculated as the average concentration at –4, –2, and 0 h relative to the start of the infusion), and U(t) is the apoA-I infusion rate. The time origin coincides with the start of the apoA-I infusion.

Second, apoA-I concentrations in plasma and lymph were modeled simultaneously to provide the fractional rate of transfer of apoA-I from plasma to IF (k_p-if) and the mean residence time of apoA-I in IF (MRT_if). ApoA-I concentrations in lymph were adjusted for the effect of variations in lymph flow rate by entering lymph albumin concentration as an independent variable (13). A two-compartment model was used, composed of a single pool for plasma apoA-I and a single pool for IF apoA-I. Transfer from plasma to IF was assumed to be linearly dependent on plasma apoA-I concentration. The disappearance of apoA-I from IF represented its return to plasma and any degradation by peripheral cells. The model is described by the following equations:

where c_l(t) is the apoA-I concentration in lymph, c_L0 is the lymph apoA-I concentration at the start of the experiment, c_P(t) is the plasma apoA-I concentration, c_LC(t) is the lymph apoA-I concentration corrected for lymph flow rate, a(t) is the lymph albumin concentration, a₀ is the average lymph albumin concentration during the experiment, and k_dis is the fractional disappearance rate of apoA-I from IF. The time origin was taken as the first measurement of lymph apoA-I concentration.

The kinetic parameters of exogenous apoA-I were estimated using a nonlinear, weighted, least-squares algorithm. The weight was defined as the reciprocal of the square of the nominal measurement error, with a coefficient of variation of 10%. The precision of the parameter estimates was obtained from the Fisher information matrix and expressed as coefficient of variation (14). For the rate constant for elimination, these were all <18% (mean, 11.4%); for distribution volume, they were <11% (mean, 7.6%); and with one exception (subject 5), they were <35% (mean, 25.0%) for k_p-if and <38% (mean, 25.3%) for MRT_if. In subject 5, precision was 81% for k_p-if and 83% for MRT_if. A value of <100% is regarded as acceptable for such parameter estimates (14).

In addition to calculation of the precision of parameter estimates, model validation included assessment of model fit using a plot of weighted residuals and use of the Runs test to evaluate the random distribution of residuals (14).

	RESULTS

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Plasma apoA-I concentration increased on average by 62.2 mg/dl during the infusion and returned to baseline by 4.5 days (range, 3.0–5.8 days). As in our other studies (11), this was accompanied by rapid but transient increases in plasma HDL unesterified cholesterol and preß apoA-I concentrations and slower increases in plasma HDL cholesteryl ester and apoA-I concentrations (data not shown).

Plasma apoA-I, lymph apoA-I, and lymph albumin concentrations in all subjects are shown in Fig. 1 . Lymph apoA-I/albumin ratios are also shown. As documented previously (13), lymph apoA-I and albumin showed circadian variation, fluctuating inversely with lymph flow rate (i.e., with IF production rate). Average lymph flow rates in subjects 1–5 were 7.4, 24.6, 1.2, 3.4, and 2.5 µl/min, respectively. In the pooled data, flow rate was unaffected by the infusion of discs (ANOVA, P = 0.40). Plasma albumin concentration was also unchanged (data not shown).

View larger version (32K): [in this window] [in a new window]   Fig. 1. Plasma apolipoprotein A-I (apoA-I) concentrations, lymph apoA-I concentrations, lymph albumin concentrations, and lymph apoA-I/albumin ratios in each subject before, during, and after intravenous infusion of apoA-I/lecithin discs (10 mg/kg/h for 4 h). The infusion period is shown by the vertical shaded bars. Plasma albumin concentration was unchanged (not shown).

View larger version (20K): [in this window] [in a new window]   Fig. 2. Weighted residuals (means ± SD) associated with the models of plasma apoA-I and lymph apoA-I kinetics. Weighted residuals have no units.

	DISCUSSION

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In all subjects, lymph apoA-I concentration decreased during the day and increased at night. Such circadian variations occur in all lymph protein concentrations in ambulant subjects, as a consequence of the alterations in lymph flow rate (i.e., IF production rate) that are produced by changes in posture and physical activity (13, 15). The amplitude of the fluctuation varies from protein to protein as a function of molecular size. We have shown that lymph apoA-I concentration can be adjusted for this effect by reference to lymph albumin concentration (13).

Our model assumed that plasma apoA-I and IF apoA-I behave as two distinct pools. Studies of endogenous apoA-I kinetics, involving sampling of plasma alone after infusion of tracers, have also used a two-pool model, assumed to represent intravascular and extravascular compartments (20–25). Although recent work has shown that apoA-I in subclasses of plasma HDLs is actually kinetically heterogeneous, with preß apoA-I turning over faster than apoA-I (26), this is unlikely to have introduced a large error into our estimates, owing to the much greater pool size of apoA-I.

Our model also assumed that the infusion did not perturb the metabolism or kinetics of endogenous apoA-I. There is no evidence that apoA-I synthesis in liver or intestine is affected by plasma apoA-I concentration. It is well documented that the fractional elimination rate and the plasma concentration of apoA-I are negatively correlated (20–25). Although this is owing at least in part to an effect of the former on the latter, the question arises whether a primary increase in concentration decreases the fractional elimination rate. The available evidence suggests that it does not. When Doran (27) infused apoA-I/lecithin discs into rats (n = 10) and dogs (n = 4) at different doses over the ranges 120–600 mg/kg and 100–300 mg/kg, respectively, the fractional elimination rate was unchanged. When we infused the same discs at doses of 25 and 40 mg apoA-I/kg into healthy men with similar baseline apoA-I concentrations (n = 3 and 4, respectively), plasma apoA-I increased by 27 and 52 mg/dl on average, but the concentration decline thereafter was similar visually in the two groups (11). We have now modeled these data using the same modeling procedure used in the present work. The results confirmed that the fractional removal rates did not differ significantly at the two doses (2.48 ± 0.66%/h and 2.64 ± 0.47%/h at the low and high doses, respectively).

On the basis of our current understanding of the mechanisms by which macromolecules cross endothelium from plasma, it is unlikely that the infusion will have altered the fractional rate of transfer of apoA-I to IF. In contrast to small molecules, which cross endothelia bidirectionally by diffusion, proteins move from plasma to IF by convection (solvent drag), as a consequence of the flow of water through pores at cell junctions, and return to plasma exclusively via the lymphatic system (15, 28). As the infusion had no effect on lymph flow rate, there must also have been no effect on water filtration rate. Under such conditions, the flux of a macromolecule to IF is linearly related to its concentration in plasma (15, 28). We have shown that, at a constant flow rate (e.g., samples collected at the same time of day, or under standardized conditions of posture and physical exercise), the concentration of apoA-I in lymph is directly related to its concentration in plasma (8, 13).

Because we have shown that apoA-I/lecithin discs interact with plasma HDLs in vivo to increase the proportion of apoA-I in small preß HDLs and the size of HDLs (11, 29), the question arises whether these changes could have affected the movement of apoA-I across the endothelium. Although this possibility cannot be discounted, any affect is likely to have been small, because the changes in HDL subclasses are relatively short-lived (11). Furthermore, although an increase in the number of preß HDLs (smaller than HDLs) would be expected to increase the rate of transfer of apoA-I across the endothelium, enlargement of HDLs would have the opposite effect.

Our model also assumed that the disappearance of apoA-I from IF represents its return to plasma via lymph plus any degradation by peripheral cells. It is generally accepted that macromolecules return from IF to blood exclusively via the lymphatic system (15, 30), and not via venous capillaries. Degradation of apoA-I by peripheral cells makes a small contribution to total apoA-I catabolism, which occurs mostly in the liver and kidney (31).

Our data are of interest in relation to the use of apoA-I/lecithin discs in the treatment of coronary atherosclerosis (10). In the only clinical trial reported to date (9), apoA-I_Milano/lecithin discs were given at doses of 15 or 45 mg/kg at intervals of 1 week for 5 weeks. To our knowledge, there have been no comparisons of the concentrations of lipoproteins in peripheral tissue IF and artery wall IF in any species. If our present findings are representative of the latter, they suggest that native apoA-I/lecithin discs may need to be given more often than once weekly if they are to expose artery wall cells continuously to significantly increased concentrations of apoA-I. Knowledge of the parameters of apoA-I kinetics in IF could assist the design of alternative therapeutic regimens, as they enable the concentration-time curves in both plasma and IF to be predicted at different doses and infusion rates. For a hypothetical regimen consisting of a priming bolus followed by a constant infusion, Table 3 presents the doses and infusion rates that would maintain 2-fold increases in plasma and IF concentrations in the five subjects, together with the times taken to achieve those concentrations in IF.

The values we obtained for the fractional elimination rate of exogenous apoA-I mass (1.44–2.91%/h) were somewhat greater than most published values for endogenous apoA-I measured using tracers (0.4–1.8%/h) (20–25). It is not clear whether this reflects a difference between exogenous apoA-I and endogenous apoA-I or is attributable to the fact that the plasma HDL concentrations in our subjects were in the low-normal range, which is known to be associated with above-average fractional elimination rates of endogenous apoA-I (20–25).

	ACKNOWLEDGMENTS

 
The clinical and laboratory components of this work were performed at London Bridge Hospital and the Department of Cardiovascular Biochemistry, St. Bartholomew's Hospital Medical College (London), and were funded by the British Heart Foundation. The apoA-I/lecithin discs were provided by ZLB Behring (Bern, Switzerland). The authors thank T. Hovorka for help with data processing.

Manuscript received August 9, 2005 and in revised form November 29, 2005 and in re-revised form January 6, 2006.

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

1. Berman, M. 1979. Kinetic analysis of turnover data. Prog. Biochem. Pharmacol. 15: 67–108.[Medline]

2. Barrett, P. H., and D. M. Foster. 1996. Design and analysis of lipid kinetic studies. Curr. Opin. Lipidol. 7: 143–148.[Medline]

3. Foster, D. M., P. H. Barrett, G. Toffolo, W. F. Beltz, and C. Cobelli. 1993. Estimating the fractional synthetic rate of plasma apolipoproteins and lipids from stable isotope data. J. Lipid Res. 34: 2193–2205.[Abstract]

4. Marsh, J. B., F. K. Welty, and E. J. Schaefer. 2000. Stable isotope turnover of apolipoproteins of high-density lipoproteins in humans. Curr. Opin. Lipidol. 11: 261–266.[CrossRef][Medline]

5. Marsh, J. B., F. Welty, A. H. Lichtenstein, S. Lamon-Fava, and E. J. Schaefer. 2002. Apolipoprotein B metabolism in humans: studies with stable isotope-labeled amino-acid precursors. Atherosclerosis. 162: 227–244.[CrossRef][Medline]

6. Nanjee, M. N., J. Stocks, I. P. Stepanova, C. J. Cooke, W. L. Olszewski, E. Miller, M. I. Mackness, H. Hattori, R. Wilson, R. A. Riemersma, et al. 2000. Oxidative modification of low density lipoproteins in normal peripheral tissue fluid (Abstract). Circulation. 102: II-283.

7. Nanjee, M. N., C. J. Cooke, J. Wong, R. L. Hamilton, W. L. Olszewski, and N. E. Miller. 2001. Composition and ultrastructure of size subclasses of normal human peripheral lymph lipoproteins. Quantification of cholesterol uptake by HDLs in tissue fluids. J. Lipid Res. 42: 639–648.[Abstract/Free Full Text]

8. Nanjee, M. N., C. J. Cooke, W. L. Olszewski, and N. E. Miller. 2000. Lipid and apolipoprotein concentrations in prenodal leg lymph of fasted humans. Associations with plasma concentrations in normal subjects, lipoprotein lipase deficiency, and LCAT deficiency. J. Lipid Res. 41: 1317–1327.[Abstract/Free Full Text]

9. Nissen, S. E., T. Tsunoda, E. M. Tuzcu, P. Schoenhagen, C. J. Cooper, M. Yasin, G. M. Eaton, M. A. Lauer, W. S. Sheldon, C. L. Grines, et al. 2003. Effect of recombinant apoA-I_Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. J. Am. Med. Assoc. 290: 2292–2300.[Abstract/Free Full Text]

10. Miller, N. E., M. N. Nanjee, I. P. Miller, and E. A. Brinton. 2005. Effects of intravenous apoA-I, HDLs and apoA-I/phospholipid discs on vascular metabolism and atherosclerosis in animals and humans. Curr. Med. Chem. 5: 315–320.[CrossRef]

11. Nanjee, M. N., J. E. Doran, P. G. Lerch, and N. E. Miller. 1999. Acute effects of intravenous infusion of apolipoprotein A-I/phosphatidylcholine discs on plasma lipoproteins in humans. Arterioscler. Thromb. Vasc. Biol. 19: 979–989.[Abstract/Free Full Text]

12. Nanjee, M. N., J. R. Crouse, J. M. King, R. Hovorka, S. E. Rees, E. R. Carson, J-J. Morgenthaler, P. Lerch, and N. E. Miller. 1996. Effects of intravenous infusion of lipid-free apoA-I in humans. Arterioscler. Thromb. Vasc. Biol. 16: 1203–1214.[Abstract/Free Full Text]

13. Cooke, C. J., M. N. Nanjee, I. P. Stepanova, W. L. Olszewski, and N. E. Miller. 2004. Variations in lipid and apolipoprotein concentrations in human leg lymph: effects of posture and physical exercise. Atherosclerosis. 173: 39–45.[CrossRef][Medline]

14. Carson, E. R., C. Cobelli, and L. Finkelstein. 1983. The Mathematical Modeling of Metabolic and Endocrine Systems. John Wiley & Sons, New York.

15. Olszewski, W. L., editor. 1991. Lymph Stasis: Pathophysiology, Diagnosis and Treatment. CRC Press, Boston, MA.

16. Rutuli, G., and K-E. Arfors. 1977. Protein concentration in interstitial and lymphatic fluids from the subcutaneous tissue. Acta Physiol. Scand. 99: 1–8.[Medline]

17. Powers, M. R., and D. R. Bell. 1990. Initial equilibration of albumin and IgG in rabbit hind paw skin and lymph. Microvasc. Res. 40: 230–245.[CrossRef][Medline]

18. Engeset, A., M. Aas, W. Olszewski, and J. Sokolowski. 1979. Time of exchange of ¹³¹I-labeled albumin between plasma and peripheral lymph in man. Lymphology. 12: 77–80.[Medline]

19. Bergan, T., A. Engeset, W. Olszewski, N. Østby, and R. Solberg. 1986. Extravascular penetration of highly protein-bound flucloxacillin. Antimicrob. Agents Chemother. 30: 729–732.[Abstract/Free Full Text]

20. Magill, P., S. N. Rao, N. E. Miller, A. Nicoll, J. Brunzell, J. St. Hilaire, and B. Lewis. 1982. Relationships between the metabolism of high-density and very-low-density lipoproteins in men: studies of apolipoprotein kinetics and lipoprotein lipase activity. Eur. J. Clin. Invest. 12: 113–120.[Medline]

21. Brinton, E. A., S. Eisenberg, and J. L. Breslow. 1991. Increased apoA-I and apoA- II fractional catabolic rate in patients with low high density lipoprotein-cholesterol levels with or without hypertriglyceridemia. J. Clin. Invest. 87: 536–544.[Medline]

22. Brinton, E. A., S. Eisenberg, and J. L. Breslow. 1990. A low-fat diet decreases high density lipoprotein cholesterol levels by decreasing HDL apolipoprotein transport rates. J. Clin. Invest. 85: 144–151.[Medline]

23. Brinton, E. A., S. Eisenberg, and J. L. Breslow. 1994. Human HDL cholesterol levels are determined by apoA-I fractional catabolic rate, which correlates inversely with HDL particle size. Arterioscler. Thromb. Vasc. Biol. 14: 707–720.[Abstract/Free Full Text]

24. Gylling, H., G. L. Vega, and S. M. Grundy. 1992. Physiologic mechanisms for reduced apolipoprotein A-I concentrations associated with low levels of high density lipoprotein cholesterol in patients with normal plasma lipids. J. Lipid Res. 33: 1527–1539.[Abstract]

25. Schaefer, E. J., L. A. Zech, L. L. Jenkins, T. J. Bronzert, E. A. Rubalcaba, F. T. Lindgren, R. L. Aamodt, and H. B. Brewer, Jr. 1982. Human apolipoprotein A-I and A-II metabolism. J. Lipid Res. 23: 850–862.[Abstract]

26. Chétiveaux, M., K. Ouguerram, Y. Zair, P. Maugère, I. Falconi, H. Nazih, and M. Krempf. 2004. New model for kinetic studies of HDL metabolism in humans. Eur. J. Clin. Invest. 34: 262–267.[CrossRef][Medline]

27. Doran. J. E. 1998. Investigator's Brochure for Reconstituted High-Density Lipoproteins (rHDL). ZLB Central Laboratory, Blood Transfusion Service SRC, Bern, Switzerland.

28. Michel, C. C. 1996. Transport of macromolecules through microvascular walls. Cardiovasc. Res. 32: 644–653.[CrossRef][Medline]

29. Nanjee, M. N., C. J. Cooke, R. Garvin, F. Semeria, G. Lewis, W. L. Olszewski, and N. E. Miller. 2001. Intravenous apoA-I/lecithin discs increase pre-beta HDL concentration in tissue fluid and stimulate reverse cholesterol transport in humans. J. Lipid Res. 42: 1586–1593.[Abstract/Free Full Text]

30. Szabo, G., E. Anda, and E. Vandor. 1972. The effect of muscle activity on the lymphatic and venous transport of lactate dehydrogenase. Lymphology. 5: 111–114.[Medline]

31. Pittman, R. C., and D. Steinberg. 1984. Sites and mechanisms of uptake and degradation of high density and low density lipoproteins. J. Lipid Res. 25: 1577–1585.[Abstract]

32. Nanjee, M. N., C. J. Cooke, W. L. Olszewski, and N. E. Miller. 1997. Regulation of pre-beta high density lipoproteins in human tissue fluids in vivo (Abstract). Circulation. 96: 1–662.

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This Article Abstract Full Text (PDF) All Versions of this Article: M500358-JLR200v1 47/5/975    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hovorka, R. Articles by Miller, N. E. Search for Related Content PubMed PubMed Citation Articles by Hovorka, R. Articles by Miller, N. E. Social Bookmarking                      What's this?