© 1997 American Heart Association, Inc.
Articles |
Large Versus Small Unilamellar Vesicles Mediate Reverse Cholesterol Transport In Vivo Into Two Distinct Hepatic Metabolic Pools
Implications for the Treatment of Atherosclerosis
From the Department of Biochemistry, Medical College of Pennsylvania, Philadelphia, Pa (W.V.R., K.J.W.); and Vascular and Cardiac Diseases, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co, Ann Arbor, Mich (K.D.M., A.D.E., M.E.P., T.J.R., C.L.B.). Dr Williams is now with the Division of Endocrinology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pa.
Correspondence to Kevin Jon Williams, Division of Endocrinology, Thomas Jefferson University, 1020 Locust St, Suite 349, Philadelphia, PA 19107-6799 or Charles L. Bisgaier, Vascular and Cardiac Diseases, Parke-Davis Pharmaceutical Research, 2800 Plymouth Rd, Ann Arbor, MI 48105 E-mail bisgaic{at}aa.wl.com.
Abstract Phospholipid liposomes are synthetic mediators of
"reverse" cholesterol transport from
peripheral tissue to liver in vivo and can shrink
atherosclerotic lesions in animals. Hepatic disposal of this
cholesterol, however, has not been examined. We compared
hepatic effects of large (
120-nm) and small (35-nm) unilamellar
vesicles (LUVs and SUVs), both of which mediate reverse
cholesterol transport in vivo but were previously shown to
be targeted to different cell types within the liver. On days 1, 3, and
5, rabbits were intravenously injected with 300 mg
phosphatidylcholine (LUVs or SUVs) per kilogram body weight or with the
equivalent volume of saline. After each injection, LUV- and
SUV-injected animals showed large increases in plasma concentrations of
unesterified cholesterol, indicating mobilization of tissue
stores. After hepatic uptake of this cholesterol, however,
SUV-treated animals developed persistently elevated plasma LDL
concentrations, which by day 6 had increased to more than four times
the values in saline-treated controls. In contrast, LUV-treated animals
showed normal LDL levels. By RNase protection assay, SUVs suppressed
hepatic LDL receptor mRNA at day 6 (to 61±4% of control, mean±SEM),
whereas LUVs caused a statistically insignificant stimulation. Hepatic
HMG-CoA reductase message was also significantly suppressed with SUV,
but not LUV treatment, and hepatic 7
-hydroxylase message showed a
similar trend. These data on hepatic mRNA levels indicate that SUVs,
but not LUVs, substantially perturbed liver cholesterol
homeostasis. We conclude that LUVs and SUVs mobilize
peripheral tissue cholesterol and deliver it to
the liver, but to distinct metabolic pools that exert
different regulatory effects. The effects of one of these artificial
particles, SUVs, suggest that reverse cholesterol transport
may not always be benign. In contrast, LUVs may be a suitable
therapeutic agent, because they mobilize peripheral
cholesterol to the liver without suppressing hepatic LDL
receptor mRNA and without provoking a subsequent rise in plasma LDL
levels.
Key Words: atherosclerosis • HDL • gene expression • cholesterol • therapy
This article has been cited by other articles:
 |
|
 |
|
  D. Duffy and D. J. Rader Emerging Therapies Targeting High-Density Lipoprotein Metabolism and Reverse Cholesterol Transport Circulation, February 28, 2006; 113(8): 1140 - 1150. [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. Williams and I. Tabas Lipoprotein Retention--and Clues for Atheroma Regression Arterioscler Thromb Vasc Biol, August 1, 2005; 25(8): 1536 - 1540. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Ballantyne and V. Nambi Apolipoprotein A-I and high-density lipoprotein: Is this the beginning of the era of noninvasive angioplasty? J. Am. Coll. Cardiol., October 6, 2004; 44(7): 1436 - 1438. [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Burgess, J. Boucher, T. A-M. Neville, P. Rouillard, C. Stamler, S. Zachariah, and D. L. Sparks Phosphatidylinositol promotes cholesterol transport and excretion J. Lipid Res., July 1, 2003; 44(7): 1355 - 1363. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Chiesa, E. Monteggia, M. Marchesi, P. Lorenzon, M. Laucello, V. Lorusso, C. Di Mario, E. Karvouni, R. S. Newton, C. L. Bisgaier, et al. Recombinant Apolipoprotein A-IMilano Infusion Into Rabbit Carotid Artery Rapidly Removes Lipid From Fatty Streaks Circ. Res., May 17, 2002; 90(9): 974 - 980. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. T. Thuahnai, S. Lund-Katz, D. L. Williams, and M. C. Phillips Scavenger Receptor Class B, Type I-mediated Uptake of Various Lipids into Cells. INFLUENCE OF THE NATURE OF THE DONOR PARTICLE INTERACTION WITH THE RECEPTOR J. Biol. Chem., November 16, 2001; 276(47): 43801 - 43808. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. K. Shah, S. Kaul, J. Nilsson, and B. Cercek Exploiting the Vascular Protective Effects of High-Density Lipoprotein and its Apolipoproteins: An Idea Whose Time for Testing Is Coming, Part II Circulation, November 13, 2001; 104(20): 2498 - 2502. [Full Text] [PDF]
|
|
|
|
|
|
K. J. Williams, R. Scalia, K. D. Mazany, W. V. Rodrigueza, and A. M. Lefer Rapid Restoration of Normal Endothelial Functions in Genetically Hyperlipidemic Mice by a Synthetic Mediator of Reverse Lipid Transport Arterioscler Thromb Vasc Biol, April 1, 2000; 20(4): 1033 - 1039. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. K. Spady Reverse Cholesterol Transport and Atherosclerosis Regression Circulation, August 10, 1999; 100(6): 576 - 578. [Full Text] [PDF]
|
|
|
|
|
|
M. N. Nanjee, J. E. Doran, P. G. Lerch, and N. E. Miller Acute Effects of Intravenous Infusion of ApoA1/Phosphatidylcholine Discs on Plasma Lipoproteins in Humans Arterioscler Thromb Vasc Biol, April 1, 1999; 19(4): 979 - 989. [Abstract] [Full Text] [PDF]
|
|