© 1998 American Heart Association, Inc.
Brief Review |
The Adipocyte, Fatty Acid Trapping, and Atherogenesis
From the Mike Rosenbloom Laboratory for Cardiovascular Research, McGill University, Montreal, Canada (A.D.S., K.C.); Department of Medicine, Huddinge University Hospital, Huddinge, Sweden (P.A.); and The Oxford Lipid Metabolism Group, Sheikh Rashid Laboratory, The Radcliffe Infirmary, Oxford, England (L.K.M.S., K.N.F.).
Correspondence to Allan D. Sniderman, MD, Mike Rosenbloom Laboratory for Cardiovascular Research, Room H7.22, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec H3A 1A1, Canada. E-mail asniderm{at}is.rvh.mcgill.ca
Key Words: ASP • adipose tissue • obesity • atherogenesis • fatty acids
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Introduction |
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 Top Introduction The ASP PathwayThe ASP Pathway and...Clinical Causes of Reduced...References |
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Much effort has been spent to identify the factors that contribute to coronary artery disease. Not surprisingly, adipose tissue has gained little attention to date in this search because no immediate and critical links between adipocyte metabolism and atherogenesis may be evident to most people. But coronary artery disease is a public health problem only in societies with high fatty acid intakes; therefore, our purpose is to outline a hypothesis that adipose tissue dysfunction may be a very common—indeed, perhaps even the most common—cause of the dyslipoproteinemia and insulin resistance that so frequently lead to coronary disease. This complex and multifaceted syndrome has received many names, depending on the original point of interest. Amongst these names are hyperapoB,1 familial combined hyperlipidemia,2 syndrome X,3 the plurimetabolic syndrome,4 the visceral fat syndrome,5 familial dyslipidemic hypertension,6 the atherogenic lipoprotein phenotype,7 and the deadly quartet.8 Whether these titles are different names for the same disorder or different disorders with similar features is not clear; but it is the pathophysiology of their common features on which we will concentrate. Among the most important of these features are increased numbers of the smaller, denser LDL particles, postprandial hyperlipemia, hypertriglyceridemia, low HDL cholesterol, high fasting and postprandial fatty acid levels, and insulin resistance.
Until now, excess release of fatty acids from adipocytes caused by increased lipolysis9 has been the only mechanism suggested to link adipocyte dysfunction and dyslipidemia. In our opinion, although excess lipolysis may be of importance in certain situations, it is not likely to be the sole link between adipose tissue dysfunction and atherosclerosis. The hypothesis that will be outlined herein differs substantially from the current views and is based on the metabolic insights that have been gained from the recent recognition of the ASP pathway.10 Along with insulin, ASP is a principal determinant of the rate of triglyceride synthesis in adipocytes11 and therefore is a principal determinant of the rate of fatty acid uptake or, as we shall describe it herein, fatty acid trapping by adipocytes. In brief, we postulate that failure to trap the normal proportion of dietary fatty acids in adipocytes leads to their abnormal diversion to liver and muscle, and from this abnormal diversion stems the complex array of metabolic alterations listed above that so markedly increase the risk of vascular disease in these patients.
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The ASP Pathway |
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TopIntroductionThe ASP PathwayThe ASP Pathway and...Clinical Causes of Reduced...References |
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To outline our hypothesis, we first must review the major features of the ASP pathway. Adipocytes synthesize triglyceride from the fatty acids delivered to them by the triglyceride-rich lipoproteins, chylomicrons, and VLDL, and the triglyceride in adipocytes constitutes the energy store from which fatty acids are released as needed. Thus, the processes that regulate the rate at which adipocytes store and release energy are of considerable interest. The rate of both of these is determined, in large part, by the ASP pathway, which is constituted as follows. Adipocytes synthesize and secrete the three proteins of the alternate complement pathway: the third component of complement (C3), factor B, and factor D (or adipsin).12 These proteins interact to produce a 77–amino acid fragment of C3, the terminal arginine of which is removed by carboxypeptidases to produce ASP.10 The two most potent in vitro stimulants of triglyceride synthesis in adipocytes are insulin and ASP. Interestingly, the stimulatory effects of ASP are independent of and additive to those of insulin. ASP achieves its effect by increasing the activity of diacylglycerol acyltransferase,13 the last enzyme involved in the synthesis of a triglyceride molecule. ASP also increases specific membrane transport of glucose by stimulating the translocation of glucose transporters from the cytosol to the cell membrane, a mechanism that is identical to but independent of insulin.14 15 16 As human adipocytes differentiate, they develop the capacity to synthesize the precursors of ASP, and as they enlarge, their capacity to synthesize ASP increases in parallel.12 17 Moreover, during differentiation, their capacity to synthesize triglyceride increases, and importantly, so does their response to ASP.17 Adipocytes from obese subjects remain responsive to ASP.18 By contrast, larger adipocytes are less responsive to insulin than smaller ones.19 20 Thus, insulin and ASP share features in common, but they also differ in important aspects.
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The ASP Pathway and Trapping of Fatty Acids by Adipocytes |
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TopIntroductionThe ASP PathwayThe ASP Pathway and...Clinical Causes of Reduced...References |
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To trap dietary fatty acids in adipocytes, two things must happen in sequence (Fig 1
). First, the fatty
acids must be released from chylomicron triglyceride by the
action of LPL.21 Next, and critically, these
fatty acids must be taken up by the adipocyte and incorporated into
triglyceride. The rate at which LPL can hydrolyze
lipoprotein triglycerides is determined, in the first
instance, by the number of active LPL molecules in contact with that
particle, but it is also determined by the rate at which the fatty
acids that are liberated can be removed from the capillary
microenvironment. If they are not (Fig 2), then capillary fatty acid
concentrations will rise abnormally, LPL activity will be product
inhibited,22 and lipolysis will be reduced. In
addition, the chylomicron particles and LPL will be prematurely
detached from the endothelial surface before the normal
amount of triglyceride has been removed from them,
producing a triglyceride-rich chylomicron
remnant.23 24
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Much evidence now exists that the rate at which chylomicron
triglycerides are hydrolyzed is not determined by the mass
of LPL itself, the enzyme under most circumstances being present in
excess of need.25 As the primary determinants of
the rate of adipocyte triglyceride synthesis, ASP and
insulin control the rate at which the fatty acids released from the
chylomicron particle can be trapped by the adipocyte. Fatty acids that
do not enter the adipocyte enter the general circulation, from which
they reach the liver. Chylomicron remnants also are removed by the
liver, the triglyceride they contain contributing to the
hepatic fatty acid flux. There is, therefore, necessarily an inverse
relation between the fatty acids trapped by the adipocyte and the fatty
acids received by the liver and muscle. Under normal circumstances (Fig 1
), approximately half of the fatty acids released from chylomicrons
are trapped immediately by adipocytes, and half enter the general
circulation.26 If fatty acid trapping is reduced
(Fig 2), a smaller proportion of fatty acids from chylomicrons will
enter adipocytes and a larger proportion, as fatty acids or
triglyceride-rich chylomicron remnants, will enter the
systemic circulation again.
All the adverse consequences predicted to occur from decreased fatty
acid trapping by adipocytes have in fact been shown to occur frequently
in patients with increased plasma apo B (Fig 3). Fasting plasma fatty acid levels are
often elevated,27 and postprandially, they often
rise abnormally as well.28 Postprandial plasma
triglyceride clearance is
prolonged,29 and chylomicron remnants accumulate
in plasma.30 VLDL secretion is
increased,31 presumably secondary to increased
delivery of triglyceride-rich remnants and fatty acids to
the liver.32 Because VLDL secretion is increased,
production of LDL particles,33 many
of which are smaller and denser than normal34 due
to increased core lipid exchange, is increased. Increased core lipid
exchange is anticipated from the increased secretion rate of VLDL
particles, the hypertriglyceridemia, and
the increased fatty acid concentrations35 that
are present. Increased cholesterol
ester–triglyceride exchange also may explain why the HDL
cholesterol levels are often reduced as well.
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Insulin resistance is among the most important of the multiple abnormalities in the hyperapoB syndrome.27 Multiple mechanisms might be responsible. Clearest among these are the documented effects of fatty acid on insulin and glucose metabolism. Fatty acids compete with glucose for entry and oxidation by muscle.36 They also impede insulin extraction by the liver37 and stimulate hepatic gluconeogenesis.38 Given the in vitro data that indicate ASP affects glucose transport in skeletal muscle,15 reduced responsiveness to ASP would be expected to reduce both fatty acid and glucose extraction by this tissue. Whatever the exact mechanism(s) responsible, it appears that reduced fatty acid trapping can account for all of the metabolic manifestations of the hyperapoB/insulin resistance syndrome.
In the scenario outlined above, the increased secretion of VLDL particles represents a response of the liver to increased delivery of fatty acids, and although the exact mechanisms governing this response remain to be elucidated in detail, there is, at this point, overwhelming experimental evidence supporting the linkage between increased delivery of fatty acids and increased output of VLDL particles.39 40 It is also important to point out that ASP seems to have little direct effect on the liver,41 indicating that regulation of triglyceride synthesis in liver and adipose tissue is different, and therefore a reduced rate of triglyceride synthesis in peripheral tissues caused by impaired response to ASP does not predict a reduced rate of hepatic triglyceride synthesis.
To be sure, there are many other factors, insulin important among them,42 that influence the rate and composition of apo B-100 particles secreted by the liver that we will not consider here. And we would stress that multiple defects exist, other than reduced fatty acid trapping, that can produce increased secretion of hepatic apo B-100 particles. From a pathophysiological viewpoint, however, it is interesting to note that many of these, along with increased delivery of fatty acids to the liver, share the consequence of increasing the mass of cholesterol ester within the liver, suggesting a final common pathway, at least for this series of disorders, that leads to increased secretion of hepatic apo B-100 particles.43 44
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Clinical Causes of Reduced Fatty Acid Trapping |
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TopIntroductionThe ASP PathwayThe ASP Pathway and...Clinical Causes of Reduced...References |
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Two clinical causes of reduced fatty acid trapping now seem likely. The first is a fault in the ASP receptor, and the second is omental obesity. ASP activates adipocyte triglyceride synthesis secondary to activation of a protein kinase C signal transduction pathway45 after specific interaction with a cell membrane receptor,46 and studies of cultured skin fibroblasts that used radiolabeled ASP in normal subjects have shown that stimulation of triglyceride synthesis is proportionate to specific binding of ASP to cell membrane. Furthermore, such studies have documented substantially reduced specific binding in patients with hyperapoB, resulting in markedly reduced stimulation of triglyceride synthesis.46 Moreover, adipocytes from patients with hyperapoB have reduced rates of triglyceride synthesis compared with adipocytes from normal subjects.47 Taken together, these data point to a defective ASP receptor being present in a substantial proportion of patients with hyperapoB. A defective ASP receptor would result in reduced fatty acid trapping by the adipocyte, and this reduction would result, by the mechanisms outlined above (Figs 2
and 3), in the
abnormalities that characterize the syndrome. Of importance,
Reynisdottir et al48 have now shown that the
alternate hypothesis, namely, increased fatty acid release due to
increased adipocyte lipolysis, does not explain the
metabolic abnormalities in patients with familial combined
hyperlipidemia because their lipolytic responses and
indeed the mass of hormone-sensitive lipase in their adipocytes are
both reduced, not increased. If ASP plays the same role in regulating
reuptake of fatty acids released from adipocytes as it does in
promoting esterification of fatty acids derived from
triglyceride-rich lipoproteins, then decreased
effectiveness of the ASP pathway will result in increased fatty acid
release from adipocytes without any change in intrinsic adipocyte
lipolytic activity. Individuals with omental obesity also frequently manifest all the features of this syndrome, and the pathogenesis in these individuals may follow much the same route. Regional differences in adipocyte function have been documented. Lipolysis seems to be greater in omental than in subcutaneous adipocytes, and this finding would tend to increase fatty acid flux to the liver.49 On the other hand, triglyceride synthesis has also been shown to be less in omental than in subcutaneous adipocytes, and this would result in reduced fatty acid trapping in these cells.50 51 Although the metabolic basis for this reduced triglyceride synthetic capacity remains to be established definitively, if adipocyte fatty acid trapping is reduced, the same broad sequence of metabolic consequences can be anticipated in omental obesity as in ASP receptor–defective hyperapoB.
Is it not, however, a contradiction in terms to hypothesize that
obesity may be associated with impaired triglyceride
synthesis? We would state not, because the distinction must be made
between the short-term and long-term fates of fatty acids that are
ingested or synthesized in excess of metabolic need.
Consider first an obese individual with a normal ASP pathway and
therefore normal fatty acid trapping. As illustrated in Fig 4, after the fat load, the majority of
the dietary fatty acids are trapped in the adipocyte, the mass of these
cells increasing in consequence. However, relatively little of the
dietary fatty acid reaches the liver. After the meal, the needs of
skeletal muscle and other tissues for fatty acids are met primarily by
output of fatty acids from the adipocyte. Output of
triglyceride from the liver in VLDL is modest because
delivery was limited. There is, therefore, a net influx of fatty acids
to adipose tissue during the meal and a net efflux after the meal, the
size of the adipose tissue mass varying as these occur. Nevertheless,
if net intake or synthesis of fatty acids exceeds net oxidation or
incorporation into other biomolecules, adipose tissue mass will
increase because it is the only tissue with the capacity to store
increasing amounts of triglyceride.
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Now consider an obese individual with reduced fatty acid trapping. As
shown in Fig 4, compared with the obesity with normal fatty acid
trapping, less of the dietary fatty acids are immediately deposited
into adipose tissue in the early postprandial period, relatively more
arriving at the liver. Therefore, during this time, adipose tissue
triglyceride mass will increase less than in the obese
individual with normal fatty acid trapping, whereas
triglyceride mass in the liver will increase more than in
the normal individual. During and after the meal, however, VLDL
triglyceride output will be increased to avoid excessive
triglyceride deposition in the liver. Part of this VLDL
triglyceride will be used by muscle, but the excess will be
presented to the adipocyte. VLDL allows, therefore, a second
chance to deposit the fatty acids within the adipocyte. Therefore, just
as in the normal individual, fatty acids in excess of
metabolic need will be deposited in adipose tissue. This
conclusion follows because the ASP pathway and insulin determine the
rate of adipocyte triglyceride synthesis, not whether fatty
acids will eventually be deposited in this tissue. The difference
between normal and reduced fatty acid trapping relates not to the
ultimate destination of the fatty acids but to how many turns of the
metabolic wheel are required for the excess fatty acids to
reach the one site of storage: adipose tissue.
In summary, we present the hypothesis that the adipocyte may play a much larger role in the genesis of the common atherogenic dyslipoproteinemias than previously considered. We specifically postulate that this role relates to reduced fatty acid trapping caused by defective functioning of the ASP pathway. We have focused here on the ASP pathway, but the model of fatty acid trapping will apply also to insulin, whose role in adipose tissue metabolism has been appreciated for much longer. As does ASP, insulin stimulates triglyceride synthesis, and insulin resistance, therefore, will result in decreased fatty acid uptake as well as increased fatty acid release.
Obviously, much remains to be learned about the regulation of fatty acid transport, storage, and utilization, and the hypotheses presented here need to be tested directly. Experiments in appropriate transgenic models are obviously of crucial significance. Nevertheless, the concepts presented fit well, we believe, with the tight epidemiological links between dietary fatty acid intake and the societal incidence of coronary artery disease and provide a framework in which to reconsider old observations, to reevaluate present dogma, and to generate new experimental approaches.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by the Medical Research Council of Canada, The Swedish Medical Research Council, and The British Heart Foundation.
Received April 24, 1997; accepted October 2, 1997.
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C. Verseyden, S. Meijssen, H. van Dijk, H. Jansen, and M. C. Cabezas Effects of atorvastatin on fasting and postprandial complement component 3 response in familial combined hyperlipidemia J. Lipid Res., November 1, 2003; 44(11): 2100 - 2108. [Abstract] [Full Text] [PDF]
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C.J.M. Halkes, H. van Dijk, C. Verseyden, P.P.Th. de Jaegere, H.W.M Plokker, S. Meijssen, D.W. Erkelens, and M. C. Cabezas Gender Differences in Postprandial Ketone Bodies in Normolipidemic Subjects and in Untreated Patients With Familial Combined Hyperlipidemia Arterioscler Thromb Vasc Biol, October 1, 2003; 23(10): 1875 - 1880. [Abstract] [Full Text] [PDF]
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T. M. Wolever and C. Mehling Long-term effect of varying the source or amount of dietary carbohydrate on postprandial plasma glucose, insulin, triacylglycerol, and free fatty acid concentrations in subjects with impaired glucose tolerance Am. J. Clinical Nutrition, March 1, 2003; 77(3): 612 - 621. [Abstract] [Full Text] [PDF]
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 N. Weber, E. Klein, and K. D. Mukherjee Stereospecific Incorporation of Palmitoyl, Oleoyl and Linoleoyl Moieties into Adipose Tissue Triacylglycerols of Rats Results in Constant sn-1:sn-2:sn-3 in Rats Fed Rapeseed, Olive, Conventional or High Oleic Sunflower Oils, but Not in Those Fed Coriander Oil J. Nutr., February 1, 2003; 133(2): 435 - 441. [Abstract] [Full Text] [PDF]
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 K. Evans, G. C. Burdge, S. A. Wootton, M. L. Clark, and K. N. Frayn Regulation of Dietary Fatty Acid Entrapment in Subcutaneous Adipose Tissue and Skeletal Muscle Diabetes, September 1, 2002; 51(9): 2684 - 2690. [Abstract] [Full Text] [PDF]
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 N. Roglans, E. Sanguino, C. Peris, M. Alegret, M. Vazquez, T. Adzet, C. Diaz, G. Hernandez, J. C. Laguna, and R. M. Sanchez Atorvastatin Treatment Induced Peroxisome Proliferator-Activated Receptor alpha Expression and Decreased Plasma Nonesterified Fatty Acids and Liver Triglyceride in Fructose-Fed Rats J. Pharmacol. Exp. Ther., July 1, 2002; 302(1): 232 - 239. [Abstract] [Full Text] [PDF]
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P. M. H. Eurlings, C. J. H. van der Kallen, J. M. W. Geurts, P. Kouwenberg, W. D. Boeckx, and T. W. A. de Bruin Identification of differentially expressed genes in subcutaneous adipose tissue from subjects with familial combined hyperlipidemia J. Lipid Res., June 1, 2002; 43(6): 930 - 935. [Abstract] [Full Text] [PDF]
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S. Meijssen, H. van Dijk, C. Verseyden, D.W. Erkelens, and M. C. Cabezas Delayed and Exaggerated Postprandial Complement Component 3 Response in Familial Combined Hyperlipidemia Arterioscler Thromb Vasc Biol, May 1, 2002; 22(5): 811 - 816. [Abstract] [Full Text] [PDF]
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S. Meijssen, R. J. Derksen, S. Bilecen, D. W. Erkelens, and M. C. Cabezas In Vivo Modulation of Plasma Free Fatty Acids in Patients with Familial Combined Hyperlipidemia Using Lipid-Lowering Medication J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1576 - 1580. [Abstract] [Full Text] [PDF]
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N. Weber, E. Klein, and K. D. Mukherjee The Composition of the Major Molecular Species of Adipose Tissue Triacylglycerols of Rats Reflects Those of Dietary Rapeseed, Olive and Sunflower Oils J. Nutr., April 1, 2002; 132(4): 726 - 732. [Abstract] [Full Text] [PDF]
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C. Verseyden, S. Meijssen, and M. C. Cabezas Postprandial changes of apoB-100 and apoB-48 in TG rich lipoproteins in familial combined hyperlipidemia J. Lipid Res., February 1, 2002; 43(2): 274 - 280. [Abstract] [Full Text] [PDF]
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N. R. Matthan, K. Cianflone, A. H. Lichtenstein, L. M. Ausman, M. Jauhiainen, and P. J. H. Jones Hydrogenated fat consumption affects acylation- stimulating protein levels and cholesterol esterification rates in moderately hypercholesterolemic women J. Lipid Res., November 1, 2001; 42(11): 1841 - 1848. [Abstract] [Full Text] [PDF]
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 A. D. Sniderman, T. Scantlebury, and K. Cianflone Hypertriglyceridemic HyperapoB: The Unappreciated Atherogenic Dyslipoproteinemia in Type 2 Diabetes Mellitus Ann Intern Med, September 18, 2001; 135(6): 447 - 459. [Abstract] [Full Text] [PDF]
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H. A. Koistinen, H. Vidal, S.-L. Karonen, E. Dusserre, P. Vallier, V. A. Koivisto, and P. Ebeling Plasma Acylation Stimulating Protein Concentration and Subcutaneous Adipose Tissue C3 mRNA Expression in Nondiabetic and Type 2 Diabetic Men Arterioscler Thromb Vasc Biol, June 1, 2001; 21(6): 1034 - 1039. [Abstract] [Full Text] [PDF]
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K. Ylitalo, P. Pajukanta, S. Meri, R. M. Cantor, N. Mero-Matikainen, J. Vakkilainen, I. Nuotio, and M.-R. Taskinen Serum C3 but Not Plasma Acylation-Stimulating Protein Is Elevated in Finnish Patients With Familial Combined Hyperlipidemia Arterioscler Thromb Vasc Biol, May 1, 2001; 21(5): 838 - 843. [Abstract] [Full Text] [PDF]
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 A. D. Sniderman, J. Bergeron, and J. Frohlich Apolipoprotein B versus lipoprotein lipids: vital lessons from the AFCAPS/TexCAPS trial Can. Med. Assoc. J., January 1, 2001; 164(1): 44 - 47. [Full Text] [PDF]
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D. Kalant, S. Phélis, B. A. Fielding, K. N. Frayn, K. Cianflone, and A. D. Sniderman Increased postprandial fatty acid trapping in subcutaneous adipose tissue in obese women J. Lipid Res., December 1, 2000; 41(12): 1963 - 1968. [Abstract] [Full Text]
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E. B Tsihlias, A. L Gibbs, M. I McBurney, and T. M. Wolever Comparison of high- and low-glycemic-index breakfast cereals with monounsaturated fat in the long-term dietary management of type 2 diabetes Am. J. Clinical Nutrition, August 1, 2000; 72(2): 439 - 449. [Abstract] [Full Text] [PDF]
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S. Meijssen, M. C. Cabezas, T. B. Twickler, H. Jansen, and D. W. Erkelens In vivo evidence of defective postprandial and postabsorptive free fatty acid metabolism in familial combined hyperlipidemia J. Lipid Res., July 1, 2000; 41(7): 1096 - 1102. [Abstract] [Full Text]
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 J.S. Yudkin Relationship of serum C3 complement with insulin resistance and coronary heart disease--cause, consequence or common antecedent? Eur. Heart J., July 1, 2000; 21(13): 1036 - 1039. [PDF]
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 I. Murray, P. J. Havel, A. D. Sniderman, and K. Cianflone Reduced Body Weight, Adipose Tissue, and Leptin Levels Despite Increased Energy Intake in Female Mice Lacking Acylation-Stimulating Protein Endocrinology, March 1, 2000; 141(3): 1041 - 1049. [Abstract] [Full Text] [PDF]
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J. M. Gill and A. E Hardman Postprandial lipemia: effects of exercise and restriction of energy intake compared1 Am. J. Clinical Nutrition, February 1, 2000; 71(2): 465 - 471. [Abstract] [Full Text] [PDF]
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J. Pihlajamaki, L. Karjalainen, P. Karhapaa, I. Vauhkonen, and M. Laakso Impaired Free Fatty Acid Suppression During Hyperinsulinemia Is a Characteristic Finding in Familial Combined Hyperlipidemia, but Insulin Resistance Is Observed Only in Hypertriglyceridemic Patients Arterioscler Thromb Vasc Biol, January 1, 2000; 20(1): 164 - 170. [Abstract] [Full Text] [PDF]
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 M. Meilinger, C. Gschwentner, I. Burger, M. Haumer, M. Wahrmann, L. Szollar, J. Nimpf, and M. Huettinger Metabolism of Activated Complement Component C3 Is Mediated by the Low Density Lipoprotein Receptor-related Protein/alpha 2-Macroglobulin Receptor J. Biol. Chem., December 31, 1999; 274(53): 38091 - 38096. [Abstract] [Full Text] [PDF]
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L. K. M. Summers, B. A. Fielding, S. L. Herd, V. Ilic, M. L. Clark, P. T. Quinlan, and K. N. Frayn Use of structured triacylglycerols containing predominantly stearic and oleic acids to probe early events in metabolic processing of dietary fat J. Lipid Res., October 1, 1999; 40(10): 1890 - 1898. [Abstract] [Full Text]
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I. Murray, A. D. Sniderman, and K. Cianflone Mice lacking acylation stimulating protein (ASP) have delayed postprandial triglyceride clearance J. Lipid Res., September 1, 1999; 40(9): 1671 - 1676. [Abstract] [Full Text]
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