Plasma high-density lipoproteins.

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12. Rosenberg SA, Kaplan HS, Glatstein EJ, et al: Combined modality therapy of Hodgkin's disease: a report on the Stanford trials. Cancer 42:991-1000, 1978 13. Portlock CS, Rosenberg SA, Glatstein E, et al: Impact of salvage treatment on initial relapses in patients with Hodgkin disease, Stages I-III. Blood 51:825-833, 1978 14. DeVita VT, Canellos GP, Moxley JH III: A decade of combination chemotherapy of advanced Hodgkin's disease. Cancer. 30:1495-1504, 1972 15. Bonadonna G, Zucali R, Monfardini S, et al: Combination chemotherapy of Hodgkin's disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer 36:252-259, 1975 16. DeVita VT, Lewis BJ, Rozencweig M, et al: The chemotherapy of Hodgkin's disease: past experiences and future directions. Cancer 42:979-990, 1978 17. Bonnadonna G, Fossati V, DeLena M: MOPP-vs-MOPP plus ABVD in Stage IV Hodgkin's disease. Proc Am Assoc Cancer Res Am Soc Clin Oncol 19:363, 1978 18. Frei E III, Luce JK, Gamble JF, et al: Combination chemotherapy of advanced Hodgkin's disease: induction and maintenance of remission. Ann Intern Med 79:376-382, 1973 19. Prosnitz LR, Farber LR, Fisher JJ, et al: Long term remissions with combined modality therapy for advanced Hodgkin's disease. Cancer 37:2826-2833, 1976 20. Goodman R, Mauch P, Piro A, et al: Stage IIB and IIIB Hodgkin's disease: results of combined modality treatment. Cancer 40:84-89, 1977 21. Rosenberg SA, Kaplan HS: The management of Stages I, II, and III Hodgkin's disease with combined radiotherapy and chemotherapy. Cancer 35:55-63, 1975 22. Aisenberg AC: Hematogenous dissemination of Hodgkin's disease. Ann Intern Med 77:810-811, 1972 23. Peters MV: The need for a new clinical classification in Hodgkin's disease. Cancer Res 31:1713-1722, 1971 24. Goodman R, Rosenthal D, Botnick L, et al: Stage IIIA Hodgkin's disease: results of treatment with total nodal irradiation. Proc Am Assoc Cancer Res Am Soc Clin Oncol 18:348, 1977 25. Johnson RE, Zimbler H, Berard CW, et al: Radiotherapy results for nodular sclerosing Hodgkin's disease after clinical staging. Cancer 39:1439-1444, 1977 26. Desser RK, Golomb HM, Ultmann JE, et al: Prognostic classification of Hodgkin disease in pathologic Stage III, based on anatomic considerations. Blood 49:883-893, 1977 27. Fuks Z, Glatstein E, Marsa GW, et al: Long-term effects of external radiation of the pituitary and thyroid glands. Cancer 37:1152-1161, 1976 28. Carmel RJ, Kaplan HS: Mantle irradiation in Hodgkin's disease: an analysis of technique, tumor eradication, and complications. Cancer 37:2813-2825, 1976 29. Hutchison GB: Survival and complications of radiotherapy following involved and extended field therapy of Hodgkin's disease, Stage I and II: a collaborative study. Cancer 38:288-305, 1976 30. Sherins RJ, DeVita VT Jr: Effect of drug treatment for lymphoma on male reproduction capacity: studies of men in remission after therapy. Ann Intern Med 79:216-220, 1973 31. Sweet DL Jr, Roth DG, Desser RK, et al: Avascular necrosis of the femoral head with combination therapy. Ann Intern Med 85:67-68, 1976 32. Coleman CN, Williams CJ, Flint A, et al: Hematologic neoplasia in patients treated for Hodgkin's disease. N Engl J Med 297:1249-1252, 1977 33. Toland DM, Coltman CA Jr: Second malignancies (SM) complicating Hodgkin's disease: the Southwest Oncology Group experience. Proc Am Assoc Cancer Res Am Soc Clin Oncol 18:351, 1977 34. Canellos GP, DeVita VT, Arseneau JC, et al: Second malignancies complicating Hodgkin's disease in remission. Lancet 1:947-949, 1975 35. Weitzman S, Aisenberg AC: Fulminant sepsis after the successful treatment of Hodgkin's disease. Am J Med 62:47-50, 1977 36. Chilcote RR, Baehner RL, Hammond D, et al: Septicemia and meningitis in children splenectomized for Hodgkin's disease. N Engl J Med 295:798-800, 1976 37. Siber GR, Weitzman SA, Aisenberg AC, et al: Impaired antibody response to pneumococcal vaccine after treatment for Hodgkin's disease. N Engl J Med 299:442-448, 1978 38. Selker RG, Jacobs SA, Moore P: Interstitial pulmonary fibrosis as a complication of 1,3-bis-(2-chlorethyl)-1-nitrosourea (BCNU) therapy. Proc Am Assoc Cancer Res Am Soc Clin Oncol 19:333, 1978 39. Stonehill EH: Impact of cancer therapy on survival. Cancer 42:10081014, 1978

Nov. 30, 1978

CURRENT CONCEPTS Plasma High-Density Lipoproteins ALAN R. TALL, M.B., B.S., AND DONALD M. SMALL, M.D. W HY all the recent excitement about highdensity lipoproteins (HDL)? Because of the strong inverse relation between plasma levels of HDL and mortality from cardiovascular disease.1,2 Increased serum levels of HDL protect against atherosclerosis, and decreased levels predispose to it.' In this review, we discuss the measurement and normal levels of HDL, their chemical composition, the properties of the molecules making up HDL and our view of the structure of different HDL particles. The present evidence suggests that HDL or its precursors are produced by both the intestine and the liver. Furthermore, HDL precursors are both directly secreted into plasma and derived from the surface components of chylomicrons and very-low-density lipoproteins (VLDL). We propose a possible molecular mechanism by which HDL precursors can be produced from the surface of chylomicrons or VLDL during their catabolism in peripheral tissue. Finally, we discuss potential clinical implications of enhanced or defective chylomicron and VLDL catabolism. We measure HDL by centrifuging plasma at a density greater than the lipoproteins but less than the other plasma proteins (1.21 g per milliliter). The buoyant lipoprotein fractions are recovered, and the high-density lipoproteins are separated by further centrifugation or by selective precipitation of the nonHDL lipoproteins by means of heparin and manganous chloride. HDL concentrations may be expressed in terms of the total amounts of lipoprotein in milligrams per deciliter, or by the concentration of cholesterol contained in the HDL fraction. The normal quantities for HDL cholesterol are shown in Table 1.4 Men have fairly constant values whereas women appear to reach peak levels in the fifth decade. Women taking estrogens have about 15 per cent higher levels of HDL cholesterol than those on combined estrogen-progesterone therapy or on no medication.5 PROBABLE STRUCTURE OF HDL PARTICLES What are HDL? HDL are very small aggregates of lipids and proteins that circulate in the lymph and blood plasma. To understand their structure and

COMPOSITION

AND

From the Biophysics Division, departments of Medicine and Biochemistry, Boston University School of Medicine, Boston, and Columbia University, College of Physicians and Surgeons and the Presbyterian Hospital in the City- of New York (address reprint requests to Dr. Small at the Biophysics Division, Department of Medicine, Boston University School of Medicine, 80 E. Concord St., Boston, MA 02118). Supported by research grants (HL-18623 and HL-20303) and a training grant (HL-07291) from the U.S. Public Health Service.

The New England Journal of Medicine Downloaded from nejm.org at PENN STATE UNIVERSITY on November 20, 2015. For personal use only. No other uses without permission. From the NEJM Archive. Copyright © 2010 Massachusetts Medical Society. All rights reserved.

Table 1. Normal HDL Cholestei Valus* AGo

CROLUTSIOL VAM;

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NORMALUAN NW/of

yr

54*18 56*13 57*17 65*14'

0.4

.49*13

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51*13

~2MO

106-39 iAft E

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VMEDICAL INTELLIGENCE - TALL AND SMALL

Vol. 299 No. 22

4911 ;

46: 6*1

48*13

-42*8

3070 35480 40-65

3545S 30645 3-70 30-65

30465 3045

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function, we need to understand the properties of the different lipids and proteins that make up HDL. About 90 per cent by weight of the protein of human HDL are the A apoproteins, A-I and A-II. The A-I accounts for 70 per cent of the total protein, and A-II for about 20 per cent; other peptides, called C and E peptides, make up the remaining few per cent. A-I has a molecular weight of about 28,000 whereas A-II and C peptides are smaller. The major lipids of HDL are cholesterol esters, cholesterol and phospholipids, principally lecithin (Fig. 1). Cholesterol esters are completely insoluble in aqueous systems and separate as an oily phase. Both phospholipid and free cholesterol are insoluble in water, but together they form a lamellar structure composed of bilayers of phospholipid and cholesterol separated from each other by layers of water, as shown in Figure 1. Thus, in a pure aqueous system these lipids would separate as large globs of insoluble lamellar or oily structures.6 How, then, are they packaged in HDL as particles so tiny approximately 10 nm (100 A) - that they pass easily from plasma to extracellular fluid? The secret is in the apoproteins. These remarkable peptides are protein detergent molecules capable of solubilizing phospholipids and cholesterol in large quantities. In fact, 1 g of HDL apoprotein, or specifically A-I, can solubilize up to 2.5 g of phospholipid in a disklike micelle.7 Some choje!terol can be dissolved in the phospholipid bilayer (Fig. 1). These structures are analogous to the lecithin-cholesterol-bile-salt micelles found in bile.8 However, in bile the bile salt is the detergent, whereas the apoproteins are the detergent in plasma. Although apoproteins dissolve phospholipids and cholesterol, they do not dissolve pure cholesterol esters. How, therefore, do these insoluble molecules get into HDL? The important studies of Glomset9 and Norum1o on patients with lecithin cholesterol acyltransferase (LCAT) deficiency implicate this enzyme in the production of HDL cholesterol esters. LCAT requires A-I protein as cofactor and catalyzes the reaction leci-

thin + cholesterol -e cholesterol ester + lysolecithin. Patients lacking LCAT have little or no cholesterol esters, and their HDL are discoidal.10 The composition and structure of these disks are quite similar to those of disks formed in vitro by incubation of HDL apoproteins with lecithin and cholesterol (see Fig. 1). Incubation of these discoidal lipoproteins with normal plasma or purified LCAT produces cholesterol esters within the particle and converts the disk to a sphere. The physical properties of the lipids determine this change. Both substrates, lecithin and cholesterol, are present in the bilayer, with their reaction group facing the water (Fig. 1). One of the products, lysolecithin, is removed by binding to plasma albumin. The other product, cholesterol ester, is almost entirely hydrophobic and therefore seeks the only hydrophobic environment available - between the fatty acyl chains of the lecithins. Thus, as cholesterol esters are formed, the lecithin-cholesterol bilayer is split by the intruding esters, and the discoidal particle becomes a sphere. Since the cholesterol leaves the surface as cholesterol ester, more cholesterol can enter the particle and can be converted to cholesterol ester until the available source of HDL lecithin is exhausted. The HDL particles isolated from normal plasma are the spherical cholesterol-ester-containing particles. The preponderance of discoidal HDL in LCAT-deficient patients10 indicates that spherical cholesterol-estercontaining HDL are not directly secreted but are T

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Figure 1. Lamellar Bilayered Structures, the LCAT Reaction and Spherical Plasma HDL. Above, the different molecules in HDL are shown. Left, phospholipids, such as lecithin and free cholesterol, form lamellar bilayers in aqueous systems, which, in the presence of apo A-I or apo A-Il, form small disklike complexes. The apoproteins surround the hydrophobic parts of the phospholipids to render the whole complex soluble. These discoidal apoprotein-lecithin-cholesterol complexes are good substrates for the LCAT reaction, in which cholesterol and lecithin are converted to cholesterol ester and lysolecithin. In the plasma, the lysolecithin formed by the reaction is removed from the particle surface by albumin, whereas the cholesterol ester is insoluble in the interface and partitions into the oily parts of the particle. As the reaction proceeds, the discoidal particle becomes a sphere with a cholesterol ester core. Such spherical particles are consistent with the structure of circulating plasma HDL.


1234


probably derived from the discoidal apoprotein-lecithin-cholesterol precursors by the action of LCAT.10

Nov. 30, 1978

previous observations made in man that HDL phospholipid rises after fat ingestion.18 Although the case for VLDL is not as clear as that for chylomicrons, C peptides are transferred to HDL during VLDL catabolism,'9 and in vitro lipolysis of VLDL leads to transfer of phospholipid into HDL.20

PROBABLE SOURCES OF PLASMA HDL If spherical HDL found in normal plasma are derived from lecithin and cholesterol present in bilayers or discoidal aggregates, where are these biA POSSIBLE MECHANISM FOR FORMATION OF HDL layered precursors produced? HDL precursors appear PRECURSORS FROM THE SURFACE OF CHYLOMICRONS to come from two sources: from direct secretion of disOR VLDL coidal HDL from liver and intestine into plasma or We can suggest a molecular mechanism for the forlymph; and from the surface components of triglyceride-rich lipoproteins such as chylomicrons. In the rat, mation of bilayered HDL precursors from the surface discoidal HDL is produced by perfused liver" and of triglyceride-rich particles, such as chylomicrons small intestine.'2 The intestine can synthesize A pep- and VLDL, because of the following facts. As noted tides,13 and intestinal lymph contains discoidal HDL above, phospholipids and some soluble apoproteins rich in apo-A peptides and lecithin but poor in cho- are transferred en masse from chylomicrons to HDL lesterol and its esters.'2 The quantity of discoidal in vivo. Lipolysis of VLDL in the perfused rat heart HDL secreted into the lymph appears to depend on leads to formation of a discoidal HDL particle conwhat is in the digestive tract; however, specific details taining the VLDL phospholipid and VLDL C-apoof how diet affects apoprotein synthesis and intestinal proteins.20 Selective delipidation of the chylomicron core in vitro causes the surface components to form HDL secretion are needed. Chylomicrons from the intestine and VLDL from phospholipid-cholesterol-A-protein lamellar aggrethe liver are triglyceride-transporting emulsion parti- gates appearing as bilayered phospholipid vesicles; cles, stabilized by a monomolecular surface film of similar vesicles appear in the HDL fraction after inphospholipid, apoproteins and a small amount of travenous injection of chylomicrons in the rat.21 Folds cholesterol. The core contains triglyceride, choles- of lipid bilayer have been observed to arise from the terol esters and some of the free cholesterol. Chylomi- surface of chylomicrons during in vitro lipolysis.22 crons and VLDL are partially degraded in skeletal Finally, lipoprotein lipase leads to selective removal of muscle, adipose tissue and other tissues by lipopro- triglyceride from chylomicrons and VLDL that causes tein lipase, an enzyme on the capillary endothelium. shrinkage of the lipoprotein core.14 Figure 2 shows the Lipoprotein lipase selectively hydrolyzes the lipopro-- probable result: shrinkage causes redundance of the tein triglyceride, forming monoglyceride and fatty polar surface constituents - phospholipids, unesteriacid that are partly taken up by the tissues and partly fied cholesterol, and apoproteins. The increase in removed by albumin. As triglyceride is removed, the lateral pressure occurring in the surface of the partichylomicron shrinks and is released back into the cir- cle causes the monolayer to fold into bilayers that proculation as a remnant particle that is rapidly removed trude from the particle surface. Some of the bilayer may be dissolved as discoidal micelles in association by the liver."4 During the transformation of chylomicron to rem- with the detergent A or C apoproteins present in chynant not only triglyceride but also soluble apopro- lomicron surface. However, since there are not enough teins (A + C) and phospholipids are lost from the A or C apoproteins to convert all the bilayer to disks, chylomicrons and are rapidly transferred into the most of the bilayer fragments probably leave the surplasma HDL fraction. Fresh chylomicrons isolated face as larger sheets that can seal into phospholipid from intestinal lymph contain appreciable amounts of vesicles (hollow spheres). Subsequently, these sheets A-apoproteins.1' Fat feeding causes increased intesti- and vesicles are converted into spherical HDL by the nal mucosal synthesis of A peptides, increased forma- interaction with the circulating pool of HDL and the tion of chylomicrons and a subsequent rise in plasma action of LCAT. Since apo A-I is loosely integrated into the spherical apoA-I levels'5; however, chylomicrons allowed to circulate in the plasma for a short time contained no HDL particle,23 plasma HDL can act as a source of apoA-I, implying rapid transfer of chylomicron apo A-I. Intact HDL releases part of its apo A-I when apoA-I mass into HDL. In man, >90 per cent of incubated with model phospholipid membranes24 or labeled A peptides of chylomicrons were found in vesicles and leads to the formation of soluble discoiHDL one hour after intravenous injection,'6 and in the dal phospholipid-apoprotein complexes. Thus, the inrat a similar transfer of radioactivity of newly syn- corporation of chylomicron-derived phospholipid into thesized chylomicron-soluble apoproteins (mainly A HDL probably depends on the pre-existing pool of apo A-I in the circulating spherical plasma HDL. As a peptides) to HDL was found in 30 minutes." The transfer of soluble peptides from chylomicrons consequence of losing some of its emulsifier, apo A-I, to HDL is paralleled by a similar rapid transfer of the spherical HDL particle becomes thermodynamiphospholipid in the rat." This transfer may explain cally unstable and could fuse with another lipopro-


Vol. 299 No. 22

MEDICAL INTELLIGENCE - TALL AND SMALL -

d

M_

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lowm

Figure 2. Possible Mechanism for the Transfer of Surface Compoments from Chylomicrons to HDL Fraction during Lipolysis of Chylomicron. Lipoprotein lipase situated in the capillary endothelium hydrolyzes chylomicron triglyceride (lower left). The surface of the chylomicron contains phospholipids, free cholesterol, soluble A and C apoproteins (shown as hatched bodies) and apo B protein (labeled B). In 1, as triglyceride is removed, during lipolysis, the core shrinks, and the redundant surface constituents form lipid bilayer folds projecting from the chylomicron. In 2, a disklike particle could be formed directly from the apoprotein and phospholipids of the surface of the chylomicron. In 3, however, most of the excess material probably comes off as unstable bilayered sheets. In 4, these sheets seal to form vesicles - a more stable form of the bilayer. In 5, the circulating spherical high-density lipoprotein may interact with any of these bilayered lamellar structures (redundant folds, sheets or vesicles), donating A-I apoprotein. In 6, any of these bilayered fragments (sheets, vesicles or disks) are good substrates for the LCAT reaction if some A-I apoprotein is present. Thus, the pool of high-density lipoprotein helps to convert the bilayer fragments to new spherical high-density lipoprotein. In 7, however, the apo A-I-depleted spherical HDL has lost a large fraction of its surface and is thus unstable. Such particles could potentially fuse with various other lipoproteins disgorging their cholesterol ester core into such particles. In 8, if fusion occurred with the chylomicron, cholesterol esters, originally present in the circulating HDL, could be transported back to the liver in the remnant,

tein.24 Since chylomicron remnants are avidly taken up by the liver25 their fusion with unstable HDL could provide a possible route for transfer of HDL cholesterol ester to the liver. During the transformation of precursor particles into spherical HDL there is probably a large influx of cholesterol into the HDL fraction. The driving force in this input is the relative deficiency of cholesterol in the chylomicron surface and in the chylomicron-derived precursors of HDL13"17 as compared to other circulating lipoproteins and cellular elements, which would result in a chemical gradient for movement of cholesterol into HDL precursors. The LCAT reaction would gradually transform this free cholesterol into esters and thus form spherical HDL (Fig. 1). An unsolved problem is the metabolic fate of HDL cholesterol ester. If some is transferred to larger lipoproteins by

fusion mechanisms, as suggested above, or by way of a specific cholesterol ester-triglyceride exchange protein,26 HDL could protect against atherosclerosis by providing a mechanism for transfer of cholesterol from the tissues to the liver.8 However, HDL may simply transport cholesterol from one tissue to the other. In fact, the exact metabolic link between HDL and atherosclerosis is not yet clearly understood. HDL FORMATION IN HEALTH AND DISEASE Since HDL can be formed as a result of lipolysis, HDL formation is probably accelerated when increased flux of triglyceride-carrying lipoproteins is associated with normal or enhanced lipoprotein lipase activity. For example, increased VLDL flux and normal lipase activity occur with alcohol consumption


1236


and are associated with increased HDL concentration.27 Exercise results in increased triglyceride extraction from chylomicrons that is probably associated with increased lipoprotein lipase activity and exercise-increased HDL levels. Since insulin stimulates lipoprotein lipase, diabetic patients receiving adequate insulin therapy should have higher lipoprotein lipase activity and increased levels of HDL as compared to diabetic patients receiving inadequate insulin. Conversely, impaired peripheral catabolism of triglyceride-rich lipoproteins may cause a partial block in HDL formation. In some hypertriglyceridemic patients (for example, those with congenital deficiency of lipoprotein lipase4 or uremic patients with deficient hepatic lipase25), accumulation of triglyceride-carrying lipoproteins reflects defective lipoprotein catabolism and is associated with low HDL. In the future, it may be possible to influence HDL levels by altering production of HDL derived by lipolysis. Drugs such as heparin might increase the rate of chylomicron hydrolysis and lead to increases in HDL. In addition, since the small intestine is a source of HDL components, modifications of diet or the enterohepatic circulation may affect HDL production. For instance, if the diet could be modified so that more phospholipids and HDL apoproteins were secreted on chylomicrons, increased levels of chylomicron-derived HDL precursors might be produced, leading to increased levels of circulating HDL. Since interventions that increase HDL levels cannot yet be equated with protection against atherosclerosis, there will be a need for prospective studies evaluating the effect of such interventions on atherosclerotic vascular disease. REFERENCES 1. Barr DP, Russ EM, Eder HA: Protein-lipid relationships in human plasma. II. In atherosclerosis and related conditions. Am J Med 11:480-

493, 1951 2. Miller GJ, Miller NE: Plasma-high-density-lipoprotein concentration and development of ischaemic heart-disease. Lancet 1:16-19, 1975 3. Rhoads GG, Gulbrandsen CL, Kagan A: Serum lipoproteins and coronary heart disease in a population study of Hawaii Japanese men. N Engl J Med 294:293-298, 1976 4. Fredrickson D, Goldstein JL, Brown MS: The familial hyperlipoproteinemias, The Metabolic Basis of Inherited Disease. Edited by JB Stanbury, JB Wyngaarden, DS Fredrickson. New York, McGraw-Hill, 1978, pp 604-655

Nov. 30, 1978

5. Cheung MC, Albers JJ: The measurement of apolipoprotein A-I and AII levels in men and women by immunoassay. J Clin Invest 60:43-50, 1977 6. Small M, Shipley GG: Physical-chemical basis of lipid deposition in atherosclerosis. Science 185:222-229, 1974 7. Tall AR, Small DM, Deckelbaum RJ, et al: Structure and thermodynamic properties of high density lipoprotein recombinants. J Biol Chem 252:4701-4711, 1977 8. Small DM: Eppinger Prize Lecture. II. Bile salts of the blood: high density lipoprotein systems and cholesterol removal, Proceedings of the Fourth International Congress on Liver and Bile. Edited by L Bianchi. Lancaster, England, MTP Press, 1977, pp 89-99 9. Glomset JA: The plasma lecithin:cholesterol acyltransferase reaction. J Lipid Res 9:155-167, 1968 10. Forte T, Norum KR, Glomset JA, et al: Plasma lipoproteins in familial lecithin:cholesterol acyltransferase deficiency: structure of low and high density lipoproteins as revealed by electron microscopy. J Clin Invest 50:1141-1148, 1971 11. Hamilton RL, Williams MC, Fielding CT, et al: Discoidal bilayer structure of nascent high density lipoproteins from perfused rat liver. J Clin Invest 58:667-680, 1976 12. Green PHR, Tall AR, Glickman RM: Rat intestine secretes discoid high density lipoprotein. J Clin Invest 61:528-534, 1978 13. Glickman RM, Green PHR: The intestine as a source of apolipoprotein A'. Proc Natl Acad Sci USA 74:2569-2573, 1977 14. Redgrave TG: Formation of cholesterol ester-rich particulate lipid during metabolism of chylomicrons. J Clin Invest 49:465-471, 1970 15. Glickman RM, Green PHR, Lees RS, et al: Apoprotein A-I synthesis in normal intestinal mucosa and in Tangier disease. N Engl J Med (in press) 16. Schaefer EJ, Jenkins LL, Brewer BB Jr: Human chylomicron apolipoprotein metabolism. Biochem Biophys Res Commun 80:405-412, 1978 17. Redgrave TG, Small DM: Transfer of surface components of chylomicrons to the high density lipoprotein fraction during chylomicron catabolism in the rat. Circulation 58:Suppi 2:11-14, 1978 18. Havel RJ: Early effects of fat ingestion on lipids and lipoproteins of serum in man. J Clin Invest 36:848-854, 1957 19. Havel RJ, Kane JP, Kashyap ML: Interchange of apolipoproteins between chylomicrons and high density lipoproteins during alimentary lipemia in man. J Clin Invest 52:32-38, 1973 20. Chajek T, Eisenberg S: Very low density lipoproteins: metabolism of phospholipids, cholesterol and apolipoprotein C in the isolated perfused rat heart. J Clin Invest 62:1654-1665, 1978 21. Tall AR, Green PHR, Abreu E, et al: Formation of high density lipoproteins from chylomicrons. Circulation 58:Suppl 2:11-15, 1978 22. Blanchette-Mackie EJ, Scow RO: Retention of lipolytic products in chylomicrons incubated with lipoprotein lipase: electron microscopy study. J Lipid Res 17:57-67, 1976 23. Tall AR, Deckelbaum RJ, Small DM, et al: Thermal behavior of human plasma high density lipoprotein. Biochim Biophys Acta 487:145-153, 1977 24. Tall AR, Hogan V, Askinazi L, et al: Interaction of plasma high density lipoproteins with dimyristoyl-lecithin multilamellar liposomes. Biochemistry 17:322-326, 1978 25. Andersen JM, Nervi FO, Dietschy JM: Rate constants for the uptake of cholesterol from various intestinal and serum lipoprotein fractions by the liver of the rat in vivo. Biochim Biophys Acta 486:298-307, 1977 26. Chajek T, Fielding CJ: Isolation and characterization of a human serum cholesteryl ester transfer protein. Proc Natl Acad Sci USA 75:3445-3449, 1978 27. Wilson DE, Schreibman PH, Brewster AC, et al: The enhancement of alimentary lipemia by ethanol in man. J Lab Clin Med 75:264-274, 1970 28. Mordasini R, Frey F, Flury W, et al: Selective deficiency of hepatic triglyceride lipase in uremic patients. N Engl J Med 297:1362-1366, 1977


Plasma lipoproteins mediate platelet adhesion.

Alcohol consumption and plasma lipoproteins.

Alcohol consumption and plasma lipoproteins.

Plasma lipoproteins in renal transplant patients.

The plasma lipoproteins: structure and metabolism.

Hepatic clearance of plasma low density lipoproteins.

Plasma lipoproteins in familial hepatic lipase deficiency.

Plasma lipoproteins in renal transplant patients.

Plasma lipids and lipoproteins in liver disease.

Swine lipoproteins and atherosclerosis. Changes in the plasma lipoproteins and apoproteins induced by cholesterol feeding.

Plasma distribution of cyclosporine within lipoproteins and "in vitro" transfer between very-low-density lipoproteins, low-density lipoproteins, and high-density lipoproteins.

Amphipathic helixes and plasma lipoproteins: a computer study.

Plasma lipids and lipoproteins in young patients with brain infarction.

Thermal transitions in human plasma low density lipoproteins.

The effect of hypolipidemic drugs on plasma lipoproteins.

The significance of plasma lipoproteins on erythrocyte aggregation and sedimentation.

Separation of plasma lipoproteins with a tabletop ultracentrifuge.

Distribution of FK 506 in plasma lipoproteins in transplant patients.

Plasma lipids, lipoproteins and apolipoproteins in two kindreds of hypobetalipoproteinemia.

Controlled storage of biological energy: The role of plasma lipoproteins.

Plasma lipoproteins, lipid transport, and atherosclerosis: recent developments.

A modified method for preparative ultracentrifugation of plasma lipoproteins.

Oxidative stress and plasma lipoproteins in cancer patients.

Characterization of the apolipoproteins of rat plasma lipoproteins.