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• W2009013500 abstract "LDLs in humans comprise multiple distinct subspecies that differ in their metabolic behavior and pathologic roles. Metabolic turnover studies suggest that this heterogeneity results from multiple pathways, including catabolism of different VLDL and IDL precursors, metabolic remodeling, and direct production. A common lipoprotein profile designated atherogenic lipoprotein phenotype is characterized by a predominance of small dense LDL particles. Multiple features of this phenotype, including increased levels of triglyceride rich lipoprotein remnants and IDLs, reduced levels of HDL and an association with insulin resistance, contribute to increased risk for coronary heart disease compared with individuals with a predominance of larger LDL. Increased atherogenic potential of small dense LDL is suggested by greater propensity for transport into the subendothelial space, increased binding to arterial proteoglycans, and susceptibility to oxidative modification. Large LDL particles also can be associated with increased coronary disease risk, particularly in the setting of normal or low triglyceride levels. Like small LDL, large LDL exhibits reduced LDL receptor affinity compared with intermediate sized LDL.Future delineation of the determinants of heterogeneity of LDL and other apoB-containing lipoproteins may contribute to improved identification and management of patients at high risk for atherosclerotic disease. LDLs in humans comprise multiple distinct subspecies that differ in their metabolic behavior and pathologic roles. Metabolic turnover studies suggest that this heterogeneity results from multiple pathways, including catabolism of different VLDL and IDL precursors, metabolic remodeling, and direct production. A common lipoprotein profile designated atherogenic lipoprotein phenotype is characterized by a predominance of small dense LDL particles. Multiple features of this phenotype, including increased levels of triglyceride rich lipoprotein remnants and IDLs, reduced levels of HDL and an association with insulin resistance, contribute to increased risk for coronary heart disease compared with individuals with a predominance of larger LDL. Increased atherogenic potential of small dense LDL is suggested by greater propensity for transport into the subendothelial space, increased binding to arterial proteoglycans, and susceptibility to oxidative modification. Large LDL particles also can be associated with increased coronary disease risk, particularly in the setting of normal or low triglyceride levels. Like small LDL, large LDL exhibits reduced LDL receptor affinity compared with intermediate sized LDL. Future delineation of the determinants of heterogeneity of LDL and other apoB-containing lipoproteins may contribute to improved identification and management of patients at high risk for atherosclerotic disease. Distinct VLDL, IDL, and LDL subpopulations have been identified and defined on the basis of a number of characteristics, including particle buoyant density, size, charge, and lipid and apolipoprotein content [reviewed in (1Krauss R.M. Physical heterogeneity of apolipoprotein B-containing lipoproteins.in: Lippel K. Proceedings of the Workshop on Lipoprotein Heterogeneity. US Govt. Printing Office, Washington, D.C.1987: 15-21Google Scholar, 2Krauss R.M. Relationship of intermediate and low-density lipoprotein subspecies to risk of coronary artery disease.Am. Heart J. 1987; 113: 578-582Google Scholar, 3Alaupovic P. The lipoprotein family concept and its clinical significance.Nutr. Metab. Cardiovasc. Dis. 1992; 2: 52-59Google Scholar)] (Table 1). In normolipidemic humans there are at least two physically distinct species of VLDL: larger VLDL (VLDL-1, Sf 60–400), and smaller (VLDL-2, Sf 20–60), as well as two subspecies of IDL (1Krauss R.M. Physical heterogeneity of apolipoprotein B-containing lipoproteins.in: Lippel K. Proceedings of the Workshop on Lipoprotein Heterogeneity. US Govt. Printing Office, Washington, D.C.1987: 15-21Google Scholar, 2Krauss R.M. Relationship of intermediate and low-density lipoprotein subspecies to risk of coronary artery disease.Am. Heart J. 1987; 113: 578-582Google Scholar, 4Musliner T.A. Giotas C. Krauss R.M. Presence of multiple subpopulations of lipoproteins of intermediate density in normal subjects.Arteriosclerosis. 1986; 6: 79-87Google Scholar, 5Meyer B.J. Caslake M.J. McConnell M.M. Packard C.J. Two subpopulations of intermediate density lipoprotein and their relationship to plasma triglyceride and cholesterol levels.Atherosclerosis. 2000; 153: 355-362Google Scholar). The larger form of IDL, designated IDL-1, appears to form a continuum with VLDL-2, such that together, these represent a spectrum of particles of SF 14–60 and d < 1.010 g/ml (1Krauss R.M. Physical heterogeneity of apolipoprotein B-containing lipoproteins.in: Lippel K. Proceedings of the Workshop on Lipoprotein Heterogeneity. US Govt. Printing Office, Washington, D.C.1987: 15-21Google Scholar). Most of the differences in size among VLDL and IDL are due to the esterified lipid core since the phospholipid/cholesterol/apolipoprotein coat is of constant thickness in these lipoproteins (6Packard C.J. Shepherd J. Joerns S. Gotto Jr., A.M. Taunton O.D. Very low density and low density lipoprotein subfractions in type III and type IV hyperlipoproteinemia. Chemical and physical properties.Biochim. Biophys. Acta. 1979; 572: 269-282Google Scholar, 7Sata T. Havel R.J. Jones A.L. Characterization of subfractions of triglyceride-rich lipoproteins separated by gel chromatography from blood plasma of normolipemic and hyperlipemic humans.J. Lipid Res. 1972; 13: 757-768Google Scholar). Compared with larger VLDL, smaller VLDL and IDL are enriched in cholesteryl ester, depleted in triglyceride, and have a lower ratio of apoE and apoC to apoB (6Packard C.J. Shepherd J. Joerns S. Gotto Jr., A.M. Taunton O.D. Very low density and low density lipoprotein subfractions in type III and type IV hyperlipoproteinemia. Chemical and physical properties.Biochim. Biophys. Acta. 1979; 572: 269-282Google Scholar, 7Sata T. Havel R.J. Jones A.L. Characterization of subfractions of triglyceride-rich lipoproteins separated by gel chromatography from blood plasma of normolipemic and hyperlipemic humans.J. Lipid Res. 1972; 13: 757-768Google Scholar).TABLE 1Physicochemical properties of apolipoprotein B containing lipoproteins subspeciesPeak SfDensity Peak (gm/ml)Diameter (Å)%PR%CE%UC%TG%PLVLDL (4)VLDL-160–400<1.006330–70011865817VLDL-220–601.006–1.010300–330182492922IDL (4)IDL 112–201.008–1.022285–3001735101621IDL 210–161.013–1.019272–2851737111321LDL (11, 12, 127)LDL-I7–121.019–1.023272–28518439722LDL-II5–71.023–1.028265–2721945104231.028–1.034256–26521459322LDL-III3–51.034–1.041247–256224683211.041–1.044242–24724447321LDL-IV0–31.044–1.051233–242264275191.051–1.06220–23329407618PR, protein; TG, triglycerides; CE, cholesteryl ester; PL, phospholipids; UC, unesterified cholesterol. Open table in a new tab PR, protein; TG, triglycerides; CE, cholesteryl ester; PL, phospholipids; UC, unesterified cholesterol. Nondenaturing gradient gel electrophoresis has identified as many as seven distinct subspecies of LDL (8Krauss R. Burke D. Identification of multiple subclasses of plasma low density lipoproteins in normal humans.J. Lipid Res. 1982; 23: 97-104Google Scholar, 9McNamara J.R. Campos H. Ordovas J.M. Peterson J. Wilson P.W. Schaefer E.J. Effect of gender, age, and lipid status on low density lipoprotein subfraction distribution. Results from the Framingham Offspring Study.Arteriosclerosis. 1987; 7: 483-490Google Scholar) that have been grouped, based on density, into four major subclasses designated LDL-I through -IV, from the largest, most buoyant to the smallest, most dense (1Krauss R.M. Physical heterogeneity of apolipoprotein B-containing lipoproteins.in: Lippel K. Proceedings of the Workshop on Lipoprotein Heterogeneity. US Govt. Printing Office, Washington, D.C.1987: 15-21Google Scholar, 2Krauss R.M. Relationship of intermediate and low-density lipoprotein subspecies to risk of coronary artery disease.Am. Heart J. 1987; 113: 578-582Google Scholar, 8Krauss R. Burke D. Identification of multiple subclasses of plasma low density lipoproteins in normal humans.J. Lipid Res. 1982; 23: 97-104Google Scholar). Therefore LDL do not comprise a population of particles with a continuously variable size, but there are a number of subclasses of particles with relatively discrete size and density. Subspeciation of LDL particles appears to involve differences in surface lipid content and conformational changes in apoB-100, including increased exposure on the particle surface (10Segrest J.P. Jones M.K. De Loof H. Dashti N. Structure of apolipoprotein B-100 in low density lipoproteins.J. Lipid Res. 2001; 42: 1346-1367Google Scholar). Features of apoB structure that may contribute to stepwise change in LDL particle diameters have been described recently (10Segrest J.P. Jones M.K. De Loof H. Dashti N. Structure of apolipoprotein B-100 in low density lipoproteins.J. Lipid Res. 2001; 42: 1346-1367Google Scholar). Mass concentrations of subfractions across the VLDL-IDL-LDL spectrum can be determined by chromatographic and ultracentrifugal techniques (1Krauss R.M. Physical heterogeneity of apolipoprotein B-containing lipoproteins.in: Lippel K. Proceedings of the Workshop on Lipoprotein Heterogeneity. US Govt. Printing Office, Washington, D.C.1987: 15-21Google Scholar, 2Krauss R.M. Relationship of intermediate and low-density lipoprotein subspecies to risk of coronary artery disease.Am. Heart J. 1987; 113: 578-582Google Scholar, 11Swinkels D.W. Hak-Lemmers H.L. Demacker P.N. Single spin density gradient ultracentrifugation method for the detection and isolation of light and heavy low density lipoprotein subfractions.J. Lipid Res. 1987; 28: 1233-1239Google Scholar, 12Krauss R.M. Blanche P.J. Detection and quantification of LDL subfractions.Curr. Opin. Lipidol. 1992; 3: 377-383Google Scholar). In addition, methods have been described for evaluating size distribution of apoB containing lipoproteins by NMR spectroscopy (13Otvos J.D. Jeyarajah E.J. Bennett D.W. Krauss R.M. Development of a proton nuclear magnetic resonance spectroscopic method for determining plasma lipoprotein concentrations and subspecies distributions from a single, rapid measurement.Clin. Chem. 1992; 38: 1632-1638Google Scholar). Subspeciation of apoB-100-containing particles also has been described as a function of differing content of other apolipoproteins (3Alaupovic P. The lipoprotein family concept and its clinical significance.Nutr. Metab. Cardiovasc. Dis. 1992; 2: 52-59Google Scholar). In plasma of normolipidemic subjects, the most abundant particles contain only apoB-100 with lesser concentrations of particles containing apoB-100 in conjunction with apoC-III and apoE, singly and in combination (14Alaupovic P. Apolipoprotein composition as the basis for classifying plasma lipoproteins. Characterization of ApoA- and ApoB-containing lipoprotein families.Prog. Lipid Res. 1991; 30: 105-138Google Scholar, 15Kandoussi A. Cachera C. Parsy D. Bard J.M. Fruchart J.C. Quantitative determination of different apolipoprotein B containing lipoproteins by an enzyme linked immunosorbent assay: apoB with apoC-III and apoB with apoE.J. Immunoassay. 1991; 12: 305-323Google Scholar). ApoB only particles are most commonly found in LDL, whereas most particles with apoC-III and apoE are triglyceride-rich particles. There is, however, evidence for the presence of these apolipoproteins in LDL, particularly at the extremes of the density ranges (16Lee D.M. Alaupovic P. Composition and concentration of apolipoproteins in very-low-and low-density lipoproteins of normal human plasma.Atherosclerosis. 1974; 19: 501-520Google Scholar), (La Belle, Krauss et al., unpublished observations). VLDL subspecies lacking apoE appear to comprise one third of total VLDL (17Campos E. Jackle S. Chi Chen G. Havel R.J. Isolation and characterization of two distinct species of human very low density lipoproteins lacking apolipoprotein E.J. Lipid Res. 1996; 37: 1897-1906Google Scholar), and have been shown to have increased content of phosphatidylethanolamine (18Fielding P.E. Fielding C.J. An apo-E-free very low density lipoprotein enriched in phosphatidylethanolamine in human plasma.J. Biol. Chem. 1986; 261: 5233-5236Google Scholar). Isolation and definition of lipoprotein subfractions due to apolipoprotein composition is challenging as all apolipoproteins are exchangeable with the exception of apoB. Using anti apoE and apoC-III immunoaffinity chromatography in sequence and then ultracentrifugation, it has been demonstrated recently that VLDL with apoC-III is increased in hypertriglyceridemic patients and carries most of the apoE. The concentrations of particles without apoE and without apoC-III were similar between a hypertriglyceridemic and a normolipidemic group, but distributed more to VLDL and IDL than to the LDL density range. In contrast, concentrations of particles without apoC-III and apoE were increased in hypercholesteremic patients (19Campos H. Perlov D. Khoo C. Sacks F.M. Distinct patterns of lipoproteins with apoB defined by presence of apoE or apoC-III in hypercholesterolemia and hypertriglyceridemia.J. Lipid Res. 2001; 42: 1239-1249Google Scholar). These findings are consistent with evidence as described below that VLDL particles with apoC-III have decreased clearance and may therefore promote atherosclerosis. It has been suggested (Fig. 1)that there is metabolic channeling within the VLDL-IDL-LDL delipidation cascade such that parallel processing pathways generate different IDL and LDL products from different triglyceride-rich lipoprotein precursors (20Packard C.J. Gaw A. Demant T. Shepherd J. Development and application of a multicompartmental model to study very low density lipoprotein subfraction metabolism.J. Lipid Res. 1995; 36: 172-187Google Scholar, 21Ehnholm C. Mahley R.W. Chappell D.A. Weisgraber K.H. Ludwig E. Witztum J.L. Role of apolipoprotein E in the lipolytic conversion of beta-very low density lipoproteins to low density lipoproteins in type III hyperlipoproteinemia.Proc. Natl. Acad. Sci. USA. 1984; 81: 5566-5570Google Scholar, 22Gaw A. Packard C.J. Murray E.F. Lindsay G.M. Griffin B.A. Caslake M.J. Vallance B.D. Lorimer A.R. Shepherd J. Effects of simvastatin on apoB metabolism and LDL subfraction distribution.Arterioscler. Thromb. 1993; 13: 170-189Google Scholar, 23Caslake M.J. Packard C.J. Gaw A. Murray E. Griffin B.A. Vallance B.D. Shepherd J. Fenofibrate and LDL metabolic heterogeneity in hypercholesterolemia.Arterioscler. Thromb. 1993; 13: 702-711Scopus (112) Google Scholar, 24Gaw A. Packard C.J. Caslake M.J. Griffin B.A. Lindsay G.M. Thomson J. Vallance B.D. Wosornu D. Shepherd J. Effects of ciprofibrate on LDL metabolism in man.Atherosclerosis. 1994; 108: 137-148Google Scholar). Very large VLDLs normally yield small amounts of LDL (25Packard C.J. Munro A. Lorimer A.R. Gotto A.M. Shepherd J. Metabolism of apolipoprotein B in large triglyceride-rich very low density lipoproteins of normal and hypertriglyceridemic subjects.J. Clin. Invest. 1984; 74: 2178-2192Google Scholar, 26Stalenhoef A.F. Malloy M.J. Kane J.P. Havel R.J. Metabolism of apolipoproteins B-48 and B-100 of triglyceride-rich lipoproteins in normal and lipoprotein lipase-deficient humans.Proc. Natl. Acad. Sci. USA. 1984; 81: 1839-1843Google Scholar) since their delipidation generally ceases in the VLDL or IDL density range with the formation of remnants that may be cleared from the plasma or persist in the circulation. Variation in plasma triglyceride is principally a function of changing VLDL-1 levels (27Gofman J.W. Delalla O. Glazier F. Freeman N.K. Lindgren D. Nichols A.V. Strisower B. Tramplin A.R. The serum lipoprotein transport system in health, metabolic disorders, atherosclerosis and coronary artery disease.Plasma. 1954; 2: 413-484Google Scholar). The fractional conversion rate from VLDL-1 to VLDL-2 is reduced 90% in LpL deficiency (20Packard C.J. Gaw A. Demant T. Shepherd J. Development and application of a multicompartmental model to study very low density lipoprotein subfraction metabolism.J. Lipid Res. 1995; 36: 172-187Google Scholar, 26Stalenhoef A.F. Malloy M.J. Kane J.P. Havel R.J. Metabolism of apolipoproteins B-48 and B-100 of triglyceride-rich lipoproteins in normal and lipoprotein lipase-deficient humans.Proc. Natl. Acad. Sci. USA. 1984; 81: 1839-1843Google Scholar), indicating that a substantial portion of VLDL-2 represents lipolytic remnants of larger particles. Lipolysis of VLDL is not affected by hepatic lipase deficiency (28Demant T. Carlson L.A. Holmquist L. Karpe F. Nilsson-Ehle P. Packard C.J. Shepherd J. Lipoprotein metabolism in hepatic lipase deficiency: studies on the turnover of apolipoprotein B and on the effect of hepatic lipase on high density lipoprotein.J. Lipid Res. 1988; 29: 1603-1611Google Scholar), by homozygous familial hypercholesterolemia (29James R.W. Martin B. Pometta D. Fruchart J.C. Duriez P. Puchois P. Farriaux J.P. Tacquet A. Demant T. Clegg R.J. Munro A. Oliver M.F. Packard C.J. Shepherd J. Apolipoprotein B metabolism in homozygous familial hypercholesterolemia.J. Lipid Res. 1989; 30: 159-169Google Scholar), or by homozygosity for apoE-2 (30Demant T. Bedford D. Packard C.J. Shepherd J. Influence of apolipoprotein E polymorphism on apolipoprotein B-100 metabolism in normolipemic subjects.J. Clin. Invest. 1991; 88: 1490-1501Google Scholar). A portion of VLDL-2 also arises by direct hepatic production, indicating further biochemical heterogeneity within the VLDL particle spectrum. While the rate of VLDL-1 secretion is dependent on triglyceride availability (31Shepherd J. Packard C.J. Stewart J.M. Atmeh R.F. Clark R.S. Boag D.E. Carr K. Lorimer A.R. Ballantyne D. Morgan H.G. Veitch Lawrie T.D. Apolipoprotein A and B (Sf 100–400) metabolism during bezafibrate therapy in hypertriglyceridemic subjects.J. Clin. Invest. 1984; 74: 2164-2177Google Scholar, 32Dachet C. Cavallero E. Martin C. Girardot G. Jacotot B. Effect of gemfibrozil on the concentration and composition of very low density and low density lipoprotein subfractions in hypertriglyceridemic patients.Atherosclerosis. 1995; 113: 1-9Google Scholar, 33Tan C.E. Foster L. Caslake M.J. Bedford D. Watson T.D. McConnell M. Packard C.J. Shepherd J. Relations between plasma lipids and postheparin plasma lipases and VLDL and LDL subfraction patterns in normolipemic men and women.Arterioscler. Thromb. Vasc. Biol. 1995; 15: 1839-1848Google Scholar), VLDL-2 secretion may be more dependent on cholesterol synthesis (34Pease R.J. Leiper J.M. Regulation of hepatic apolipoprotein-B-containing lipoprotein secretion.Curr. Opin. Lipidol. 1996; 7: 132-138Google Scholar), cholesterol ester availability (34Pease R.J. Leiper J.M. Regulation of hepatic apolipoprotein-B-containing lipoprotein secretion.Curr. Opin. Lipidol. 1996; 7: 132-138Google Scholar) and microsomal transfer protein activity (35Lin M.C. Gordon D. Wetterau J.R. Microsomal triglyceride transfer protein (MTP) regulation in HepG2 cells: insulin negatively regulates MTP gene expression.J. Lipid Res. 1995; 36: 1073-1081Google Scholar). Smaller VLDLs are more effective ligands than their larger counterparts for LDL receptors (36Chappell D.A. Fry G.L. Waknitz M.A. Muhonen L.E. Pladet M.W. Low density lipoprotein receptors bind and mediate cellular catabolism of normal very low density lipoproteins in vitro.J. Biol. Chem. 1993; 268: 25487-25493Google Scholar). Studies in LDL receptor deficient and VLDL receptor transgenic mice suggested a role for the VLDL receptor in peripheral uptake of VLDL (37Tacken P.J. Teusink B. Jong M.C. Harats D. Havekes L.M. van Dijk K.W. Hofker M.H. LDL receptor deficiency unmasks altered VLDL triglyceride metabolism in VLDL receptor transgenic and knockout mice.J. Lipid Res. 2000; 41: 2055-2062Google Scholar). Since apoB seems not to be in a receptor-competent conformation on large triglyceride-rich VLDL (38Gianturco S.H. Gotto Jr., A.M. Hwang S.L. Karlin J.B. Lin A.H. Prasad S.C. Bradley W.A. Apolipoprotein E mediates uptake of Sf 100–400 hypertriglyceridemic very low density lipoproteins by the low density lipoprotein receptor pathway in normal human fibroblasts.J. Biol. Chem. 1983; 258: 4526-4533Google Scholar), the ligand for the putative receptor is likely to be apoE, while apoC-III may play an inhibitory role by interacting with or displacing apoE (39Aalto-Setala K. Fisher E.A. Chen X. Chajek-Shaul T. Hayek T. Zechner R. Walsh A. Ramakrishnan R. Ginsberg H.N. Breslow J.L. Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apoCIII and reduced apoE on the particles.J. Clin. Invest. 1992; 90: 1889-1900Google Scholar, 40Windler E. Chao Y. Havel R.J. Regulation of the hepatic uptake of triglyceride-rich lipoproteins in the rat. Opposing effects of homologous apolipoprotein E and individual C apolipoproteins.J. Biol. Chem. 1980; 255: 8303-8307Google Scholar, 41Windler E. Chao Y. Havel R.J. Determinants of hepatic uptake of triglyceride-rich lipoproteins and their remnants in the rat.J. Biol. Chem. 1980; 255: 5475-5480Google Scholar, 42Windler E. Havel R.J. Inhibitory effects of C apolipoproteins from rats and humans on the uptake of triglyceride-rich lipoproteins and their remnants by the perfused rat liver.J. Lipid Res. 1985; 26: 556-565Google Scholar). The LRP receptor is involved in uptake of chylomicrons (43Beisiegel U. Weber W. Bengtsson-Olivecrona G. Lipoprotein lipase enhances the binding of chylomicrons to low density lipoprotein receptor-related protein.Proc. Natl. Acad. Sci. USA. 1991; 88: 8342-8346Google Scholar) and VLDL remnants (44Hussain M.M. Maxfield F.R. Mas-Oliva J. Tabas I. Ji Z.S. Innerarity T.L. Mahley R.W. Clearance of chylomicron remnants by the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor.J. Biol. Chem. 1991; 266: 13936-13940Google Scholar). The role of heparan sulfate proteoglycans in LpL (45Beisiegel U. Krapp A. Weber W. Olivecrona G. The role of alpha 2M receptor/LRP in chylomicron remnant metabolism.Ann. NY Acad. Sci. 1994; 737: 53-69Google Scholar) and apoE-mediated lipoprotein uptake (46Mann W.A. Meyer N. Weber W. Meyer S. Greten H. Beisiegel U. Apolipoprotein E isoforms and rare mutations: parallel reduction in binding to cells and to heparin reflects severity of associated type III hyperlipoproteinemia.J. Lipid Res. 1995; 36: 517-525Google Scholar, 47Ji Z.S. Fazio S. Mahley R.W. Variable heparan sulfate proteoglycan binding of apolipoprotein E variants may modulate the expression of type III hyperlipoproteinemia.J. Biol. Chem. 1994; 269: 13421-13428Google Scholar) has been demonstrated. Recently it has been shown that apoB-48 may mediate the binding of triglyceride rich lipoproteins to a human monocyte-macrophage receptor (48Gianturco S.H. Ramprasad M.P. Song R. Li R. Brown M.L. Bradley W.A. Apolipoprotein B-48 or its apolipoprotein B-100 equivalent mediates the binding of triglyceride-rich lipoproteins to their unique human monocyte-macrophage receptor.Arterioscler. Thromb. Vasc. Biol. 1998; 18: 968-976Google Scholar). While most remnants of large VLDL are rapidly cleared from plasma without undergoing further intravascular metabolism (25Packard C.J. Munro A. Lorimer A.R. Gotto A.M. Shepherd J. Metabolism of apolipoprotein B in large triglyceride-rich very low density lipoproteins of normal and hypertriglyceridemic subjects.J. Clin. Invest. 1984; 74: 2178-2192Google Scholar, 26Stalenhoef A.F. Malloy M.J. Kane J.P. Havel R.J. Metabolism of apolipoproteins B-48 and B-100 of triglyceride-rich lipoproteins in normal and lipoprotein lipase-deficient humans.Proc. Natl. Acad. Sci. USA. 1984; 81: 1839-1843Google Scholar), not all large VLDL are metabolized by this route. In Watanabe heritable hyperlipidemic (WHHL) rabbits, a relatively high proportion of IDL and LDL production results from catabolism of a minor subpopulation of large apoE-containing VLDL particles that are cleared slowly from plasma (49Yamada N. Shames D.M. Takahashi K. Havel R.J. Metabolism of apolipoprotein B-100 in large very low density lipoproteins in blood plasma.J. Clin. Invest. 1988; 82: 2106-2113Google Scholar). A metabolic relationship of large VLDL with small dense LDL in humans is suggested by recent stable isotope kinetic studies indicating increased transport of large VLDL through a metabolic cascade to small IDL in subjects with a predominance of small dense LDL (50Krauss R.M. Hellerstein M.K. Neese R.A. Blanche P.J. La Belle M. Shames D.M. Altered metabolism of large low density lipoproteins in subjects with predominance of small low density lipoproteins.Circulation. 1995; 92: I-102Google Scholar). The finding that VLDL-1 and small dense LDL are metabolically related is also described in the model by Packard et al. (51Packard C.J. Shepherd J. Lipoprotein heterogeneity and apolipoprotein B metabolism.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 3542-3556Google Scholar) in which CETP is required for the formation of small dense LDL. However, as described further below, there is evidence that CETP is not required for this process. IDL and LDL represent discrete, thermodynamically stable particle configurations that are reached sequentially during the course of intravascular catabolism of VLDL. The transformations from VLDL to IDL and LDL are enabled by the presence of sufficient triglyceride to sustain lipolysis. This process also appears to depend on an as yet uncharacterized apoE-dependent mechanism (21Ehnholm C. Mahley R.W. Chappell D.A. Weisgraber K.H. Ludwig E. Witztum J.L. Role of apolipoprotein E in the lipolytic conversion of beta-very low density lipoproteins to low density lipoproteins in type III hyperlipoproteinemia.Proc. Natl. Acad. Sci. USA. 1984; 81: 5566-5570Google Scholar), resulting in loss of apoE from most LDL particles. A portion of the IDL fraction is catabolized directly from plasma, probably via the LDL receptor since the rate of this process is dramatically reduced in FH homozygotes (29James R.W. Martin B. Pometta D. Fruchart J.C. Duriez P. Puchois P. Farriaux J.P. Tacquet A. Demant T. Clegg R.J. Munro A. Oliver M.F. Packard C.J. Shepherd J. Apolipoprotein B metabolism in homozygous familial hypercholesterolemia.J. Lipid Res. 1989; 30: 159-169Google Scholar, 52Soutar A.K. Myant N.B. Thompson G.R. The metabolism of very low density and intermediate density lipoproteins in patients with familial hypercholesterolaemia.Atherosclerosis. 1982; 43: 217-231Google Scholar). ApoE phenotype influences the conversion of IDL to LDL. In normolipidemic apoE-2 homozygotes, a 60% reduction in the rate of transfer of IDL to LDL was observed while direct catabolism of the fraction, presumably mediated by its apoB component, was normal (30Demant T. Bedford D. Packard C.J. Shepherd J. Influence of apolipoprotein E polymorphism on apolipoprotein B-100 metabolism in normolipemic subjects.J. Clin. Invest. 1991; 88: 1490-1501Google Scholar). Although in vivo kinetic studies have not definitively established the specific precursor-product pathways for the generation of individual LDL subclasses, studies in animal models have indicated that separate pathways may be responsible for production of differing forms of LDL. In rats, kinetic studies have shown that larger LDLs (Sf 5–12) are derived via a VLDL-IDL metabolic cascade, but small dense LDLs (Sf 0–5), which comprise 65% of total LDL mass, do not appear to derive from this pathway (53Fidge N.H. Poulis P. Metabolic heterogeneity in the formation of low density lipoprotein in the rat: evidence for the independent production of a low density lipoprotein subfraction.J. Lipid Res. 1975; 19: 342-349Google Scholar). In monkeys, it has been reported that the metabolic behavior of LDL derived from endogenously radiolabeled hepatic lipoprotein precursors often differs from that of radiolabeled autologous plasma LDL (54Murthy V.N. Marzetta C.A. Rudel L.L. Zech L.A. Foster D.M. Hepatic apoB-100 lipoproteins and plasma LDL heterogeneity in African green monkeys.Am. J. Physiol. 1990; 258: E1041-E1057Google Scholar, 55Johnson F.L. St Clair R.W. Rudel L.L. Studies on the production of low density lipoproteins by perfused livers from nonhuman primates. Effect of dietary cholesterol.J. Clin. Invest. 1983; 72: 221-236Google Scholar). Kinetic analysis and studies involving nascent lipoproteins from perfused livers (55Johnson F.L. St Clair R.W. Rudel L.L. Studies on the production of low density lipoproteins by perfused livers from nonhuman primates. Effect of dietary cholesterol.J. Clin. Invest. 1983; 72: 221-236Google Scholar, 56Marzetta C.A. Johnson F.L. Zech L.A. Foster D.M. Rudel L.L. Metabolic behavior of hepatic VLDL and plasma LDL apoB-100 in African green monkeys.J. Lipid Res. 1989; 30: 357-370Google Scholar) suggested that plasma LDL in these monkeys may be derived from a variety of precursors, with each source giving rise to metabolically (and possible physically) distinct LDL particles. In a spontaneously hypercholesterolemic strain of pigs, two metabolically distinct LDL subclasses have been characterized: the larger, more buoyant species appears to accumulate as a results of both increased production and reduced receptor clearance resulting from an apoB mutation (57Checovich W.J. Aiello R.J. Attie A.D. Overproduction of a buoyant low density lipoprotein subspecies in spontaneously hypercholesterolemic mutant pigs.Arterioscler. Thromb. 1991; 11: 351-361Google Scholar). This subclass does not appear to arise either from catabolism of plasma VLDL, or from enlargement of smaller LDL (58C" @default.
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• W2009013500 date "2002-09-01" @default.
• W2009013500 modified "2023-10-14" @default.
• W2009013500 title "Metabolic origins and clinical significance of LDL heterogeneity" @default.
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