Changes in lipoprotein(a), oxidized phospholipids, and LDL subclasses with a low-fat high-carbohydrate diet

Low-fat diets have been shown to increase plasma concentrations of lipoprotein(a) Lp(a), a preferential lipoprotein carrier of oxidized phospholipids (OxPLs) in plasma, as well as small dense LDL particles. We sought to determine whether increases in plasma Lp(a) induced by a low-fat high-carbohydrate (LFHC) diet are related to changes in OxPL and LDL subclasses. We studied 63 healthy subjects after 4 weeks of consuming, in random order, a high-fat low-carbohydrate (HFLC) diet and a LFHC diet. Plasma concentrations of Lp(a) (P < 0.01), OxPL/apolipoprotein (apo)B (P < 0.005), and OxPL-apo(a) (P < 0.05) were significantly higher on the LFHC diet compared with the HFLC diet whereas LDL peak particle size was significantly smaller (P < 0.0001). Diet-induced changes in Lp(a) were strongly correlated with changes in OxPL/apoB (P < 0.0001). The increases in plasma Lp(a) levels after the LFHC diet were also correlated with decreases in medium LDL particles (P < 0.01) and increases in very small LDL particles (P < 0.05). These results demonstrate that induction of increased levels of Lp(a) by an LFHC diet is associated with increases in OxPLs and with changes in LDL subclass distribution that may reflect altered metabolism of Lp(a) particles. Low-fat diets have been shown to increase plasma concentrations of lipoprotein(a) Lp(a), a preferential lipoprotein carrier of oxidized phospholipids (OxPLs) in plasma, as well as small dense LDL particles. We sought to determine whether increases in plasma Lp(a) induced by a low-fat high-carbohydrate (LFHC) diet are related to changes in OxPL and LDL subclasses. We studied 63 healthy subjects after 4 weeks of consuming, in random order, a high-fat low-carbohydrate (HFLC) diet and a LFHC diet. Plasma concentrations of Lp(a) (P < 0.01), OxPL/apolipoprotein (apo)B (P < 0.005), and OxPL-apo(a) (P < 0.05) were significantly higher on the LFHC diet compared with the HFLC diet whereas LDL peak particle size was significantly smaller (P < 0.0001). Diet-induced changes in Lp(a) were strongly correlated with changes in OxPL/apoB (P < 0.0001). The increases in plasma Lp(a) levels after the LFHC diet were also correlated with decreases in medium LDL particles (P < 0.01) and increases in very small LDL particles (P < 0.05). These results demonstrate that induction of increased levels of Lp(a) by an LFHC diet is associated with increases in OxPLs and with changes in LDL subclass distribution that may reflect altered metabolism of Lp(a) particles. Oxidized phospholipids (OxPLs) play an important role in inflammation and in progression of atherosclerosis (1Steinberg D. Parthasarathy S. Carew T.E. Khoo J.C. Witztum J.L. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity.N. Engl. J. Med. 1989; 320: 915-924Crossref PubMed Google Scholar, 2Navab M. Berliner J.A. Watson A.D. Hama S.Y. Territo M.C. Lusis A.J. Shih D.M. Van Lenten B.J. Frank J.S. Demer L.L. et al.The Yin and Yang of oxidation in the development of the fatty streak. A review based on the 1994 George Lyman Duff Memorial Lecture.Arterioscler. Thromb. Vasc. Biol. 1996; 16: 831-842Crossref PubMed Scopus (611) Google Scholar). Levels of OxPL on apolipoprotein (apo)B-100 (OxPL/apoB) lipoproteins can be measured with the monoclonal antibody E06, which binds OxPL but not native phospholipids (3Friedman P. Horkko S. Steinberg D. Witztum J.L. Dennis E.A. Correlation of antiphospholipid antibody recognition with the structure of synthetic oxidized phospholipids. Importance of Schiff base formation and aldol condensation.J. Biol. Chem. 2002; 277: 7010-7020Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar). 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Med. 2005; 353: 46-57Crossref PubMed Scopus (590) Google Scholar), carotid, and peripheral arterial disease (7Tsimikas S. Kiechl S. Willeit J. Mayr M. Miller E.R. Kronenberg F. Xu Q. Bergmark C. Weger S. Oberhollenzer F. et al.Oxidized phospholipids predict the presence and progression of carotid and femoral atherosclerosis and symptomatic cardiovascular disease: five-year prospective results from the Bruneck study.J. Am. Coll. Cardiol. 2006; 47: 2219-2228Crossref PubMed Scopus (154) Google Scholar) and predict death and myocardial infarction in unselected populations (8Kiechl S. Willeit J. Mayr M. Viehweider B. Oberhollenzer M. Kronenberg F. Wiedermann C.J. Oberthaler S. Xu Q. Witztum J.L. et al.Oxidized phospholipids, lipoprotein(a), lipoprotein-associated phospholipase A2 activity, and 10-year cardiovascular outcomes: prospective results from the Bruneck study.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 1788-1795Crossref PubMed Scopus (209) Google Scholar). 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Krauss R.M. plasma concentrations of lipoprotein(a) a high-carbohydrate diet are associated with increased plasma concentrations of apolipoprotein to apolipoprotein J. 2007; PubMed Scopus Google Scholar). the on the diets a and the subjects to diet and were to with the subjects were with < of total of the was by were to from and of the subjects a by the and of were after an after the diets Plasma were of from in and a of and Plasma was Plasma total and concentrations were by on an These were in as by the of the and was measured after of plasma of of lipoprotein Chem. PubMed Scopus Google Scholar), and LDL was from the of et al. of the of low-density lipoprotein in plasma, of the Chem. PubMed Scopus Google Scholar). and were measured by and Lp(a) plasma concentrations were measured in by a with was to the of OxPL lipoprotein the monoclonal antibody E06, which binds to the of oxidized but not native phospholipids (4Tsimikas S. Witztum J.L. Miller E.R. Sasiela W.J. Szarek M. Olsson A.G. Schwartz G.G. High-dose atorvastatin reduces total plasma levels of oxidized phospholipids and immune complexes present on apolipoprotein B-100 in patients with acute coronary syndromes in the MIRACL trial.Circulation. 2004; 110: 1406-1412Crossref PubMed Scopus (186) Google Scholar). A of plasma in was to with monoclonal antibody which binds lipoprotein particles D.M. Curtiss L.K. Witztum J.L. monoclonal of apolipoprotein Chem. 1986; PubMed Scopus Google Scholar, Witztum J.L. Curtiss L.K. S. of the lipoprotein of B. by a monoclonal 1986; PubMed Google Scholar). a of was to well and an of particles are in well The of OxPL was with as (4Tsimikas S. Witztum J.L. Miller E.R. Sasiela W.J. Szarek M. Olsson A.G. Schwartz G.G. High-dose atorvastatin reduces total plasma levels of oxidized phospholipids and immune complexes present on apolipoprotein B-100 in patients with acute coronary syndromes in the MIRACL trial.Circulation. 2004; 110: 1406-1412Crossref PubMed Scopus (186) Google Scholar, 5Tsimikas S. Bergmark C. Beyer R.W. Patel R. Pattison J. Miller E. Juliano J. Witztum J.L. Temporal increases in plasma markers of oxidized low-density lipoprotein strongly reflect the presence of acute coronary syndromes.J. Am. Coll. Cardiol. 2003; 41: 360-370Crossref PubMed Scopus (315) Google Scholar, 10Tsimikas S. Lau H.K. Han K.R. Shortal B. Miller E.R. Segev A. Curtiss L.K. Witztum J.L. Strauss B.H. Percutaneous coronary intervention results in acute increases in oxidized phospholipids and lipoprotein(a): short-term and long-term immunologic responses to oxidized low-density lipoprotein.Circulation. 2004; 109: 3164-3170Crossref PubMed Scopus (213) Google Scholar, S. Witztum J.L. The role of oxidized phospholipids in lipoprotein(a) 2008; PubMed Scopus Google Scholar). by the OxPL/apoB is of LDL The in the of the OxPL/apoB not the plasma but the of on well of the OxPL are present on Lp(a) in as shown (9Bergmark C. Dewan A. Orsoni A. Merki E. Miller E.R. Shin M.J. Binder C.J. Horkko S. Krauss R.M. Chapman M.J. et al.A novel function of lipoprotein a as a preferential carrier of oxidized phospholipids in human plasma.J. Lipid Res. 2008; 49: 2230-2239Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar), the OxPL/apoB OxPL on Lp(a). We also measured OxPL on Lp(a) particles a of the which by Lp(a) plasma levels can and is not to the well with Lp(a) in subjects with Lp(a) levels which the of is to an in patients that the OxPL particle the OxPL/apoB the was a of plasma which is in the of Lp(a) levels in monoclonal antibody which binds S. Lau H.K. Han K.R. Shortal B. Miller E.R. Segev A. Curtiss L.K. Witztum J.L. Strauss B.H. Percutaneous coronary intervention results in acute increases in oxidized phospholipids and lipoprotein(a): short-term and long-term immunologic responses to oxidized low-density lipoprotein.Circulation. 2004; 109: 3164-3170Crossref PubMed Scopus (213) Google Scholar), was on well and to Lp(a) from OxPL was with as We as OxPL-apo(a) as of which the total OxPL on Lp(a). the OxPL/apoB not the of OxPL particle the small of OxPL that may be present on the are (9Bergmark C. Dewan A. Orsoni A. Merki E. Miller E.R. Shin M.J. Binder C.J. Horkko S. Krauss R.M. Chapman M.J. et al.A novel function of lipoprotein a as a preferential carrier of oxidized phospholipids in human plasma.J. Lipid Res. 2008; 49: 2230-2239Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar). concentrations of plasma lipoprotein were measured by and as a function of small and LDL from and to and medium small and very small LDL R.M. of of plasma lipoproteins in Lipid Res. Full Text PDF PubMed Google Scholar). with of plasma was as of peak LDL and Lp(a) particle R.M. of of plasma lipoproteins in Lipid Res. Full Text PDF PubMed Google Scholar, D.M. Krauss R.M. LDL particle size in a diet is related to J. 2000; PubMed Scopus Google Scholar, H. J.L. in plasma and of size Lipid Res. 1989; Full Text PDF PubMed Google Scholar). was are as was to the of the LDL size, and lipoprotein subclass were was to in and between the HFLC diet and the LFHC diet. was to in OxPL on Lp(a) between the HFLC and the LFHC diet. were to the between changes in and was to determine to the in Lp(a). The were changes in LDL and < were The of the are in shown in plasma concentrations of (P < (P < Lp(a) (P < 0.01), OxPL/apoB (P < 0.005), and OxPL-apo(a) (P < 0.05) were significantly higher with the LFHC diet with the HFLC diet. total (P LDL (P < (P < and (P < were on the LFHC are in a high-fat low-carbohydrate (HFLC) and low-fat high-carbohydrate (LFHC) are were oxidized phospholipids apolipoprotein oxidized phospholipids on low-fat diet high-fat in a are are were oxidized phospholipids apolipoprotein oxidized phospholipids on low-fat diet high-fat Plasma lipoprotein concentrations and LDL and Lp(a) peak particle are shown in with the HFLC and small significantly increased on the LFHC diet. and medium LDL whereas small and very small LDL increased on the LFHC diet compared with the HFLC diet. the LFHC diet significantly LDL peak particle from to Lp(a) peak particle not between the lipoprotein concentrations and size high-fat low-carbohydrate (HFLC) and low-fat high-carbohydrate (LFHC) LDL LDL LDL LDL peak particle peak particle are were in a are were that changes in Lp(a) were significantly correlated with changes in OxPL/apoB < and LDL < there were associations between changes in Lp(a) and plasma total (P (P and in Lp(a) with the LFHC diet were strongly related to increases in OxPL/apoB (P < showed the associations between changes in Lp(a) and changes in OxPL/apoB were of changes in plasma total LDL and not increases in OxPL/apoB with the LFHC diet were associated with LDL (P < 0.01), (P < and total (P not between changes in Lp(a) and and < LDL < LDL LDL < LDL LDL < oxidized phospholipids apolipoprotein low-fat diet high-fat < < in a oxidized phospholipids apolipoprotein low-fat diet high-fat We a between the changes in medium and very small LDL < and and small LDL < 0.05) not The changes in Lp(a) were correlated to changes with medium LDL (P < 0.01) and with changes in very small LDL (P < 0.05) that as shown in the between Lp(a) and medium LDL and the increase in Lp(a) with there was a in medium LDL from to with diet. of the of the changes in Lp(a) was by changes in medium and very small changes in levels of medium and very small LDL in an increase of the in Lp(a) from to Lp(a) peak particle was correlated with LDL peak particle the LFHC diet (P < 0.01) but not on the HFLC diet (P not and changes in peak particle of LDL and Lp(a) were not correlated (P The results of intervention a demonstrate that an LFHC diet increases levels of Lp(a) and and that a increase in OxPL on Lp(a) particles. the correlated changes in Lp(a) and OxPL/apoB were of changes in plasma total LDL and The of OxPL on particles in the novel the of Lp(a) S. Witztum J.L. The role of oxidized phospholipids in lipoprotein(a) 2008; PubMed Scopus Google Scholar). the OxPL/apoB monoclonal antibody was to was from and studies that of the OxPLs are present on Lp(a) particles LDL S. Witztum J.L. The role of oxidized phospholipids in lipoprotein(a) 2008; PubMed Scopus Google Scholar). and immunological studies on Lp(a) have that of OxPL associated with lipoproteins are present on on the and in the (9Bergmark C. Dewan A. Orsoni A. Merki E. Miller E.R. Shin M.J. Binder C.J. Horkko S. Krauss R.M. Chapman M.J. et al.A novel function of lipoprotein a as a preferential carrier of oxidized phospholipids in human plasma.J. Lipid Res. 2008; 49: 2230-2239Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 11Edelstein C. Pfaffinger D. Hinman J. Miller E. Lipkind G. Tsimikas S. Bergmark C. Getz G.S. Witztum J.L. Scanu A.M. Lysine-phosphatidylcholine adducts in kringle V impart unique immunological and potential pro-inflammatory properties to human apolipoprotein(a).J. Biol. Chem. 2003; 278: 52841-52847Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, C. B. Pfaffinger D. Scanu A.M. The oxidized phospholipids to human apolipoprotein(a) not from low-density lipoproteins and are of J. 2009; PubMed Scopus Google Scholar). OxPL from oxidized LDL may be to Lp(a) in a and (9Bergmark C. Dewan A. Orsoni A. Merki E. Miller E.R. Shin M.J. Binder C.J. Horkko S. Krauss R.M. Chapman M.J. et al.A novel function of lipoprotein a as a preferential carrier of oxidized phospholipids in human plasma.J. Lipid Res. 2008; 49: 2230-2239Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar). the of OxPL that is present on the of and the of OxPL on Lp(a) particles is not and is that OxPL/apoB which reflect OxPL on are elevated in coronary (6Tsimikas S. Brilakis E.S. Miller E.R. McConnell J.P. Lennon R.J. Kornman K.S. Witztum J.L. Berger P.B. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease.N. Engl. J. Med. 2005; 353: 46-57Crossref PubMed Scopus (590) Google Scholar), carotid, and femoral atherosclerosis (7Tsimikas S. Kiechl S. Willeit J. Mayr M. Miller E.R. Kronenberg F. Xu Q. Bergmark C. Weger S. Oberhollenzer F. et al.Oxidized phospholipids predict the presence and progression of carotid and femoral atherosclerosis and symptomatic cardiovascular disease: five-year prospective results from the Bruneck study.J. Am. Coll. Cardiol. 2006; 47: 2219-2228Crossref PubMed Scopus (154) Google Scholar) and the of the in myocardial and (8Kiechl S. Willeit J. Mayr M. Viehweider B. Oberhollenzer M. Kronenberg F. Wiedermann C.J. Oberthaler S. Xu Q. Witztum J.L. et al.Oxidized phospholipids, lipoprotein(a), lipoprotein-associated phospholipase A2 activity, and 10-year cardiovascular outcomes: prospective results from the Bruneck study.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 1788-1795Crossref PubMed Scopus (209) Google Scholar). may as a subjects cardiovascular changes in the OxPL/apoB in to are well and have an increase in OxPL/apoB levels as well as Lp(a) in studies with have increases of in OxPL/apoB and Lp(a) with of and atorvastatin in the MIRACL (4Tsimikas S. Witztum J.L. Miller E.R. Sasiela W.J. Szarek M. Olsson A.G. Schwartz G.G. High-dose atorvastatin reduces total plasma levels of oxidized phospholipids and immune complexes present on apolipoprotein B-100 in patients with acute coronary syndromes in the MIRACL trial.Circulation. 2004; 110: 1406-1412Crossref PubMed Scopus (186) Google Scholar) and A. Miller E. M. F. Witztum J.L. Tsimikas S. Relationship between of oxidized low-density lipoprotein, coronary and from the of with Lipid study.J. Am. Coll. Cardiol. 2008; PubMed Scopus Google Scholar) in with J. A. Miller E.R. Witztum J.L. Tsimikas S. Oxidized low-density lipoprotein in with and of Am. Coll. 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Dennis B.H. et of with as a in subjects with a risk studies in the and J. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). in Lp(a) and OxPL/apoB with changes in LDL were in a of diets with and the diet in was not and its from in compared with the diets and a of that of the diets to on Lp(a) and OxPL/apoB M. G. A. Witztum J.L. Horkko S. in plasma levels of oxidized low-density lipoprotein and Thromb. Vasc. Biol. 2004; PubMed Scopus Google Scholar). have that increases in OxPL/apoB in to low-fat diets in which not have Lp(a) and Lp(a) is the OxPL We have in which have Lp(a) but Lp(a) not OxPL S. M. Miller Miller E.R. M. Bergmark C. P. Witztum J.L. plasma oxidized B-100 with of oxidized phospholipids from after a potential of atherosclerosis Thromb. Vasc. Biol. 2007; 27: PubMed Scopus Google Scholar). the and the increase in OxPL/apoB in plasma was associated with of OxPL in the with of M. S. E. Witztum J.L. P. 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Krauss R.M. plasma concentrations of lipoprotein(a) a high-carbohydrate diet are associated with increased plasma concentrations of apolipoprotein to apolipoprotein J. 2007; PubMed Scopus Google Scholar). in Lp(a) after the LFHC diet were correlated with changes in medium LDL that the metabolism of Lp(a) and medium LDL may be the in medium LDL and the increase in Lp(a) are after the LFHC diet. have shown an between changes of Lp(a) and very small LDL that the increase in very small LDL with an LFHC diet is associated with a smaller increase in Lp(a) (P < 0.05). of the in changes in Lp(a) was by the changes in medium and very small LDL particles. the of may have been to the that the very small LDL also a of plasma Lp(a) particles F. serum of lipoproteins in PubMed Scopus Google Scholar). changes in medium and very small the increase in Lp(a) was the in metabolism of LDL may be the formation the of the increase in is that the was of is that there was between the R.M. of and on J. 2006; PubMed Scopus Google Scholar) have shown a intervention of 4 weeks is to of plasma and the results demonstrate that an LFHC diet results in increased plasma Lp(a) and its associated oxidized phospholipids and that increases may be by changes in LDL metabolism to altered LDL subclass studies are to the and of The the and S. and and and S. in cardiovascular disease high-fat low-carbohydrate low-fat high-carbohydrate lipoprotein(a) oxidized lipoprotein