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Effects of bezafibrate on the composition of very low density lipoproteins in type IV hyperlipoproteinemia
A therosclerosis, 42 ( 1982) 245-249 Elsevier/North-Holland Scientific
245 Publishers,
Ltd.
Effects of Bezafibrate on the Composition of Very Low Density Lipoproteins in Type IV Hyperlipoproteinemia Peter Schwandt,
Peter Weisweiler, Michael Drosner Peter Janetschek
and
Medical Deportment II, Klinikum Grosshadern, University of Munich, Marchioninistr. 15, D-8000 Munich 70 (F.R.G.) (Received 24 July, 1981) (Revised, received 13 October, 198 1) (Accepted 13 October, 1981)
As compared to normolipoproteinemic controls 10 male subjects with primary type IV hyperlipoproteinemia had higher apolipoprotein E and lower apolipoprotein C-II concentrations in the very low density lipoprotein (VLDL) fraction. After 8 weeks of treatment with 0.6.g/day bezafibrate, cholesterol and triglyceride in the serum and VLDL were significantly lower. The decrease of VLDL lipids was accompanied by a significant decrease of the apolipoproteins and of the lipid/protein ratio in VLDL. The analysis of the soluble VLDL apolipoproteins revealed a decrease of apo E and an increase of apo Cl and apo C2, resulting in a decrease of the apo E/ape C ratio. Key words: Bezafibrate - Type IV hyperlipoproteinemia - Very low density lipoprotein composition.
Introduction The lipid-lowering drug bezafibrate effectively lowers the concentration of very low density lipoprotein (VLDL) lipids [l] and serum apolipoprotein (apo) B [2]. These effects are associated with an increase in the high density lipoprotein subfraction HDL,[3] and an activation of the lipoprotein and hepatic triglyceride lipases [4]. There are no data on VLDL apolipoproteins. Apo B represents the number of VLDL-particles [S], the C-apolipoproteins modulate the lipoprotein lipase activity [6] -e.g. apo C2 activates [7,8] and apo C3 appears to inhibit [9] enzyme activity-and 0021-9lSO/82/oooO-0/~2.75
0 1982 Elsevier/North-Holland
Scientific
Publishers,
Ltd.
246
apo E is involved in receptor binding [lo]. In hypertriglyceridemic patients the mean concentrations of apo C2 in VLDL are lower than in normal subjects [ 111. The apo CZ/apo C3 area ratio is therefore decreased in type IV patients [ 12,131. Furthermore, in severe hypertriglyceridemic subjects the apo E/ape C ratio is increased [7]. Thus altered apolipoprotein concentrations in VLDL are likely to be causally related to the disturbed VLDL metabolism in hypertriglyceridemia. As an extension of a previous investigation [14] this study reports the effects of bezafibrate on VLDL apolipoproteins and lipids in patients with type IV hyperlipoproteinemia.
Patients and Methods Ten male normal-weight subjects with primary type IV hyperlipoproteinemia according to the WHO criteria [ 151 and 15 healthy subjects as controls were studied. On the basis of medical history, physical examination and laboratory investigations they had no renal, hepatic or endocrine disorders. Patients (type IV diet) and controls (usual diet) maintained their accustomed diets for several weeks (as documented by 24-h dietary records) and their baseline levels of serum cholesterol ( * 5%) and triglycerides (C 10%) were stable (as documented by 2 determinations throughout the preceding 4 weeks) before the start of the study. Fasting blood samples (12 h) were analyzed in patients before and after 600 mg/day treatment with bezafibrate for 8 ‘weeks and in controls. VLDL were separated by tube slicing after ultracentrifugation in a Beckman rotor 40.3 (d = 1.006 g/ml, 105000 X g, 4’C, 24 h). Cholesterol and triglycerides were measured enzymatically in serum and VLDL (Kits, Boehringer Mannheim, F.R.G.). The apo B concentrations in VLDL were determined by electroimmunoassay as described previously [ 161and the soluble apolipoproteins according to the method of Kane et al. [17] in 7.5% polyacrylamide gel columns containing 8 mol/l urea (application of 0.1 mg protein, staining with Amidoschwarz 10 B, destaining with 7% acetic acid, density scanning at 570 nm with a scanner-integrator from Hirschmann, Munich, F.R.G.). All samples for gel electrophoresis were analyzed within 1 week under identical conditions. Significances were calculated by the Wilcoxon rank test (paired and unpaired testing).
Results As shown in Table 1 the concentrations of cholesterol and triglycerides in serum and in VLDL were significantly decreased after treatment with bezafibrate for 8 weeks. Furthermore, the level of soluble VLDL apolipoproteins and the VLDL lipid/protein ratio (which was not significantly different between pretreatment values and controls) were lowered by bezafibrate. The analysis of the soluble VLDL apolipoproteins by gel electrophoresis revealed a decrease in apo E, an increase in apo Cl and apo C2 and consequently a decrease
247
TABLE
I
CHOLESTEROL AND TRIGLYCERIDES IN SERUM AND VLDL, AND VLDL LIPID (CHOLESTEROL + TRIGLYCERIDES)/PROTEIN APOLIPOPROTEINS) RATIO BEFORE AND AFTER TREATMENT
VLDL
APOLIPOPROTEINS (APO B + SOLUBLE WITH BEZAFIBRATE (Mt-
SD)
Serum cholesterol (mg/dl) Serum triglyceride (mg/dl) VLDL cholesterol (mg/dl) VLDL triglyceride (mg/dl) VLDL apo B (mg/dl) Soluble VLDL apolipoproteins VLDL lipid/protein ratio
8- week treatment (n= IO)
Control (n= 15)
330 656 188 478
288 390 101 299
181 98 16 70
2101” i-3610° * 840° +310°0
50 f 93 * 4.66i
(mg/dl)
Wilcoxon rank test. Pretreatment pretreatment vs control (unpaired
Pretreatment (n= 10)
41 * 27 60 & 38** 3.96* 1.96 *
2000 4500 2.39
vs 8-week treatment testing): O” P
* 87: *1994* & 86** *146*
(paired
testing):
* PiO.025,
*43 *54 19 *59
6 ‘2 13 -c4 4.52* 1.99 **
P
in the apo E/ape C area ratio (Table 2). Among the C-apolipoproteins there was a significant increase in the apo C2/apo C3, area ratio. As compared to the controls the VLDL of the hypertriglyceridemic patients had higher apo E and lower apo C2 concentrations before treatment.
TABLE
2
ANALYSIS OF THE SOLUBLE VLDL APOLIPOPROTEINS WITH BEZAFIBRATE (Mk SD)
Unidentified protein Apo E C-apolipoproteins apoC1 \ apo C2 % dye uptake apo C3, I apo C3, I Apo E/ape C-area ratio Apo CZ/apo C3, -area ratio Wilcoxon treatment
rank test. vs control
BEFORE
AND AFTER
TREATMENT
Pretreatment (n= 10)
8-week treatment (n= 10)
Control (n= 15)
6.2 27.5 66.3 11.2 9.8 29.6 16.1
7.1 10.1 82.8 14.9 19.2 32.3 16.4
6.4 17.6 76.0 11.5 16.6 29.7 18.2
* 4.3 2 18.9’ f23.4 * 4.2 2 5.8’ * 9.6 * 5.4
0.41* 0.34*
0.180° o.ioc
* 6.4 k 8.9 i28.3 * * 2.5 * * 7.2 * * 9.5 * 4.5
0.13” 0.59”
Pretreatmemt vs 8-week treatment (paired (unpaired testing): o PcO.05, co P<0.01.
0.10 ** 0.12 **
testing):
* PcO.025,
-+- 6.8 + 7.0 k25.2 * 2.2 * 6.0 ‘- 9.5 f 6.2
0.23’ 0.56-t
0.10 0.19
** P
pre-
248
Discussion These data demonstrate that bezafibrate not only lowers VLDL but also causes compositional changes in VLDL of patients with type IV hyperlipoproteinemia. The decrease of the lipid/protein ratio indicates a reduction in size of VLDL particles [5] by bezafibrate. Similar effects have been reported for clofibrate [ 181. Opposite changes were observed in men after diets high in carbohydrates: VLDL particles tend to be larger in size [ 191. The elevation, of VLDL-apo C2 concentrations (which were lower before treatment in the hypertriglyceridemic than in the normal subjects) by bezafibrate may result in the stimulation of lipoprotein lipase [4] with an enhanced catabolism of VLDL. Since the elevated apo E/ape C area ratio in hypertriglyceridemia reflects an elevated concentration of VLDL-remnant particles [5], its decrease after the treatment with bezafibrate points to a preferential removal of these lipoproteins. This finding can be associated with the reported stimulation of the hepatic triglyceride lipase activity, which is responsible for the catabolism of remnant lipoproteins [4]. A similar decrease in the apo E/ape C area ratio was observed after thyroid hormone treatment in hypothyroid hyperlipoproteinemic patients [20]. References I Gbson, A.G., Rossner, S., Walldius, G., Carlson, L.A. and Lang, P.D., Effect of BM-15075 on lipoprotein concentrations in different types of hyperlipoproteinemia. Atherosclerosis, 27 (1977) 279. 2 Weisweiler, P. and Schwandt, P., Lipoprotein lipids and apolipoproteins after six months’ treatment with baafibrate, Artery, 5 (I 980) 402. 3 Schwandt, P. and Weisweiler, P., Effect of bezafibrate on the high-density lipoprotein subfractions HDL, and HDL, in primary hyperhpoproteinemia type IV, Artery, 7 (1980) 464. 4 Klose, G., Behrendt, J., Vollmar, J. and Greten, H., Wirkung von Bezafibrat auf die Lipoproteinlipasenaktivitat und die Leber-Triglyceridhydrolase bei gesunden Versuchspersonen. In: H. Greten. P.D. Lang and G. Schettler (Eds.), Lipoproteine und Heminfarkt, Verlag G. Witzstrock. Baden-Baden, Kiiln, New York, 1979, p. 185. 5 Eisenberg, S., Very-low-density lipoprotein metabolism, Progr. B&hem. Pharmacol., I5 (1979) 139. 6 Ganesan, D., Bass, H.B., McConathy, W.J. and Alaupovic, P., Is decreased activity of C-II activated lipoprotein lipase in type III hyperlipoproteinemia (broad+-disease) a cause or an effect of increased apolipoprotein E levels? Metabolism; 35 ( 1976) I 189. 7 Breckenridge, W.C., Little, J.A. Steiner, G., Chow, A. and Poapst, M., Hypertriglyceridemia associated with deficiency of apolipoprotein C-II, N. Engl. J. Med., 298 (1978) 1265. 8 La Rosa, J.C., Levy, RI., Herbert, P., Lux, S.E. and Fredrickson, D.S., A specific apoprotein activator for lipoprotein lipase, Biochem. Biophys. Res. Comm., 41 (1972) 57. 9 Brown, W.V. and Baginsky, M.L., Inhibition of lipoprotein lipase by an apoprotein of human very low density lipoproteins, B&hem. Biophys. Res. Comm., 46 (1972) 375. IO Innerarity, T.L. and Mahley, R.W., Enhanced binding by cultured human fibroblasts of apo Econtaining lipoproteins as compared with low-density lipoproteins, Biochemistry, 17 (1978) 1440. I I Kashyap, M.L., Srivastava, L.S., Chen, C.Y., Perisutti, G., Campbell, M., Lutmer, R.F. and Glueck, C.J., Radioimmunoassay of human apolipoprotein C II, J. Clin. Invest., 60 (1977) 171. 12 Carbon, L.A. and Ballantyne, D., Changing relative content of apolipoproteins C-II, and C-III of very low density lipoproteins in hypertriglyceridemia, Atherosclerosis, 23 (1976)563. 13 Catapano, A.L., The distribution of apo C-II and apo C-III in very low density lipoproteins of normal and type IV subjects, Atherosclerosis, 35 (1980) 419.
249
14 Drosner. M., Weisweiler, P. and Schwandt, P., Changes of the VLDL-apolipoproteinsC in primary type IV-hyperlipoproteinaemia by bezafibrate, J. Clin. Chem. Clin. Biochem., 18 (1980) 5.18 (Abstract). 15 Beaumont, J.-L., Carlson, L.A., Cooper, G.R., Fejfar, Z., Fredrickson, D.S. and Strasser, T., Classification of hyperlipidemias and hyperhpoproteinemias, Bull. Wld Hlth Org., 43 (I 970) 89 I. 16 Schwandt, P. and Weisweiler, P., The effect of D-thyroxine on lipoprotein lipids and apolipoproteins in primary type IIa hyperhpoproteinemia, Atherosclerosis, 35 (!980) 301. 17 Kane, J.P., Sata, T., Hamilton, R.L. and Havel, R.J.. Apoprotein composition of very low density lipoproteins of human serum, J. Clin. Invest., 56 (1975) 1622. 18 Naruszwicz, M.. Szostak. W.B., Cybulska, B., Kotlowska. M. and Chotlowska, E., The influence of clofibrate on lipid and protein components of very low-density lipoproteins in type IVhyperlipoproteinemia, Atherosclerosis, 35 (I 980) 383. 19 Schonfeld. G., Weidman, S.W., Witztum, J.L. and Bowen, R.M., Alterations in levels and interrelations of plasma apolipoproteins induced by diet, Metabolism. 25 (1976) 26 I. 20 Pagnan, A., Casara, D., Zanetti. G., Guarini. P. and Graggion, M., Serum lipids, “double pm-beta lipoproteinemia”, snd distribution of the apo-very-low-density (VLDL) lipoprotein peptides in hypothyroid patients before and after substitution therapy, Metabolism, 29 (1980) 1026.
245 Publishers,
Ltd.
Effects of Bezafibrate on the Composition of Very Low Density Lipoproteins in Type IV Hyperlipoproteinemia Peter Schwandt,
Peter Weisweiler, Michael Drosner Peter Janetschek
and
Medical Deportment II, Klinikum Grosshadern, University of Munich, Marchioninistr. 15, D-8000 Munich 70 (F.R.G.) (Received 24 July, 1981) (Revised, received 13 October, 198 1) (Accepted 13 October, 1981)
As compared to normolipoproteinemic controls 10 male subjects with primary type IV hyperlipoproteinemia had higher apolipoprotein E and lower apolipoprotein C-II concentrations in the very low density lipoprotein (VLDL) fraction. After 8 weeks of treatment with 0.6.g/day bezafibrate, cholesterol and triglyceride in the serum and VLDL were significantly lower. The decrease of VLDL lipids was accompanied by a significant decrease of the apolipoproteins and of the lipid/protein ratio in VLDL. The analysis of the soluble VLDL apolipoproteins revealed a decrease of apo E and an increase of apo Cl and apo C2, resulting in a decrease of the apo E/ape C ratio. Key words: Bezafibrate - Type IV hyperlipoproteinemia - Very low density lipoprotein composition.
Introduction The lipid-lowering drug bezafibrate effectively lowers the concentration of very low density lipoprotein (VLDL) lipids [l] and serum apolipoprotein (apo) B [2]. These effects are associated with an increase in the high density lipoprotein subfraction HDL,[3] and an activation of the lipoprotein and hepatic triglyceride lipases [4]. There are no data on VLDL apolipoproteins. Apo B represents the number of VLDL-particles [S], the C-apolipoproteins modulate the lipoprotein lipase activity [6] -e.g. apo C2 activates [7,8] and apo C3 appears to inhibit [9] enzyme activity-and 0021-9lSO/82/oooO-0/~2.75
0 1982 Elsevier/North-Holland
Scientific
Publishers,
Ltd.
246
apo E is involved in receptor binding [lo]. In hypertriglyceridemic patients the mean concentrations of apo C2 in VLDL are lower than in normal subjects [ 111. The apo CZ/apo C3 area ratio is therefore decreased in type IV patients [ 12,131. Furthermore, in severe hypertriglyceridemic subjects the apo E/ape C ratio is increased [7]. Thus altered apolipoprotein concentrations in VLDL are likely to be causally related to the disturbed VLDL metabolism in hypertriglyceridemia. As an extension of a previous investigation [14] this study reports the effects of bezafibrate on VLDL apolipoproteins and lipids in patients with type IV hyperlipoproteinemia.
Patients and Methods Ten male normal-weight subjects with primary type IV hyperlipoproteinemia according to the WHO criteria [ 151 and 15 healthy subjects as controls were studied. On the basis of medical history, physical examination and laboratory investigations they had no renal, hepatic or endocrine disorders. Patients (type IV diet) and controls (usual diet) maintained their accustomed diets for several weeks (as documented by 24-h dietary records) and their baseline levels of serum cholesterol ( * 5%) and triglycerides (C 10%) were stable (as documented by 2 determinations throughout the preceding 4 weeks) before the start of the study. Fasting blood samples (12 h) were analyzed in patients before and after 600 mg/day treatment with bezafibrate for 8 ‘weeks and in controls. VLDL were separated by tube slicing after ultracentrifugation in a Beckman rotor 40.3 (d = 1.006 g/ml, 105000 X g, 4’C, 24 h). Cholesterol and triglycerides were measured enzymatically in serum and VLDL (Kits, Boehringer Mannheim, F.R.G.). The apo B concentrations in VLDL were determined by electroimmunoassay as described previously [ 161and the soluble apolipoproteins according to the method of Kane et al. [17] in 7.5% polyacrylamide gel columns containing 8 mol/l urea (application of 0.1 mg protein, staining with Amidoschwarz 10 B, destaining with 7% acetic acid, density scanning at 570 nm with a scanner-integrator from Hirschmann, Munich, F.R.G.). All samples for gel electrophoresis were analyzed within 1 week under identical conditions. Significances were calculated by the Wilcoxon rank test (paired and unpaired testing).
Results As shown in Table 1 the concentrations of cholesterol and triglycerides in serum and in VLDL were significantly decreased after treatment with bezafibrate for 8 weeks. Furthermore, the level of soluble VLDL apolipoproteins and the VLDL lipid/protein ratio (which was not significantly different between pretreatment values and controls) were lowered by bezafibrate. The analysis of the soluble VLDL apolipoproteins by gel electrophoresis revealed a decrease in apo E, an increase in apo Cl and apo C2 and consequently a decrease
247
TABLE
I
CHOLESTEROL AND TRIGLYCERIDES IN SERUM AND VLDL, AND VLDL LIPID (CHOLESTEROL + TRIGLYCERIDES)/PROTEIN APOLIPOPROTEINS) RATIO BEFORE AND AFTER TREATMENT
VLDL
APOLIPOPROTEINS (APO B + SOLUBLE WITH BEZAFIBRATE (Mt-
SD)
Serum cholesterol (mg/dl) Serum triglyceride (mg/dl) VLDL cholesterol (mg/dl) VLDL triglyceride (mg/dl) VLDL apo B (mg/dl) Soluble VLDL apolipoproteins VLDL lipid/protein ratio
8- week treatment (n= IO)
Control (n= 15)
330 656 188 478
288 390 101 299
181 98 16 70
2101” i-3610° * 840° +310°0
50 f 93 * 4.66i
(mg/dl)
Wilcoxon rank test. Pretreatment pretreatment vs control (unpaired
Pretreatment (n= 10)
41 * 27 60 & 38** 3.96* 1.96 *
2000 4500 2.39
vs 8-week treatment testing): O” P
* 87: *1994* & 86** *146*
(paired
testing):
* PiO.025,
*43 *54 19 *59
6 ‘2 13 -c4 4.52* 1.99 **
P
in the apo E/ape C area ratio (Table 2). Among the C-apolipoproteins there was a significant increase in the apo C2/apo C3, area ratio. As compared to the controls the VLDL of the hypertriglyceridemic patients had higher apo E and lower apo C2 concentrations before treatment.
TABLE
2
ANALYSIS OF THE SOLUBLE VLDL APOLIPOPROTEINS WITH BEZAFIBRATE (Mk SD)
Unidentified protein Apo E C-apolipoproteins apoC1 \ apo C2 % dye uptake apo C3, I apo C3, I Apo E/ape C-area ratio Apo CZ/apo C3, -area ratio Wilcoxon treatment
rank test. vs control
BEFORE
AND AFTER
TREATMENT
Pretreatment (n= 10)
8-week treatment (n= 10)
Control (n= 15)
6.2 27.5 66.3 11.2 9.8 29.6 16.1
7.1 10.1 82.8 14.9 19.2 32.3 16.4
6.4 17.6 76.0 11.5 16.6 29.7 18.2
* 4.3 2 18.9’ f23.4 * 4.2 2 5.8’ * 9.6 * 5.4
0.41* 0.34*
0.180° o.ioc
* 6.4 k 8.9 i28.3 * * 2.5 * * 7.2 * * 9.5 * 4.5
0.13” 0.59”
Pretreatmemt vs 8-week treatment (paired (unpaired testing): o PcO.05, co P<0.01.
0.10 ** 0.12 **
testing):
* PcO.025,
-+- 6.8 + 7.0 k25.2 * 2.2 * 6.0 ‘- 9.5 f 6.2
0.23’ 0.56-t
0.10 0.19
** P
pre-
248
Discussion These data demonstrate that bezafibrate not only lowers VLDL but also causes compositional changes in VLDL of patients with type IV hyperlipoproteinemia. The decrease of the lipid/protein ratio indicates a reduction in size of VLDL particles [5] by bezafibrate. Similar effects have been reported for clofibrate [ 181. Opposite changes were observed in men after diets high in carbohydrates: VLDL particles tend to be larger in size [ 191. The elevation, of VLDL-apo C2 concentrations (which were lower before treatment in the hypertriglyceridemic than in the normal subjects) by bezafibrate may result in the stimulation of lipoprotein lipase [4] with an enhanced catabolism of VLDL. Since the elevated apo E/ape C area ratio in hypertriglyceridemia reflects an elevated concentration of VLDL-remnant particles [5], its decrease after the treatment with bezafibrate points to a preferential removal of these lipoproteins. This finding can be associated with the reported stimulation of the hepatic triglyceride lipase activity, which is responsible for the catabolism of remnant lipoproteins [4]. A similar decrease in the apo E/ape C area ratio was observed after thyroid hormone treatment in hypothyroid hyperlipoproteinemic patients [20]. References I Gbson, A.G., Rossner, S., Walldius, G., Carlson, L.A. and Lang, P.D., Effect of BM-15075 on lipoprotein concentrations in different types of hyperlipoproteinemia. Atherosclerosis, 27 (1977) 279. 2 Weisweiler, P. and Schwandt, P., Lipoprotein lipids and apolipoproteins after six months’ treatment with baafibrate, Artery, 5 (I 980) 402. 3 Schwandt, P. and Weisweiler, P., Effect of bezafibrate on the high-density lipoprotein subfractions HDL, and HDL, in primary hyperhpoproteinemia type IV, Artery, 7 (1980) 464. 4 Klose, G., Behrendt, J., Vollmar, J. and Greten, H., Wirkung von Bezafibrat auf die Lipoproteinlipasenaktivitat und die Leber-Triglyceridhydrolase bei gesunden Versuchspersonen. In: H. Greten. P.D. Lang and G. Schettler (Eds.), Lipoproteine und Heminfarkt, Verlag G. Witzstrock. Baden-Baden, Kiiln, New York, 1979, p. 185. 5 Eisenberg, S., Very-low-density lipoprotein metabolism, Progr. B&hem. Pharmacol., I5 (1979) 139. 6 Ganesan, D., Bass, H.B., McConathy, W.J. and Alaupovic, P., Is decreased activity of C-II activated lipoprotein lipase in type III hyperlipoproteinemia (broad+-disease) a cause or an effect of increased apolipoprotein E levels? Metabolism; 35 ( 1976) I 189. 7 Breckenridge, W.C., Little, J.A. Steiner, G., Chow, A. and Poapst, M., Hypertriglyceridemia associated with deficiency of apolipoprotein C-II, N. Engl. J. Med., 298 (1978) 1265. 8 La Rosa, J.C., Levy, RI., Herbert, P., Lux, S.E. and Fredrickson, D.S., A specific apoprotein activator for lipoprotein lipase, Biochem. Biophys. Res. Comm., 41 (1972) 57. 9 Brown, W.V. and Baginsky, M.L., Inhibition of lipoprotein lipase by an apoprotein of human very low density lipoproteins, B&hem. Biophys. Res. Comm., 46 (1972) 375. IO Innerarity, T.L. and Mahley, R.W., Enhanced binding by cultured human fibroblasts of apo Econtaining lipoproteins as compared with low-density lipoproteins, Biochemistry, 17 (1978) 1440. I I Kashyap, M.L., Srivastava, L.S., Chen, C.Y., Perisutti, G., Campbell, M., Lutmer, R.F. and Glueck, C.J., Radioimmunoassay of human apolipoprotein C II, J. Clin. Invest., 60 (1977) 171. 12 Carbon, L.A. and Ballantyne, D., Changing relative content of apolipoproteins C-II, and C-III of very low density lipoproteins in hypertriglyceridemia, Atherosclerosis, 23 (1976)563. 13 Catapano, A.L., The distribution of apo C-II and apo C-III in very low density lipoproteins of normal and type IV subjects, Atherosclerosis, 35 (1980) 419.
249
14 Drosner. M., Weisweiler, P. and Schwandt, P., Changes of the VLDL-apolipoproteinsC in primary type IV-hyperlipoproteinaemia by bezafibrate, J. Clin. Chem. Clin. Biochem., 18 (1980) 5.18 (Abstract). 15 Beaumont, J.-L., Carlson, L.A., Cooper, G.R., Fejfar, Z., Fredrickson, D.S. and Strasser, T., Classification of hyperlipidemias and hyperhpoproteinemias, Bull. Wld Hlth Org., 43 (I 970) 89 I. 16 Schwandt, P. and Weisweiler, P., The effect of D-thyroxine on lipoprotein lipids and apolipoproteins in primary type IIa hyperhpoproteinemia, Atherosclerosis, 35 (!980) 301. 17 Kane, J.P., Sata, T., Hamilton, R.L. and Havel, R.J.. Apoprotein composition of very low density lipoproteins of human serum, J. Clin. Invest., 56 (1975) 1622. 18 Naruszwicz, M.. Szostak. W.B., Cybulska, B., Kotlowska. M. and Chotlowska, E., The influence of clofibrate on lipid and protein components of very low-density lipoproteins in type IVhyperlipoproteinemia, Atherosclerosis, 35 (I 980) 383. 19 Schonfeld. G., Weidman, S.W., Witztum, J.L. and Bowen, R.M., Alterations in levels and interrelations of plasma apolipoproteins induced by diet, Metabolism. 25 (1976) 26 I. 20 Pagnan, A., Casara, D., Zanetti. G., Guarini. P. and Graggion, M., Serum lipids, “double pm-beta lipoproteinemia”, snd distribution of the apo-very-low-density (VLDL) lipoprotein peptides in hypothyroid patients before and after substitution therapy, Metabolism, 29 (1980) 1026.