Atherosclerosis, 88 (1991) 175-181 0 1991 Elsevier Scientific Publishers ADONIS 002191509100121F

ATHERO

175 Ireland,

Ltd. 0021-9150/91/$03.50

04638

Effects of probucol on plasma lipoprotein subfractions and activities of lipoprotein lipase and hepatic triglyceride lipase Yasuhiko Homma ‘, Emilio H. Moriguchi ‘, Hiroya Sakane I, Hideki Ozawa ‘, Haruo Nakamura 2 and Yuichiro Goto ’ ’Department of Internal Medicine, Tukai Unicersity School of Medicine, Bohseidai, Isehara 259-l 1 (Japan) and ’ First Department of Internal Medicine, National Defense Medical Collage, 3-2, Namiki, Tokorozawa 35’9 (Japan) (Received 4 November. 1989) (Revised, received 1 February, 1991) (Accepted 5 February, 1991)

Summary

The effects of 12 weeks treatment with probucol on plasma liporotein subfraction levels and on LPL and HTGL activities were investigated. Plasma VLDL-C, VLDL-TG, VLDL-apo B levels were not changed. Probucol significantly reduced plasma IDL-C and IDL-apo B levels by 26.7% and 23.8%, respectively. Plasma cholesterol and apo B levels of large light LDL (LDL,) were decreased significantly by 27.8% and 23.2% by probucol treatment. Plasma cholesterol and apo B levels of small heavy LDL (LDL,) remained unchanged. Probucol markedly reduced plasma HDL, levels. The reduction rates of plasma TC, TG and apo A-I levels of HDL, were 43.0%, 43.6% and 47.0%. Probucol significantly decreased HDL,-C and HDL,-apo A-I levels by 18.0% and 19.2%. LPL activities in the post-heparin plasma were decreased significantly from 2.53 + 0.71 pmol free fatty acids (FFA)/ml/h to 1.71 t_ 0.71 Fmol FFA/ml/h by probucol while HTGL activities remained unchanged. We conclude that probucol suppresses LPL activity and decreases plasma IDL, LDL, and HDL, levels due to disturbances of VLDL conversion to LDL, via IDL and of HDL, conversion to HDL,.

Key words: Probucol; Lipoprotein Hyperlipoproteinemia

subfraction; Lipoprotein

Correspondence to: Yasuhiko Homma, M.D., Department of Internal Medicine, Tokai University School of Medicine, Bohseidai, Isehara, 259-11, Japan. Tel. 81-463-93-1121 ext. 2200; Fax: 81-463-93-6679.

lipase; Hepatic triglyceride lipase;

Introduction Low density lipoprotein (LDL) is a heterogenous lipoprotein fraction [1,2]. When LDL is frac-

176 tionated into two fractions i.e. the large light LDL and the small heavy LDL, the atherogenic effect is not the same. Plasma large light LDL levels are increased in familial hypercholesterolemia that frequently complicates premature atherosclerosis [3,4]. Some papers reported that the small heavy LDL was increased in the plasma of coronary heart disease (CHD) patients [5,6]. Crouse et al. [5] demonstrated that the small heavy LDL was not increased in the plasma of CHD patients when plasma triglyceride levels were matched. Thus it has still not been well defined which fraction of LDL is more atherogenie. Probucol is an antioxidant and potent hypocholesterolemic agent [7-241. It is also well known to reduce plasma high density lipoprotein (HDL) levels, especially HDL, levels [10,11,1315,17,18,21,24]. However, the effects of probucol on plasma LDL distribution are not known. Lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) are the main determinants of plasma lipoprotein distribution [2,25]. LPL reTABLE PLASMA Subjects

1 2 3 4 5 h 7 8 9 10 11 12 13 14 15 16 17 18 19 20 a h ’ d

moves triglyceride from very low density lipoprotein (VLDL) and converts it to intermediate density lipoprotein (IDL), which is believed to be converted to LDL by HTGL. Analysis of plasma LDL distribution in HTGL deficiency, the in vivo injection study of anti-HTGL antibody into animals, and the in vitro incubation study of large light LDL with HTGL indicated that HTGL converted large light LDL to small heavy LDL [4,26281. The aim of this study was to investigate the effect of probucol on the metabolic interrelationship between large light LDL and small heavy LDL, based on analysis of plasma lipoprotein subfractions and the assay of LPL and HTGL activities. Materials

and methods

Clinical protocol

Probucol (1000 mg/day) was administered to 20 hyperlipoproteinemic out-patients for 12 weeks

1 LIPID

LEVELS

OF SUBJECTS

Age (yrs)

Sex

53 56 62 60 59 68 70 66 74 60 72 48 54 48 65 62 66 49 50 70

M M F F F M F F F F F M M F F M M M M M

Plasma total cholesterol level. Plasma triglyceride level. Plasma HDL-cholesterol level. Hyperlipoproteinemia.

BMI

TC a

TG h

HDL-C

(kg/m’)

(mg/dl)

(mg/dl)

(mg/dl)



HL* phenotype

20.2 21.3 21.1 24.4 26.0 24.6 24.5 26.8 24.0 22.0 21.7 26.5 24.0 24.0 26.6 21.5 25.0 26.8 26.0 24.1

268 285 251 321 254 284 319 343 314 266 389 285 269 325 272 283 262 243 216 212

114 137 142 126 104 144 163 136 102 139 212 292 206 259 198 194 202 657 347 189

50 54 59 73 52 49 72 44 69 47 44 32 50 39 68 33 50 30 30 74

IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIb IIb IIb IIb IIb IIb IIb IV IV IV

177 without any combination after 6 weeks period of no medication (Table 1). Blood sampling for the analysis of plasma lipids, apoproteins and lipoprotein subfractions was made after 12 h fasting. Then, heparin (10 U/kg body weight) was injected intravenously and the blood was taken 10 min later for the assay of LPL and HTGL activities. The postheparin plasma (PHP) was stored at - 70 ’C until the assay of LPL and HTGL activities. Plasma levels of lipids and apoproteins were measured every 4 weeks. The plasma lipoprotein subfractionation was also made at 0 and 12 weeks. The assay of LPL and HTGL activities was made at 0, 4 and 12 weeks.

LDLl

I

LDL2

Laboratory procedures (1) Plasma lipoprotein separation and measureLipoproteins were ment of lipids and apoproteins.

sequentially fractionated by ultracentrifugation by the method of Have1 et al. [30]. Plasma lipoproteins were subfractionated into VLDL (d < 1.0061, IDL (1.006

Effects of probucol on plasma lipoprotein subfractions and activities of lipoprotein lipase and hepatic triglyceride lipase.

The effects of 12 weeks treatment with probucol on plasma lipoprotein subfraction levels and on LPL and HTGL activities were investigated. Plasma VLDL...
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