Takuya Sakamoto

Delayed catabolism of high density lipoprotein apolipoproteins A-I and A-II in human cholesteryl ester transfer protein deficiency.

Deficiency of the cholesteryl ester transfer protein (CETP) in humans is characterized by markedly elevated plasma concentrations of HDL cholesterol and apoA-I. To assess the metabolism of HDL apolipoproteins in CETP deficiency, in vivo apolipoprotein kinetic studies were performed using endogenous and exogenous labeling techniques in two unrelated homozygotes with CETP deficiency, one heterozygote, and four control subjects. All study subjects were administered 13C6-labeled phenylalanine by primed constant infusion for up to 16 h. The fractional synthetic rates (FSRs) of apoA-I in two homozygotes with CETP deficiency (0.135, 0.134/d) were found to be significantly lower than those in controls (0.196 +/- 0.041/d, P < 0.01). Delayed apoA-I catabolism was confirmed by an exogenous radiotracer study in one CETP-deficient homozygote, in whom the fractional catabolic rate of 125I-apoA-I was 0.139/d (normal 0.216 +/- 0.018/d). The FSRs of apoA-II were also significantly lower in the homozygous CETP-deficient subjects (0.104, 0.112/d) than in the controls (0.170 +/- 0.023/d, P < 0.01). The production rates of apoA-I and apoA-II were normal in both homozygous CETP-deficient subjects. The turnover of apoA-I and apoA-II was substantially slower in both HDL2 and HDL3 in the CETP-deficient homozygotes than in controls. The kinetics of apoA-I and apoA-II in the CETP-deficient heterozygote were not different from those in controls. These data establish that homozygous CETP deficiency causes markedly delayed catabolism of apoA-I and apoA-II without affecting the production rates of these apolipoproteins.

Increased catabolic rate of low density lipoproteins in humans with cholesteryl ester transfer protein deficiency.

The cholesteryl ester transfer protein (CETP) transfers lipids among lipoprotein particles and plays a central role in lipoprotein metabolism. Humans with genetic deficiency of CETP have both elevated HDL cholesterol and apolipoprotein A-I concentrations as well as decreased LDL cholesterol and apolipoprotein B levels. The present study was undertaken to elucidate the metabolic basis for the decreased LDL cholesterol and apo B levels in CETP deficiency. We conducted a series of in vivo apo B kinetic studies in tow unrelated homozygotes with CETP deficiency and in control subjects. A primed constant infusion of stable isotopically labeled phenylalanine was administered to the two CETP deficient subjects and control subjects and apo B kinetic parameters in VLDL, intermediate density lipoproteins, and LDL were obtained by using a multicompartmental model. The fractional catabolic rates (FCR) of LDL apo B were significantly increased in the CETP-deficient subjects (0.56 and 0.75/d) compared with the controls (mean FCR of 0.39/d). Furthermore, the production rates of apo B in VLDL and intermediate density lipoprotein were decreased by 55% and 81%, respectively, in CETP deficiency compared with the controls. In conclusion, CETP-deficient subjects were demonstrated to have substantially increased catabolic rates of LDL apo B as the primary metabolic basis for the low plasma levels of LDL apo B. This result indicates that the LDL receptor pathway may be up-regulated in CETP deficiency.

Effects of gammalinolenic acid on plasma lipoproteins and apolipoproteins

Nineteen hypercholesterolemic patients (10 without and 9 with hypertriglyceridemia) were given evening primrose oil rich in gammalinolenic acid (GLA, 18: 3n - 6), in a placebo controlled cross-over design, over 16 weeks (8 + 8 weeks), with safflower oil as the placebo. During supplementation with evening primrose oil, dihomogammalinolenic acid (20: 3n - 6) increased in plasma lipids and red blood cells, and in subjects without hypertriglyceridemia there was a significant decrease in low density lipoprotein-cholesterol and plasma apolipoprotein B compared with the levels observed during safflower oil administration. Our results confirmed that evening primrose oil is effective in lowering low density lipoprotein in hypercholesterolemic patients.

Effects of probucol and pravastatin on plasma lipids, activities of postheparin lipoprotein lipase, and lecithin cholesterol acyltransferase and apo A-I containing lipoproteins with and without apo A-II in patients with moderate hypercholesterolemia.

In this study, plasma HDL fractions were separated by ultracentrifugation and apo A-I containing lipoproteins (A-I Lp) were then isolated using anti-apo A-I immunoaffinity chromatography. The A-I Lp were further separated into two fractions with the use of anti-apo A-II immunoaffinity chromatography. One fraction, Lp A-I, contained apo A-I without apo A-II, while the other, Lp A-I/A-II, contained both apo A-I and apo A-II. These techniques were applied to investigate the changes in HDL apoprotein composition in hypercholesterolemic subjects treated with either probucol or pravastatin. Treatment with probucol (500 mg/day) or pravastatin (10 mg/day) reduced mean plasma total cholesterol concentrations by 24% (p < 0.01) and 16% (p < 0.05), respectively. Both drugs caused some reduction in lipoprotein lipase activity, but neither had any influence on the activity of hepatic triglyceride lipase or lecithin cholesterol acyltransferase. Their effects on HDL-cholesterol levels and apoprotein composition differed markedly. Probucol significantly decreased the HDL-cholesterol concentration, the plasma apo A-I/apo A-II ratio, and the number of large particles of diameter greater than 10.4 nm. When the ratios of Lp A-I and Lp A-I/A-II for the probucol-treated subjects were compared with those in the normolipidemic controls, and with the ratios before and after administration of probucol, a remarkable decrease in the level of Lp A-I was apparent. It is presumed that the decrease in HLD-cholesterol by prolonged probucol administration reflects the decrease of Lp A-I more than the decrease of Lp A-I/A-II.(ABSTRACT TRUNCATED AT 250 WORDS)