MTP inhibitor decreases plasma cholesterol levels in LDL receptor-deficient WHHL rabbits by lowering the VLDL secretion
Introduction
In patients with homozygous familial hypercholesterolemia, especially low-density lipoprotein (LDL)-receptor null type, therapy using inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (statin), which competitively inhibits cholesterol biosynthesis and increase the LDL-receptor function, has almost no effect. To reduce the plasma cholesterol levels of homozygous familial hypercholesterolemia, reduction in the secretion of very low-density lipoprotein (VLDL)-cholesterol from the liver may be one of the important approaches.
Microsomal triglyceride transfer protein (MTP) plays an important role in the assembly of VLDL particles in the liver and of chylomicron particles in the intestine Wetterau et al., 1992, Sharp et al., 1993, Sorbera et al., 2000. In vitro studies have demonstrated that if the assembly of VLDL is suppressed, secretion of the lipoproteins is reduced Jamil et al., 1996, Gruetzmann et al., 2000. The main mechanisms of hypolipidemic effects of MTP inhibitors are largely different from inhibitors for HMG-CoA reductase. Therefore, MTP inhibitors have the possibility of lowering the plasma cholesterol levels of patients with homozygous familial hypercholesterolemia.
Recently, Wetterau et al. (1998) reported the effect of an MTP inhibitor on lipoprotein lipid levels and the triglyceride secretion rate using rats and hamsters. They also showed an MTP inhibitor that normalized the plasma lipid levels of homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits, which is an LDL receptor-deficient animal model Tanzawa et al., 1980, Kita et al., 1981. There are no original studies reporting whether MTP inhibitors suppress secretion of VLDL particles from the liver in vivo. Therefore, we attempted to examine the effects of an MTP inhibitor on the VLDL secretion rate, lipoprotein levels, and plasma vitamin E levels in homozygous WHHL rabbits, using another MTP inhibitor (2S)-2-cyclopentyl-2-{4-[(2,4-dimethyl-9H-pyrido[2,3-b]indol-9-yl)methyl]phenyl}-N-[(1S)-2-hydroxy-1-phenylethyl]ethanamide (Implitapide) (Sorbera et al., 2000).
Section snippets
Materials
Implitapide was provided by Bayer Yakuhin (Osaka, Japan). Triton WR-1339 (4-(1,1,3,3-tetramethylbutyl)phenol polymer with formaldehyde and oxirane) was purchased from Nakarai Tesque (Tokyo, Japan).
Animals
Twenty male homozygous WHHL rabbits (Shiomi et al., 1992) aged 6 months were divided into four groups, i.e., a placebo group and Implitapide-treated groups administered daily doses of 3, 6, and 12 mg/kg, respectively. Implitapide was suspended in 0.5% methylcellulose every day and was administered to
Effect of Implitapide on the plasma and lipoprotein lipid levels
All plasma lipid levels were decreased dose-dependently by Implitapide treatment. Comparing the highest dose group to the placebo group, the decrease in plasma lipid levels was 70% (P<0.01) for cholesterol (20.4±1.0 vs. 6.2±0.8 mM) and 45% (P<0.01) for triglyceride (2.0±0.4 vs. 1.1±0.1 mM). In Fig. 1, each lipoprotein containing apolipoprotein-B100 was decreased dose-dependently by Implitapide treatment. In the highest dose group, the VLDL fraction was markedly decreased: the decrease was 79% (P
Discussion
In this study, we examined whether inhibition of VLDL secretion by MTP inhibitor administration could reduce the plasma cholesterol levels even in the LDL receptor-deficient state. We found that 12 mg/kg of Implitapide markedly decreased the level of atherogenic apolipoprotein-B100-containing lipoproteins and the VLDL secretion rate in homozygous WHHL rabbits. This suggests that a potent inhibition of VLDL secretion led to a marked decrease in LDL in the plasma even in the LDL-receptor
Acknowledgements
We acknowledge Bayer Yakuhin for providing Implitapide. This work was supported in part by a research grant from Bayer Yakuhin.
References (21)
- et al.
A simple method for the isolation and purification of total lipids from animal tissues
J. Biol. Chem.
(1957) - et al.
Bay 13-9952 (Implitapide), an inhibitor of the microsomal triglyceride transfer protein (MTP), blocks secretion of apo-B-lipoproteins
Atherosclerosis
(2000) - et al.
Effects of chronic glucagons administration on rat lipoprotein composition
Biochim. Biophys. Acta
(1989) - et al.
Effects of pravastatin sodium alone and in combination with cholestyramine on hepatic, intestinal and adrenal low density lipoprotein receptors in homozygous Watanabe heritable hyperlipidemic rabbits
Jpn. J. Pharmacol.
(1992) - et al.
Protein measurement with Folin phenol reagent
J. Biol. Chem.
(1951) - et al.
Pravastatin sodium, a competitive inhibitor of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase, decreased the cholesterol content of newly secreted very-low-density lipoprotein in Watanabe heritable hyperlipidemic rabbits
Metabolism
(1994) - et al.
Inheritability of atherosclerosis and the role of lipoproteins as risk factors in the development of atherosclerosis in WHHL rabbits: risk factors related to coronary atherosclerosis are different from those related to aortic atherosclerosis
Atherosclerosis
(1992) - et al.
WHHL-rabbit: a low density lipoprotein receptor-deficient animal model for familial hypercholesterolemia
FEBS Lett.
(1980) - et al.
The inhibition in vivo of lipoprotein lipase (clearing-factor lipase) activity by Triton WR-1339
Biochem. J.
(1976) - et al.
Plasma clearance and net uptake of α-tocopherol and low-density lipoprotein by tissues in WHHL and control rabbits
Biochem. J.
(1992)