MTP inhibitor decreases plasma cholesterol levels in LDL receptor-deficient WHHL rabbits by lowering the VLDL secretion

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Abstract

To examine whether a microsomal triglyceride transfer protein (MTP)-inhibitor is effective in patients with homozygous familial hypercholesterolemia, we administered (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), a new MTP inhibitor, to low-density lipoprotein (LDL)-receptor-deficient Watanabe heritable hyperlipidemic (WHHL) rabbits at doses of 3, 6, and 12 mg/kg for 4 weeks. In the 12 mg/kg group, the plasma cholesterol and triglyceride levels were decreased by 70% and 45%, respectively, and the very low-density lipoprotein (VLDL) secretion rate was decreased by 80%. The composition of newly secreted VLDL was similar in each group. This suggests that Implitapide diminished the number of VLDL particles secreted from the liver. Although the ratio of vitamin E/LDL was not altered by Implitapide, triglyceride accumulation and a decrease in vitamin E were observed in the liver. In conclusion, an inhibition of VLDL secretion led to a decrease of plasma LDL in WHHL rabbits, and MTP inhibitors should have hypolipidemic effects against homozygous familial hypercholesterolemia.

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.

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