MTP inhibitor decreases plasma cholesterol levels in LDL receptor-deficient WHHL rabbits by lowering the VLDL secretion.
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.
Shiomi
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M
Institute for Experimental Animals, Kobe University School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, 650-0017, Kobe, Japan. ieakusm@med.kobe-u.ac.jp
Ito
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T
D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002784:Cholesterol / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood; D004195:Disease Models, Animal; D015536:Down-Regulation; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000188:drug therapy*; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008079:Lipoproteins, VLDL / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D011973:Receptors, LDL / Q000097:blood / Q000172:deficiency*; D014280:Triglycerides / Q000097:blood; D014810:Vitamin E / Q000097:blood
D002352:Carrier Proteins; D008078:Cholesterol, LDL; D007211:Indoles; D008079:Lipoproteins, VLDL; D011725:Pyridines; D011973:Receptors, LDL; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; D014810:Vitamin E; D002784:Cholesterol; C443181:implitapide