Antidyslipidemic effects of a farnesoid X receptor antagonist in primates
| Autor: | Shotaro Miura, Ryutaro Adachi, Yuichiro Amano, Mitsuyuki Shimada, Ryuichi Tozawa |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Primates medicine.medical_specialty medicine.drug_class Receptors Cytoplasmic and Nuclear General Biochemistry Genetics and Molecular Biology chemistry.chemical_compound Ezetimibe Bile acid sequestrant Internal medicine medicine Animals Cholesterol absorption inhibitor General Pharmacology Toxicology and Pharmaceutics Dyslipidemias Cholestyramine Dose-Response Relationship Drug Cholesterol Anticholesteremic Agents Reverse cholesterol transport Torcetrapib General Medicine Macaca fascicularis Endocrinology Treatment Outcome chemistry lipids (amino acids peptides and proteins) Farnesoid X receptor Female medicine.drug |
| Zdroj: | Life sciences. 106(1-2) |
| ISSN: | 1879-0631 |
| Popis: | Aims We investigated antidyslipidemic effects of a farnesoid X receptor antagonist compound-T3 in non-human primates as a novel treatment approach for dyslipidemia. Main methods Cynomolgus monkeys were fed a high-fat diet over 3 weeks. Drugs were administered to the monkeys for a week, and their plasma and fecal lipid parameters were measured. Key findings Compound-T3 dose-dependently decreased the plasma non-high-density lipoprotein (non-HDL) cholesterol and apolipoprotein B levels in high-fat diet-fed cynomolgus monkeys. The plasma levels of 7α-hydroxy-4-cholesten-3-one, a marker of hepatic cholesterol 7α-hydroxylase activity, and total fecal bile acid levels increased, suggesting that the hypocholesterolemic effects would be dependent on the activation of cholesterol catabolism in the liver. Compound-T3 significantly increased the plasma levels of HDL cholesterol and apolipoprotein A-I. In this condition, the cholesterol absorption inhibitor ezetimibe significantly decreased the plasma non-HDL cholesterol levels and increased the fecal cholesterol levels without affecting plasma HDL cholesterol and triglyceride levels. Bile acid sequestrant cholestyramine tended to decrease plasma non-HDL cholesterol and increase fecal bile acid levels. The cholesteryl ester transfer protein inhibitor torcetrapib significantly increased plasma HDL cholesterol levels without affecting plasma non-HDL cholesterol and fecal cholesterol levels. Significance The results of ezetimibe, cholestyramine, and torcetrapib treatments indicate that our high-fat diet fed monkey model would be a preferred animal model for studying non-statin type antidyslipidemic drugs. Compound-T3 significantly decreased non-HDL cholesterol levels and increased HDL cholesterol levels in the monkey model, suggesting that a farnesoid X receptor antagonist could be a therapeutic option in human dyslipidemia. |
| Databáze: | OpenAIRE |
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