The ACAT inhibitor avasimibe increases the fractional clearance rate of postprandial triglyceride-rich lipoproteins in miniature pigs
| Autor: | Dawn E. Telford, John R. Burnett, P. Hugh R. Barrett, Murray W. Huff |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Very low-density lipoprotein
medicine.medical_specialty Apolipoprotein B Metabolic Clearance Rate Swine Lipoproteins Sterol O-acyltransferase Acetates Models Biological chemistry.chemical_compound Retinyl palmitate Internal medicine Acetamides Intestine Small medicine Animals Enzyme Inhibitors Molecular Biology Triglycerides Sulfonamides Dose-Response Relationship Drug biology Triglyceride Chemistry Area under the curve Cell Biology Postprandial Period Lipids Kinetics Endocrinology Postprandial Liver biology.protein Swine Miniature Sulfonic Acids Sterol O-Acyltransferase Lipoprotein |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1738:10-18 |
| ISSN: | 1388-1981 |
| DOI: | 10.1016/j.bbalip.2005.11.010 |
| Popis: | Previously, we have shown, in vivo, that the acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitor avasimibe decreases hepatic apolipoprotein (apo) B secretion into plasma. To test the hypothesis that avasimibe modulates postprandial triglyceride-rich lipoprotein (TRL) metabolism in vivo, an oral fat load (2 g fat/kg) containing retinol was given to 9 control miniature pigs and to 9 animals after 28 days treatment with avasimibe (10 mg/kg/day, n=5; 25 mg/kg/day, n=4). The kinetic parameters for plasma retinyl palmitate (RP) metabolism were determined by multi-compartmental modeling using SAAM II. Avasimibe decreased the 2-h TRL (d1.006 g/mL; S(f)20) triglyceride concentrations by 34%. The TRL triglyceride 0-12 h area under the curve (AUC) was decreased by 21%. In contrast, avasimibe had no effect on peak TRL RP concentrations, time to peak, or its rate of appearance into plasma, however, the TRL RP 0-12 h AUC was decreased by 17%. Analysis of the RP kinetic parameters revealed that the TRL fractional clearance rate (FCR) was increased 1.4-fold with avasimibe. The TRL RP FCR was negatively correlated with very low density lipoprotein (VLDL) apoB production rate measured in the fasting state (r=-0.504). No significant changes in total intestinal lipid concentrations were observed. Thus, although avasimibe had no effect on intestinal TRL secretion, plasma TRL clearance was significantly increased; an effect that may relate to a decreased competition with hepatic VLDL for removal processes. |
| Databáze: | OpenAIRE |
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