Effects of a novel dual lipid synthesis inhibitor and its potential utility in treating dyslipidemia and metabolic syndrome
Autor: | Rose Ackermann, Gregory J. Fici, Brian Goetz, Krista L.M. Hopson, Michael E. Pape, Daniela C. Oniciu, Stephen C. Brown, Clay T. Cramer, W.G. Rajeswaran, Charles L. Bisgaier |
---|---|
Jazyk: | angličtina |
Rok vydání: | 2004 |
Předmět: |
Blood Glucose
medicine.medical_specialty Coenzyme A Hyperlipidemias QD415-436 AMP-Activated Protein Kinases Protein Serine-Threonine Kinases Weight Gain Biochemistry chemistry.chemical_compound Endocrinology fluids and secretions AMP-activated protein kinase Multienzyme Complexes Internal medicine medicine Animals Insulin Dicarboxylic Acids Carnitine Cells Cultured chemistry.chemical_classification Metabolic Syndrome biology Triglyceride Dose-Response Relationship Drug Fatty Acids Acetyl-CoA carboxylase AMPK Fatty acid Lipid metabolism Cell Biology biochemical phenomena metabolism and nutrition Lipids Rats Rats Zucker acetyl-CoA carboxylase Sterols chemistry Zucker biology.protein xenobiotic-CoA Female hepatocytes Lipid Peroxidation medicine.drug |
Zdroj: | Journal of Lipid Research, Vol 45, Iss 7, Pp 1289-1301 (2004) |
ISSN: | 0022-2275 |
Popis: | We have identified a novel omega-hydroxy-alkanedicarboxylic acid, ESP 55016, that favorably alters serum lipid variables in obese female Zucker (fa/fa) rats. ESP 55016 reduced serum non-HDL-cholesterol (non-HDL-C), triglyceride, and nonesterified fatty acid levels while increasing serum HDL-C and beta-hydroxybutyrate levels in a dose-dependent manner. ESP 55016 reduced fasting serum insulin and glucose levels while also suppressing weight gain. In primary rat hepatocytes, ESP 55016 increased the oxidation of [(14)C]palmitate in a dose- and carnitine palmitoyl transferase-I (CPT-I)-dependent manner. Furthermore, in primary rat hepatocytes and in vivo, ESP 55016 inhibited fatty acid and sterol synthesis. The "dual inhibitor" activity of ESP 55016 was unlikely attributable to the activation of the AMP-activated protein kinase (AMPK) pathway because AMPK and acetyl-CoA carboxylase (ACC) phosphorylation states as well as ACC activity were not altered by ESP 55016. Further studies indicated the conversion of ESP 55016 to a CoA derivative in vivo. ESP 55016-CoA markedly inhibited the activity of partially purified ACC. The activity of partially purified HMG-CoA reductase was not altered by the xenobiotic-CoA. These data suggest that ESP 55016-CoA favorably alters lipid metabolism in a model of diabetic dyslipidemia in part by initially inhibiting fatty acid and sterol synthesis plus enhancing the oxidation of fatty acids through the ACC/malonyl-CoA/CPT-I regulatory axis. |
Databáze: | OpenAIRE |
Externí odkaz: |