Effects of a novel dual lipid synthesis inhibitor and its potential utility in treating dyslipidemia and metabolic syndrome
We have identified a novel ω-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 β-hydr...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2004-07-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520317855 |
| _version_ | 1818676148575404032 |
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| author | Clay T. Cramer Brian Goetz Krista L.M. Hopson Gregory J. Fici Rose M. Ackermann Stephen C. Brown Charles L. Bisgaier W.G. Rajeswaran Daniela C. Oniciu Michael E. Pape |
| author_facet | Clay T. Cramer Brian Goetz Krista L.M. Hopson Gregory J. Fici Rose M. Ackermann Stephen C. Brown Charles L. Bisgaier W.G. Rajeswaran Daniela C. Oniciu Michael E. Pape |
| author_sort | Clay T. Cramer |
| collection | DOAJ |
| description | We have identified a novel ω-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 β-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 [14C]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. |
| first_indexed | 2024-12-17T08:38:52Z |
| format | Article |
| id | doaj.art-6e66dc604caa440cad0b2da77bb5ad67 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-17T08:38:52Z |
| publishDate | 2004-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-6e66dc604caa440cad0b2da77bb5ad672022-12-21T21:56:25ZengElsevierJournal of Lipid Research0022-22752004-07-0145712891301Effects of a novel dual lipid synthesis inhibitor and its potential utility in treating dyslipidemia and metabolic syndromeClay T. Cramer0Brian Goetz1Krista L.M. Hopson2Gregory J. Fici3Rose M. Ackermann4Stephen C. Brown5Charles L. Bisgaier6W.G. Rajeswaran7Daniela C. Oniciu8Michael E. Pape9Esperion Therapeutics, Inc., Ann Arbor, MI 48108Esperion Therapeutics, Inc., Ann Arbor, MI 48108Esperion Therapeutics, Inc., Ann Arbor, MI 48108Esperion Therapeutics, Inc., Ann Arbor, MI 48108Esperion Therapeutics, Inc., Ann Arbor, MI 48108Esperion Therapeutics, Inc., Ann Arbor, MI 48108Esperion Therapeutics, Inc., Ann Arbor, MI 48108Esperion Therapeutics, Inc., Ann Arbor, MI 48108Esperion Therapeutics, Inc., Ann Arbor, MI 48108Esperion Therapeutics, Inc., Ann Arbor, MI 48108We have identified a novel ω-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 β-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 [14C]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.http://www.sciencedirect.com/science/article/pii/S0022227520317855hepatocytesacetyl-CoA carboxylaseZuckerAMP-activated protein kinasexenobiotic-CoA |
| spellingShingle | Clay T. Cramer Brian Goetz Krista L.M. Hopson Gregory J. Fici Rose M. Ackermann Stephen C. Brown Charles L. Bisgaier W.G. Rajeswaran Daniela C. Oniciu Michael E. Pape Effects of a novel dual lipid synthesis inhibitor and its potential utility in treating dyslipidemia and metabolic syndrome Journal of Lipid Research hepatocytes acetyl-CoA carboxylase Zucker AMP-activated protein kinase xenobiotic-CoA |
| title | Effects of a novel dual lipid synthesis inhibitor and its potential utility in treating dyslipidemia and metabolic syndrome |
| title_full | Effects of a novel dual lipid synthesis inhibitor and its potential utility in treating dyslipidemia and metabolic syndrome |
| title_fullStr | Effects of a novel dual lipid synthesis inhibitor and its potential utility in treating dyslipidemia and metabolic syndrome |
| title_full_unstemmed | Effects of a novel dual lipid synthesis inhibitor and its potential utility in treating dyslipidemia and metabolic syndrome |
| title_short | Effects of a novel dual lipid synthesis inhibitor and its potential utility in treating dyslipidemia and metabolic syndrome |
| title_sort | effects of a novel dual lipid synthesis inhibitor and its potential utility in treating dyslipidemia and metabolic syndrome |
| topic | hepatocytes acetyl-CoA carboxylase Zucker AMP-activated protein kinase xenobiotic-CoA |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520317855 |
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