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| Status |
Public on Jun 30, 2011 |
| Title |
Expression data from livers of high fat fed rats treated with ACC inhibitor PF-04923503 |
| Organism |
Rattus norvegicus |
| Experiment type |
Expression profiling by array
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| Summary |
Fundamental alterations in lipid metabolism including increased rates of de novo lipogenesis (DNL), reduced fatty acid oxidation (FAOX) and ectopic lipid accumulation in skeletal muscle and liver are characteristic of type 2 diabetes mellitus (T2DM) and have been hypothesized to directly contribute to the molecular pathogenesis of the disease. Acetyl-CoA carboxylase (ACC) catalyzes the formation of malonyl-CoA, the rate limiting substrate for DML and key regulator of FAOX. ACC inhibitors have the potential to pharmacologically rebalance these metabolic alterations. In the present study, PF-04923503, a potent dual ACC1/ACC2 inhibitor with properties optimized for in vivo studies, suppressed levels of malonyl-CoA in primary hepatocytes, rat skeletal muscle ex vivo, as well as rat liver and skeletal muscle in vivo. This impact on malonyl-CoA was directly correlated (r2>0.9) with reduced hepatic DNL and inversely correlated with incresed rates of FAOX (r2>0.9). The pharmacological eccfect of PF-04923503 persisted with chronic treatment. High-fat fed rats treated with PF-04923503 for six weeks showed dose-dependent reductions in skeletal muscle and liver lipid accumulation. These changes correlated directly with markers for improved insulin sensitization. However, liver gene expression indicates that pharmacological inhibition results in compensation by up-regualtion of genes involved with DNL. These results suggest that pharmacological inhibition of ACC may have utility to help rebalance metabolic abnormalities in T2DM and improve insulin sensitivity.
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| Overall design |
Differential gene expression was assessed by Affymetrix microarray experiments for 15 liver samples across 3 pharmacological treatment groups (vehicle control 0.5% methylcellulose had 5 samples, PF-04923503 10mpk had 5 samples, PF-04923503 30mpk had 5 samples)
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| Contributor(s) |
Grosskurth SE, Esler WP, Kuhn M, des Etages SG, McPherson K, Amor P |
| Citation missing |
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| Submission date |
Mar 21, 2011 |
| Last update date |
Jul 31, 2017 |
| Contact name |
William Esler |
| Organization name |
Pfizer
|
| Street address |
Eastern Point Road
|
| City |
Groton |
| State/province |
CT |
| ZIP/Postal code |
06340 |
| Country |
USA |
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| Platforms (1) |
| GPL1355 |
[Rat230_2] Affymetrix Rat Genome 230 2.0 Array |
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| Samples (15)
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| Relations |
| BioProject |
PRJNA139779 |
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