Gene Expression Analysis in Rats Treated with Experimental Acetyl-Coenzyme A Carboxylase Inhibitors Suggests Interactions with the Peroxisome Proliferator-Activated Receptor α Pathway
| Autor: | Xiaojun Wang, Andrew L. Adler, Andrew R. Lisowski, Heidi S. Camp, Bradley A. Zinker, Jeffrey F. Waring, Scott E. Warder, Teresa Mcnally, Yi Yang, Yu Gui Gu, Xiangdong Xu, Eric A.G. Blomme, Moshe Weitzberg, Robert Dickinson, Christine H Healan-Greenberg |
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| Rok vydání: | 2007 |
| Předmět: |
Mice
Obese Peroxisome proliferator-activated receptor Biology Gene Expression Regulation Enzymologic Rats Sprague-Dawley Mice Lipid oxidation Gene expression Animals Humans PPAR alpha Enzyme Inhibitors Receptor Pharmacology chemistry.chemical_classification Acetyl-CoA carboxylase Biological activity Peroxisome Molecular biology Rats chemistry Biochemistry Hepatocytes Molecular Medicine Signal transduction Acetyl-CoA Carboxylase Signal Transduction |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 324:507-516 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.107.126938 |
| Popis: | Acetyl CoA carboxylase (ACC) 2, which catalyzes the carboxylation of acetyl-CoA to form malonyl-CoA, has been identified as a potential target for type 2 diabetes and obesity. Small-molecule inhibitors of ACC2 would be expected to reduce de novo lipid synthesis and increase lipid oxidation. Treatment of ob/ob mice with compound A-908292 (S) ({(S)-3-[2-(4-isopropoxy-phenoxy)-thiazol-5-yl]-1-methyl-prop-2-ynyl}-carbamic acid methyl ester), a small-molecule inhibitor with an IC(50) of 23 nM against ACC2, resulted in a reduction of serum glucose and triglyceride levels. However, compound A-875400 (R) ({(R)-3-[2-(4-isopropoxy-phenoxy)-thiazol-5-yl]-1-methyl-prop-2-ynyl}-carbamic acid methyl ester), an inactive enantiomer of A-908292 (S) with approximately 50-fold less activity against ACC2, also caused a similar reduction in glucose and triglycerides, suggesting that the glucose-lowering effects in ob/ob mice may be mediated by other metabolic pathways independent of ACC2 inhibition. To characterize the pharmacological activity of these experimental compounds at a transcriptional level, rats were orally dosed for 3 days with either A-908292 (S) or A-875400 (R), and gene expression analysis was performed. Gene expression analysis of livers showed that treatment with A-908292 (S) or A-875400 (R) resulted in gene expression profiles highly similar to known peroxisome proliferator-activated receptor (PPAR)-alpha activators. The results suggest that, in vivo, both A-908292 (S) and A-875400 (R) stimulated the PPAR-alpha-dependent signaling pathway. These results were further supported by both an in vitro genomic evaluation using rat hepatocytes and immunohistochemical evaluation using 70-kDa peroxisomal membrane protein. Overall, the gene expression analysis suggests a plausible mechanism for the similar pharmacological findings with active and inactive enantiomers of an ACC2 inhibitor. |
| Databáze: | OpenAIRE |
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