Received for publication June 11, 2007.
Revised November 15, 2007.
Accepted for publication November 15, 2007.

Gene Expression Analysis in Rats Treated With Experimental Acetyl-CoA Carboxylase Inhibitors Suggests Interactions with the PPAR Alpha Pathway

Abstract

Acetyl CoA carboxylase 2 (ACC2), 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), a small molecule inhibitor with an IC50 of 23 nM against ACC2, resulted in a reduction of serum glucose and triglyceride levels. However, compound A-875400 (R), 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. In order to characterize the pharmacological activity of these experimental compounds at a transcriptional level, rats were orally dosed for three 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 alpha (PPAR-) activators. The results suggest that, in vivo, both A-908292 (S) and A-875400 (R) stimulated the PPAR--dependent signaling pathway. These results were further supported by both an in vitro genomic evaluation using rat hepatocytes and immunohistochemical evaluation using PMP70 staining. Overall, the gene expression analysis suggests a plausible mechanism for the similar pharmacological findings with an active and inactive enantiamer of an ACC2 inhibitor.

Key words: Acetyl CoA carboxylase 2, Gene expression, Metabolic disease, Microarray, PPAR-alpha, Peroxisome proliferation