title: Gene expression analysis in rats treated with experimental acetyl-coenzyme A carboxylase inhibitors suggests interactions with the peroxisome proliferator-activated receptor alpha pathway.
abstract: 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.
authors.affiliation: Molecular and Cellular Toxicology, Abbott Laboratories, Building AP9A R463, 100 Abbott Park Road, Abbott Park, IL 60064-6125, USA. jeff.waring@abbott.com
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Waring
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: Christine H
authors.initials: CH
authors.lastname: Healan-Greenberg
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Adler
authors.forename: Robert
authors.initials: R
authors.lastname: Dickinson
authors.forename: Teresa
authors.initials: T
authors.lastname: McNally
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Wang
authors.forename: Moshe
authors.initials: M
authors.lastname: Weitzberg
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Xu
authors.forename: Andrew
authors.initials: A
authors.lastname: Lisowski
authors.forename: Scott E
authors.initials: SE
authors.lastname: Warder
authors.forename: Yu Gui
authors.initials: YG
authors.lastname: Gu
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Zinker
authors.forename: Eric A
authors.initials: EA
authors.lastname: Blomme
authors.forename: Heidi S
authors.initials: HS
authors.lastname: Camp
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D022781:Hepatocytes; D006801:Humans; D051379:Mice; D008820:Mice, Obese; D047493:PPAR alpha / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D047493:PPAR alpha; D000103:Acetyl-CoA Carboxylase