title: A novel acetyl-CoA carboxylase inhibitor reduces de novo fatty acid synthesis in HepG2 cells and rat primary hepatocytes.
abstract: To identify the novel inhibitor of de novo lipogenesis in hepatocytes, we screened for inhibitory activity of triglyceride (TG) synthesis using [14C]acetate in the human hepatoma cell line, HepG2. Using this assay system we discovered the novel compound, benzofuranyl alpha-pyrone (TEI-B00422). TEI-B00422 also inhibited the incorporation of acetate into the triglyceride (TG) fraction in rat primary hepatocytes. In HepG2 cells, the incorporation of oleate into TG was unaffected. TEI-B00422 inhibited rat hepatic acetyl-CoA carboxylase (ACC), K(i)=3.3 microM, in a competitive manner with respect to acety-CoA but not fatty acid synthase and acyl-CoA transferase/diacylglycerol. Thus, these results suggest that the inhibition of TG synthesis by TEI-B00422 is based on the inhibitory action of ACC. The structure of TEI-B00422 is totally different from the known inhibitors of ACC and may be useful in the development of therapeutic agents to combat a number of metabolic disorders.
authors.affiliation: Teijin Pharma Limited, Pharmaceutical Discovery Research Laboratories, Institute for Bio-medical Research, 4-3-2, Asahigaoka, Hino Tokyo 191-8512, Japan. y.sugimoto@teijin.co.jp
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Naniwa
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakamura
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Kato
authors.forename: Masanori
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Tanabe
authors.forename: Kinji
authors.initials: K
authors.lastname: Inoue
authors.forename: Atsushi
authors.initials: A
authors.lastname: Imaizumi
mesh_terms: D000105:Acetyl Coenzyme A / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D001572:Benzofurans / Q000008:administration & dosage*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005227:Fatty Acids / Q000378:metabolism*; D018197:Hepatoblastoma / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D011753:Pyrones / Q000008:administration & dosage*; D051381:Rats
chemical_list: D001572:Benzofurans; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D011753:Pyrones; C525071:benzofuranyl alpha-pyrone; D000105:Acetyl Coenzyme A