A novel acetyl-CoA carboxylase inhibitor reduces de novo fatty acid synthesis in HepG2 cells and rat primary hepatocytes.
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.
Sugimoto
Yoshinori
Y
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
Naniwa
Yoshimitsu
Y
Nakamura
Takayuki
T
Kato
Hirotsugu
H
Yamamoto
Masanori
M
Tanabe
Hirofumi
H
Inoue
Kinji
K
Imaizumi
Atsushi
A
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
D001572:Benzofurans; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D011753:Pyrones; C525071:benzofuranyl alpha-pyrone; D000105:Acetyl Coenzyme A