A novel acetyl-CoA carboxylase inhibitor reduces de novo fatty acid synthesis in HepG2 cells and rat primary hepatocytes |
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Authors: | Sugimoto Yoshinori Naniwa Yoshimitsu Nakamura Takayuki Kato Hirotsugu Yamamoto Masanori Tanabe Hirofumi Inoue Kinji Imaizumi Atsushi |
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Institution: | a Teijin Pharma Limited, Pharmaceutical Discovery Research Laboratories, Institute for Bio-medical Research, 4-3-2, Asahigaoka, Hino Tokyo 191-8512, Japan b Department of Regulation Biology, Faculty of Science, Saitama University, 255, Shimo-ohkubo, Sakuraku Saitama 338-8570, Japan |
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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 α-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), Ki = 3.3 μM, 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. |
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Keywords: | ACC Fatty acid synthesis Triglycerides |
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