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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Angiopoietin-Related Growth Factor Suppresses Gluconeogenesis through the Akt/Forkhead Box Class O1-Dependent Pathway in Hepatocytes

Molecular Medicine Research Laboratories, Drug Discovery Research, Astellas Pharma, Inc., Tsukuba, Japan (M.K., S.H.); Departments of Pharmaceutical Science (M.K., T.H.) and Pharmaceutical Molecular Biology (Y.O.), Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (Y.O.)

Angiopoietin-related growth factor (AGF; or Angptl6) is a liver-derived, circulating factor and is considered to be a regulator of metabolic homeostasis. AGF is capable of counteracting both obesity and obesity-related insulin resistance. However, the target tissues and the molecular mechanisms underlying the antiobesity and antidiabetic actions of AGF have not been completely defined. Using rat hepatoma H4IIEc3 cells or primary hepatocytes, we demonstrate that AGF suppresses glucose production in a concentration-dependent manner through reduced expression of a key gluconeogenic enzyme, glucose-6-phosphatase (G6Pase), at both transcriptional and translational levels. The action of AGF on glucose production was inhibited by pretreatment of the cells with LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one], a phosphoinositide 3-kinase (PI3K) inhibitor, and Akt (protein kinase B) inhibitors. AGF increased the phosphorylation of Akt and its substrates, glycogen synthase kinase 3 and forkhead box class O1 (FoxO1), a key transcription factor for G6Pase expression. Furthermore, an immunohistochemical approach with anti-FoxO1 antibody demonstrated that AGF stimulation promoted translocation of FoxO1 from the nucleus to the cytoplasm in the cells. These results suggest that in hepatocytes, AGF suppresses gluconeogenesis via reduced transcriptional activity of FoxO1 resulting from the activation of PI3K/Akt signaling cascades.

Address correspondence to: Masashi Kitazawa, Molecular Medicine Research Laboratories, Drug Discovery Research, Astellas Pharma, Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. E-mail: masashi.kitazawa{at}jp.astellas.com