Transcription Factor Foxo1 Mediates Tgf-Beta 1-Induced Apoptosis In Primary Hepatocytes

Dysregulation of hepatocyte apoptosis or failure is associated with several types of chronic liver diseases. Transforming growth factor β1 (TGF- β1) is a well-known pro-apoptotic factor in the liver, which is constituted by a receptor complex composed of TGFβ receptor type I (TβRI) and TβRII, along with transcriptional factors Smad proteins. As a member of the forkhead box O-class transcription factors, Foxo1 is a predominant regulator for hepatic glucose production. While the role of Foxo1 in functions beyond glucose metabolism is gradually recognized, since there has been increasing evidence showing the potential relationship between TGF-β1 signaling and Foxo1. Here, we investigated whether Foxo1 mediates the pro-apoptotic effect of TGF-β1 in primary hepatocytes. By using hepatocytes isolated from both of wild type (Foxo1fl/fl) and liver specific Foxo1 knockout (LFKO, albumin-Cre+/-:: Foxo1fl/fl) mice, it was found that TGF-β1 induces hepatocytes apoptosis in a Foxo1-dependent manner. We also explored the associated molecular mechanisms and demonstrated that TGF-β1 activates protein kinase A (PKA) through TβRI-Smad3, followed by phosphorylation of Foxo1 at Ser273 to promote apoptosis of hepatocytes. The significant role of pFoxo1-S273 in mediating the pro-apoptotic effect of TGF-β1 was validated by using hepatocytes isolated from Foxo1-S273A mice, which mimics the dephosphorylation of Foxo1-Ser273. The establishment of TGF-β1-PKA-Foxo1axis in this study reveals a novel role of Foxo1 in hepatic functions. Disclosure W. Ai: None. W. Liao: None. Q. Pan: None. W. Yang: None. Z. Shen: None. S. Guo: None. Y. Chen: None. Funding American Diabetes Association (1-15-CD-09 to S.G., Sr.); National Institutes of Health (R01DK095118, R56DK11833401)