Transcription Factor Forkhead Box O1 Mediates Transforming Growth Factor-β1–Induced Apoptosis in Hepatocytes

Abstract

Dysregulation of hepatocyte apoptosis 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 TGF-β receptor I and II, along with transcription factor Smad proteins. As a member of the forkhead box O (Foxo) class of transcription factors, Foxo1 is a predominant regulator of hepatic glucose production and apoptosis. In this study, we investigated the potential relationship between TGF-β1 signaling and Foxo1 in control of apoptosis in hepatocytes. By using hepatocytes isolated from both wild-type and liver-specific Foxo1 knockout mice, we found that TGF-β1 induces hepatocyte apoptosis in a Foxo1-dependent manner. We further demonstrated that TGF-β1 activates protein kinase A through TGF-β receptor I-Smad3, followed by phosphorylation of Foxo1 at Ser273 in promotion of apoptosis in hepatocytes. Moreover, Smad3 overexpression in the liver of mice promoted the levels of phosphorylated Foxo1-S273, total Foxo1, and a Foxo1-target pro-apoptotic gene Bim, which eventually resulted in hepatocyte apoptosis. We further demonstrated a crucial role of Foxo1-S273 phosphorylation in the pro-apoptotic effect of TGF-β1 by using hepatocytes isolated from Foxo1-S273A/A knock-in mice, in which the phosphorylation of Foxo1-S273 is disrupted. Taken together, we established a novel role of TGF-β1→protein kinase A→Foxo1 signaling cascades in control of hepatocyte survival.