Transcription Factor Forkhead Box 01 Mediates Transforming Growth Factor-b1-Induced Apoptosis in Hepatocytes

Dysregulation of hepatocyte apoptosis is associated with several types of chronic liver diseases. Transforming growth factor -131 (TGF-131) is a well-known pro-apoptotic factor in the liver, which con-stitutes a receptor complex composed of TGF-13 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 pre-dominant regulator of hepatic glucose production and apoptosis. This study investigated the potential relationship between TGF-131 signaling and Foxo1 in control of apoptosis in hepatocytes. TGF-131 induced hepatocyte apoptosis in a Foxo1-dependent manner in hepatocytes isolated from both wild-type and liver-specific Foxo1 knockout mice. TGF-131 activated protein kinase A through TGF-13 recep-tor I-Smad3, followed by phosphorylation of Foxo1 at Ser273 in promotion of apoptosis in hepato-cytes. 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. The study further demonstrated a crucial role of Foxo1-S273 phosphorylation in the pro-apoptotic effect of TGF-131 by using hepatocytes isolated from Foxo1-S273A/A knock-in mice, in which the phosphorylation of Foxo1-S273 was disrupted. Taken together, this study established a novel role of TGF-131->protein kinase A->Foxo1 signaling cascades in control of hepatocyte survival. (Am J Pathol 2023, 193: 1143-1155; https://doi.org/10.1016/j.ajpath.2023.05.007)