Forkhead box class O transcription factors in liver function and disease

Abstract

The forkhead box transcription factor class O (FOXO) family represents a group of transcription factors that is required for a number of stress-related transcriptional programs including antioxidant response, gluconeogenesis, cell cycle control, apoptosis, and autophagy. The liver utilizes several FOXO-dependent pathways to adapt to its routine cycles of feeding and fasting and to respond to the stresses induced by disease. FOXO1 is a direct transcriptional regulator of gluconeogenesis, reciprocally regulated by insulin, and has profound effects on hepatic lipid metabolism. FOXO3 is required for antioxidant responses and autophagy and is altered in hepatitis C infection and fatty liver. Emerging evidence suggests dysregulation of FOXO3 in some hepatocellular carcinomas. FOXOs are notable for the extensive number of functionally significant posttranslational modifications that they undergo. Recent advances in our understanding how FOXOs are regulated are providing a more detailed picture of how specific combinations of posttranslational modifications alter both nuclear translocation as well as transcriptional specificity under different conditions. This review summarizes emerging knowledge of FOXO function in the liver, FOXO changes in liver disease, and the posttranslational modifications responsible for these effects.

Keywords: FOXO1; FOXO3; FOXO4; gluconeogenesis; hepatitis C; protein methylation.

Figure 1. FOXO functions.

The FOXO transcription factors serve as a counterpoint to Akt in the control of cell proliferation and gluconeogenesis. When active, as occurs when Akt activity is suppressed, FOXOs translocate to the nucleus where they initiate transcriptional programs for cell cycle arrest, oxidative stress protection, gluconeogenesis and autophagy. A brief list of a small subset of relevant target genes is listed for each function.