title: 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.
authors.affiliation: Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA. sweinman@kumc.edu
authors.forename: Irina
authors.initials: I
authors.lastname: Tikhanovich
authors.forename: Josiah
authors.initials: J
authors.lastname: Cox
authors.forename: Steven A
authors.initials: SA
authors.lastname: Weinman
mesh_terms: D000818:Animals; D000975:Antioxidants; D001343:Autophagy; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000502:physiology*; D005943:Gluconeogenesis / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000502:physiology; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008107:Liver Diseases / Q000235:genetics*; D011499:Protein Processing, Post-Translational; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D000975:Antioxidants; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007328:Insulin
keywords: FOXO1; FOXO3; FOXO4; gluconeogenesis; hepatitis C; protein methylation