This review summarizes emerging knowledge of FOXO function in the liver, FOXO changes in liver disease, and the posttranslational modifications responsible for these effects. The liver plays a central role in adaptation to stress. It is anatomically situated as the buffer between the gut and the systemic circulation and is required to buffer large transient
fluxes of nutrients, exogenous toxins, and gut-derived bacterial products. It must optimally utilize or dispose of these products originating from the portal circulation without disturbing the much more stable environment of the systemic circulation. For this reason, the liver PD0325901 purchase engages a number of stress response pathways that regulate metabolism, immune response, organic ion transport, and cell proliferation. The ability to engage these stress response pathways allows the liver to respond
to the changing input environment. FOXO transcription factors are part of one important stress response pathway that is responsible for many of these regulatory events. They are necessary for plasticity of the organ, adaptation to fasting, Roxadustat manufacturer response to stress, and regulation of cell proliferation. This article will review the role of the FOXO family of transcription factors in the hepatic homeostatic response and discuss how regulation of this pathway is altered in liver disease. The O branch of the large forkhead family of transcription factors[1] is ubiquitously expressed and highly conserved evolutionarily.[2] The prototype of the FOXO family was first described in Caenorhabditis elegans as daf16, a factor that is required for formation of a long-lived dormant form of the organism called the dauer larval stage. Subsequently, FOXO factors were shown to play a similar medchemexpress role in higher organisms and function to prevent cellular proliferation, induce antioxidant and stress response genes, and modify insulin sensitivity.[2, 3] In mammals, there are 4 FOXO proteins, FOXO1, FOXO3a (sometimes called just FOXO3), FOXO4 and FOXO6.
While FOXO6 is largely specific to neurons, the other three factors are widely distributed and are present in most tissues. There appears to be considerable overlap in the transcriptional targets of the three, but the consequences of knock outs in mice are very different with FOXO1 knock out being embryonically lethal due to failure of angiogenesis, FOXO3 knock out producing premature ovarian failure, and FOXO4 knock out having no obvious phenotype.[4] There is also evidence that each of these can compensate to some degree for loss of the others as triple conditional knockouts resulted in lymphomas, hemagiomas, and angiosarcomas, which did not occur with double knock out combinations.
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