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Abstract
The transcription factor forkhead box (FOXO) controls important biological responses, including proliferation, apoptosis, differentiation, metabolism, and oxidative stress resistance. The transcriptional activity of FOXO is tightly regulated in a variety of cellular processes. FOXO can convert the external stimuli of insulin, growth factors, nutrients, cytokines, and oxidative stress into cell-specific biological responses by regulating the transcriptional activity of target genes. However, how a single transcription factor regulates a large set of target genes in various tissues in response to a variety of external stimuli remains to be clarified. Evidence indicates that FOXO-binding proteins synergistically function to achieve tightly controlled processes. Here, we review the elaborate mechanism of FOXO-binding proteins, focusing on adipogenesis, glucose homeostasis, and other metabolic regulations in order to deepen our understanding and to identify a novel therapeutic target for the prevention and treatment of metabolic disorders.
Highlights
Forkhead box (FOXO) transcription factors play important roles in apoptosis, the cell cycle, DNA damage repair, oxidative stress, cell differentiation, glucose metabolism, and other cellular functions [1]
PPARα was shown to bind to and antagonize FOXO1 in hepatic apoC-III expression, suggesting the importance of FOXO1 deregulation in the pathology of insulin resistance and hypertriglyceridemia. These findings suggest that PPARα is required to prevent insulin resistance and hyperglyceridemia by suppressing FOXO1 activity
Foxo1 activation is suppressed by Aktmediated phosphorylation, and Akt functions to disrupt the FOXO1-PGC1 interaction. These findings indicate that the FOXO1 and PGC1 interaction is essential for executing insulinregulated gluconeogenesis in the liver (Figure 7)
Summary
Forkhead box (FOXO) transcription factors play important roles in apoptosis, the cell cycle, DNA damage repair, oxidative stress, cell differentiation, glucose metabolism, and other cellular functions [1]. The transcriptional activity of FOXO is regulated by post-translational modification, including phosphorylation, acetylation, and ubiquitination, which determine subcellular localization, binding with DNA or other regulatory factors, and degradation, among other features. The three consensus AKT phosphorylation sites are conserved in all members of the mammalian FOXO families, except. When Akt is in the inactivated state, FOXO proteins stay in the nucleus and regulate the expression of target genes. FOXO proteins function primarily as transcription factors in the nucleus and bind to the FOXO binding consensus domain of target genes, regulating the expression of these genes. The interactions between FOXO and its binding proteins demonstrate a synergistic effect to achieve complex and tightly regulated physiological activities that are specific to different tissues. We focus on tissue-specific FOXO function in metabolism and describe the mechanism by which FOXO-binding proteins play a role in fine-tuning energy and glucose metabolism
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