New advances in molecular mechanisms and emerging therapeutic targets in alcoholic liver diseases

Figure 2 Regulation of FoxO3 and its role in alcohol-induced liver injury. Growth factors, such as insulin-like growth factor I (IGF-1), bind to their receptor and recruit insulin receptor substrate 1 (IRS-1), which further activates PI3K. Activated PI3K then converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-trisphosphate (PIP3), and PIP3 directly binds AKT to promote its activation. AKT phosphorylates FoxO3 resulting in its sequestration in the cytoplasm and interaction with 14-3-3 proteins. FoxO3 can also be ubiquitinated and degraded by the ubiquitin proteasome system, or deacetylated by SIRT1, which regulates the specificity of FoxO3 target gene expression. Dephosphorylated nuclear retained FoxO3 then binds to the promoter regions of target genes with various distinctive functions, including autophagy, DNA damage, antioxidants, cell cycle and metabolism. Acute alcohol regulates hepatic FoxO3 by inhibiting AKT, resulting in increased nuclear retention of FoxO3, which leads to increased expression of autophagy-related genes. Acute alcohol also increases acetylated levels of FoxO3, which may serve as a negative regulator of acute alcohol-induced expression of autophagy-related genes. Resveratrol activates SIRT1, which leads to FoxO3 deacetylation and enhanced expression of autophagy-related genes. Alcohol-induced activation of FoxO3 also promotes the expression of antioxidant genes. Whether alcohol affects other FoxO3-mediated target genes such as those involved in DNA damage, cell cycle and metabolism remains to be studied. Overall, alcohol-induced activation of FoxO3 protects against alcohol-induced steatosis and liver injury.