FOXO transcription factors in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a chronic progressive liver disorder that begins with simple hepatic steatosis and progresses to non-alcoholic steatohepatitis, fibrosis, cirrhosis, and even liver cancer. As the global prevalence of NAFLD rises, it is increasingly important that we understand its pathogenesis and develop effective therapies for this chronic disease. Forkhead box O (FOXO) transcription factors are key downstream regulators in the insulin/insulin-like growth factor 1 (IGF1) signaling pathway, and have been implicated in a range of cellular functions including the regulation of glucose, triglyceride, and cholesterol homeostasis. The role of FOXOs in the modulation of immune response and inflammation is complex, with reports of both pro- and anti-inflammatory effects. FOXOs are reported to protect against hepatic fibrosis by inhibiting proliferation and transdifferentiation of hepatic stellate cells. Mice that are deficient in hepatic FOXOs are more susceptible to non-alcoholic steatohepatitis than wild-type controls. In summary, FOXOs play a critical role in maintaining metabolic and cellular homeostasis in the liver, and dysregulation of FOXOs may be involved in the NAFLD development.