FOXO6 as a Transcriptional Regulator of Hepatic Metabolic Inflammation and Hepatocarcinogenesis

Abstract

FOXO6 is a member of the FOXO transcription factor family that differs from FOXO1, FOXO3, and FOXO4 in its nucleocytoplasmic regulation, remaining predominantly within the nucleus because it lacks a functional nuclear export sequence. FOXO6 activity can nevertheless be inhibited by insulin/AKT signaling, whereas impaired insulin signaling increases its transcriptional activity in hepatocytes under insulin-resistant and nutrient-rich conditions. Recent studies indicate that FOXO6 regulates hepatic metabolic pathways associated with oxidative injury, inflammatory signaling, and lipid accumulation. In hepatocellular carcinoma, increased FOXO6 expression is associated with glycolytic activity, proliferation, and invasion. We recently reported that FOXO6-dependent transcriptional regulation contributes to reactive oxygen species (ROS) production and inflammasome-associated inflammatory signaling through induction of thioredoxin-interacting protein (TXNIP). Furthermore, FOXO6 regulates lipid metabolic pathways through transcriptional activation of apolipoprotein C3 (ApoC3) and peroxisome proliferator-activated receptor (PPAR) γ together with suppression of PPARα, thereby promoting triglyceride accumulation, mitochondrial dysfunction, and lipotoxic injury in hepatocytes. These metabolic and inflammatory alterations contribute to hepatic steatosis, mitochondrial injury, and inflammatory hepatocellular damage. In hepatocellular carcinoma, increased FOXO6 expression is associated with glycolytic metabolism, angiogenic signaling, proliferative activity, immune suppression, and invasive phenotypes. FOXO6-dependent signaling interacts with STAT3, NF-κB, and β-catenin pathways involved in metabolic adaptation and tumor progression. Recent studies demonstrate relationships between increased FOXO6 expression, vascular invasion, aggressive tumor phenotypes, and reduced survival in hepatocellular carcinoma. This review examines FOXO6-associated transcriptional mechanisms involved in hepatic metabolic inflammation and hepatocarcinogenesis.