Forkhead box class O family member proteins: The biology and pathophysiological roles in diabetes

Abstract

Forkhead box class O family member proteins (FoxOs) of transcription factors are essential regulators of cellular homeostasis, including glucose and lipid metabolism, oxidative stress response and redox signaling, cell cycle progression, and apoptosis. Altered FoxO1 expression and activity have been associated with glucose intolerance, dyslipidemia and complications of diabetes. In the liver, they direct carbons to glucose or lipid utilization, thus providing a unifying mechanism for the two abnormalities of the diabetic liver: excessive glucose production, and increased lipid synthesis and secretion. In the pancreas, FoxO1 is necessary to maintain β-cell differentiation, and could be promising targets for β-cell regeneration. In endothelial cells, FoxOs strongly promote atherosclerosis through suppressing nitric oxide production and enhancing inflammatory responses. In the present review, we summarize the basic biology and pathophysiological significance of FoxOs in diabetes.

Keywords: Diabetes; Forkhead box class O family member proteins; Insulin signaling.

Figure 1

Structure and regulation of forkhead box class O family member proteins (FoxOs). (a) Schematic diagram showing the different domains that characterize human FoxOs. FoxOs share a highly conserved forkhead deoxyribonucleic acid‐binding domain (FHD), which binds to conserved sequences in the target genes. Acetylation and phosphorylation sites are depicted only in FoxO1 as a representative. (b) A model for FoxO1 regulation through insulin‐induced and phosphorylation‐dependent degradation. A, acetylation site; aa, amino acids; NES, nuclear export sequence; NLS, nuclear localization sequence; P, phosphorylation site; TAD, transactivation domain.

Figure 2

Roles of forkhead box class O family member proteins in various organs. CDKN, cycline‐dependent kinase inhibitor; C/EBPα, CCAAT/enhancer binding protein alpha; eNOS, endothelial nitric oxide synthase; GPx, glutathione peroxidase; iNOS, inducible nitric oxide synthase; MafA; v‐maf musculoaponeurotic fibrosarcoma oncogene family, protein A; MuRF1, muscle ring‐finger protein‐1; MyoD, myogenic differentiation; NeuroD, neurogenic differentiation; NF‐κB, nuclear factor‐kappa B; NOS, nitric oxide synthase; PEPCK, phosphoenolpyruvate carboxykinase; PPAR‐γ, peroxisome proliferator‐activated receptor gamma; SOD, superoxide dismutase; SREBP‐1c, sterol regulatory element‐binding protein 1c.