FoxO1 Regulates Multiple Metabolic Pathways in the Liver

Abstract

FoxO transcription factors are important targets of insulin action. To better understand the role of FoxO proteins in the liver, we created transgenic mice expressing constitutively active FoxO1 in the liver using the ␣1-antitrypsin promoter. Fasting glucose levels are increased, and glucose tolerance is impaired in transgenic (TGN) versus wild type (WT) mice. Interestingly, fasting triglyceride and cholesterol levels are reduced despite hyperinsulinemia, and post-prandial changes in triglyceride levels are markedly suppressed in TGN versus WT mice. Activation of pro-lipogenic signaling pathways (atypical protein kinase C and protein kinase B) and the ability to suppress ␤-hydroxybutyrate levels are not impaired in TGN. In contrast, de novo lipogenesis measured with 3 H 2 O is suppressed by ϳ70% in the liver of TGN versus WT mice after refeeding. Gene-array studies reveal that the expression of genes involved in gluconeogenesis, glycerol transport, and amino acid catabolism is increased, whereas genes involved in glucose utilization by glycolysis, the pentose phosphate shunt, lipogenesis, and sterol synthesis pathways are suppressed in TGN versus WT. Studies with adenoviral vectors in isolated hepatocytes confirm that FoxO1 stimulates expression of gluconeogenic genes and suppresses expression of genes involved in glycolysis, the shunt pathway, and lipogenesis, including glucokinase and SREBP-1c. Together, these results indicate that FoxO proteins promote hepatic glucose production through multiple mechanisms and contribute to the regulation of other metabolic pathways important in the adaptation to fasting and feeding in the liver, including glycolysis, the pentose phosphate shunt, and lipogenic and sterol synthetic pathways.FoxO 2 transcription factors are important targets of insulin and growth factor action, and they contribute to the regulation of cell growth, differentiation, and metabolism (1-3). FoxO proteins form a subgroup within the family of Forkhead box (or Fox) transcription factors (4). Early studies indicated that Forkhead proteins interact with insulin response sequences (IRSs) in the promoter of the IGF-binding protein-1 (IGFBP-1) and the phosphoenolpyruvate carboxykinase (PEPCK) genes (5, 6) and that signaling through phosphatidylinositol 3Ј-kinase and protein kinase B (PKB) mediates IRS-dependent effects of insulin on gene expression (7). Genetic studies of Caenorhabditis elegans revealed that DAF-16, a FoxO transcription factor, is a major target of insulin-like signaling (8, 9). DAF-16 plays an important role in the adaptation to environmental stress, including nutrient restriction, and signaling through phosphatidylinositol 3Ј-kinase and PKB suppresses the function of DAF-16. Subsequent studies revealed that FoxO proteins contain highly conserved PKB phosphorylation sites (corresponding to Thr-24, Ser-256, and Ser-319 in human FoxO1) (10 -12) and that phosphorylation at these sites suppresses transactivation and promotes nuclear exclusion of FoxO proteins through multiple mechanisms (13)...

Insulin Regulation of Cholesterol 7α-Hydroxylase Expression in Human Hepatocytes

“…In the mouse CYP7A1 gene this IRE is located in the same region and is likely a FoxO1 binding site. A recent report shows a 2-fold higher expression of CYP7A1 mRNA in FoxO1 transgenic mice, suggesting induction of mouse CYP7A1 by FoxO1 (40). In the hamster CYP7A1 gene this IRE is located upstream of a putative IRE that binds HNF3␣ and HNF4␣ (41).…”

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

“…Both SREBP1c and ChREBP upregulate lipogenic enzymes such as acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FAS). Hyperinsulinemia increases SREBP1c and ChREBP expression and further promotes hepatic DNL by inhibiting FoxO1, which normally downregulates SREBP1c expression and promotes ChREBP degradation (Deng et al 2012, Ido-Kitamura et al 2012, Zhang et al 2006. This coordinated response stimulates storage of excess dietary energy as triglycerides for future oxidation under energy-deplete conditions.…”

FGF15/FGFR4 Integrates Growth Factor Signaling with Hepatic Bile Acid Metabolism and Insulin Action

“…In support of this possibility, when FoxO1 was expressed at elevated levels in a transgenic mouse model, CYP7A1 was induced (53). To test the role of FoxO1 in CYP7A1 more directly, we evaluated CYP7A1 induction in l-FoxO1 mice where the FoxO1 gene was deleted specifically in liver (51).…”