CIDeRGeneral Information:
| Id: | 714 |
| Diseases: |
Abetalipoproteinemia
- [OMIM]
Cardiovascular disease Diabetes mellitus, type II - [OMIM] Fatty liver disease, nonalcoholic Insulin resistance |
| Mammalia | |
| review | |
| Reference: | Kamagate A and Dong HH(2008) FoxO1 integrates insulin signaling to VLDL production. Cell Cycle 7: 3162-3170 [PMID: 18927507] |
Interaction Information:
| Comment | Hypertriglyceridemia increases the incidence of cardiovascular disease by 32 % in men and 76 % in women, independent of plasma HDL-C levels. |
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Formal Description Interaction-ID: 3956 |
phenotype increases_activity of disease Cardiovascular disease |
| Comment | As a result of insulin resistance, adipose tissue undergoes unrestrained fat mobilization, resulting in elevated plasma free fatty acid (FFA) levels. |
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Formal Description Interaction-ID: 3957 |
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| Comment | An increased FFA flux into the liver stimulates hepatic lipogenesis and promotes VLDL-TG overproduction, contributing to the pathogenesis of hypertriglyceridemia. |
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Formal Description Interaction-ID: 3960 |
phenotype increased liver free fatty acid level increases_activity of process |
| Comment | Under fasting conditions, hepatic VLDL production is induced, resulting in increased VLDL secretion into the blood. |
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Formal Description Interaction-ID: 3965 |
environment fasting increases_activity of process VLDL secretion |
| Comment | In response to postprandial insulin release, hepatic VLDL production is suppressed to limit plasma triglyceride excursion. |
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Formal Description Interaction-ID: 3967 |
complex/PPI Insulin decreases_activity of process VLDL secretion |
| Comment | VLDL assembly in hepatocytes is conducted by microsomal triglyceride transfer protein (MTP), an endoplasmic reticulum resident protein. |
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Formal Description Interaction-ID: 3971 |
gene/protein affects_activity of |
| Drugbank entries | Show/Hide entries for MTTP |
| Comment | VLDL assembly in hepatocytes is conducted by microsomal triglyceride transfer protein (MTP), an endoplasmic reticulum resident protein. |
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Formal Description Interaction-ID: 3972 |
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| Drugbank entries | Show/Hide entries for MTTP |
| Comment | When heterodimerized with its small subunit protein disulphide isomerase (PDI) in the endoplasmic reticulum (ER), MTP catalyzes the transfer of lipid to nascent apolipoprotein B (apoB), a rate-limiting step in hepatic VLDL production. |
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Formal Description Interaction-ID: 3973 |
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| Drugbank entries | Show/Hide entries for MTTP |
| Comment | In humans, a lack of MTP activity, resulting from genetic lesions in its gene, causes abetalipoproteinemia or Bassen-Kornzweig syndrome, a rare autosomal recessive disorder that is characterized by defects in the assembly and secretion of triglyceride-rich lipoproteins. |
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Formal Description Interaction-ID: 3976 |
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| Drugbank entries | Show/Hide entries for MTTP |
| Comment | MTP haploinsufficiency is associated with increased hepatic fat deposition due to markedly reduced VLDL secretion in MTP+/- heterozygous mice. |
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Formal Description Interaction-ID: 3977 |
organism model MTTP+/- heterozygous mouse increases_activity of phenotype |
| Comment | MTP haploinsufficiency is associated with increased hepatic fat deposition due to markedly reduced VLDL secretion in MTP+/- heterozygous mice. |
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Formal Description Interaction-ID: 3978 |
organism model MTTP+/- heterozygous mouse decreases_activity of process VLDL secretion |
| Comment | Hepatic MTP overproduction results in excessive VLDL-TG secretion and significantly elevated plasma TG levels. |
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Formal Description Interaction-ID: 3980 |
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| Drugbank entries | Show/Hide entries for MTTP |
| Comment | MTP gene expression is negatively regulated by insulin in cultured HepG2 cells. |
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Formal Description Interaction-ID: 3982 |
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| Drugbank entries | Show/Hide entries for MTTP |
| Comment | In insulin-resistant animal models hepatic MTP mRNA levels are significantly upregulated, correlating with augmented VLDL-TG secretion. |
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Formal Description Interaction-ID: 3983 |
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| Drugbank entries | Show/Hide entries for MTTP |
| Comment | In insulin-resistant animal models hepatic MTP mRNA levels are significantly upregulated, correlating with augmented VLDL-TG secretion. |
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Formal Description Interaction-ID: 3986 |
disease Insulin resistance increases_activity of process VLDL secretion |
| Comment | Foxa2 in complex with its co-activator PGC-1beta stimulates hepatic MTP mRNA expression, contributing to increased VLDL secretion from the liver. |
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Formal Description Interaction-ID: 3989 |
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| Drugbank entries | Show/Hide entries for MTTP |
| Comment | In response to insulin action, Foxa2 is phosphorylated and dissociated from PGC-1beta, contributing to the reduction in hepatic MTP and VLDL production. |
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Formal Description Interaction-ID: 3991 |
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| Comment | In response to insulin action, Foxa2 is phosphorylated and dissociated from PGC-1beta, contributing to the reduction in hepatic MTP and VLDL production. |
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Formal Description Interaction-ID: 3992 |
complex/PPI Insulin decreases_activity of complex/PPI FOXA2-PGC-1beta complex |
| Comment | Foxa2 is predominantly localized in the cytoplasm in response to hyperinsulinemia, arguing against its direct action in promoting MTP gene expression in insulin resistant states. |
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Formal Description Interaction-ID: 3994 |
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| Drugbank entries | Show/Hide entries for MTTP |
| Comment | Peroxisome proliferator-activated receptor alpha (PPAR-alpha) stimulates hepatic MTP mRNA expression in primary cultures of mouse and rat hepatocytes, however, targeted activation of PPAR-alpha with anti-hypertriglyceridemia therapy such as fibrates helps attenuate hepatic MTP activity in animal models with diet-induced dyslipidemia. |
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Formal Description Interaction-ID: 3995 |
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| Drugbank entries | Show/Hide entries for PPARA or MTTP |
| Comment | Peroxisome proliferator-activated receptor alpha (PPAR-alpha) stimulates hepatic MTP mRNA expression in primary cultures of mouse and rat hepatocytes, however, targeted activation of PPAR-alpha with anti-hypertriglyceridemia therapy such as fibrates helps attenuate hepatic MTP activity in animal models with diet-induced dyslipidemia. |
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Formal Description Interaction-ID: 3996 |
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| Drugbank entries | Show/Hide entries for PPARA |
| Comment | Peroxisome proliferator-activated receptor alpha (PPAR-alpha) stimulates hepatic MTP mRNA expression in primary cultures of mouse and rat hepatocytes, however, targeted activation of PPAR-alpha with anti-hypertriglyceridemia therapy such as fibrates helps attenuate hepatic MTP activity in animal models with diet-induced dyslipidemia. |
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Formal Description Interaction-ID: 3997 |
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| Drugbank entries | Show/Hide entries for MTTP |
| Comment | Insulin suppresses apoB expression and promotes proteasome-mediated apoB degradation in cultured HepG2 cells, primary rat hepatocytes and, and perfused rat livers. |
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Formal Description Interaction-ID: 3998 |
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| Comment | Insulin suppresses apoB expression and promotes proteasome-mediated apoB degradation in cultured HepG2 cells, primary rat hepatocytes and, and perfused rat livers. |
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Formal Description Interaction-ID: 3999 |
complex/PPI Insulin decreases_quantity of gene/protein |
| Comment | Insulin has been shown to restrain FFA mobilization from adipose tissue by inhibiting the hormone-sensitive lipase. |
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Formal Description Interaction-ID: 4015 |
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| Comment | Insulin has been shown to restrain FFA mobilization from adipose tissue by inhibiting the hormone-sensitive lipase. |
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Formal Description Interaction-ID: 4020 |
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| Comment | In insulin states, an increased FFA flux into the liver, resulting from unrestrained fat mobilization in adipose tissue, augments apoB secretion, contributing to hepatic VLDL-TG overproduction and the development of dyslipidemia. |
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Formal Description Interaction-ID: 4021 |
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| Comment | In insulin states, an increased FFA flux into the liver, resulting from unrestrained fat mobilization in adipose tissue, augments apoB secretion, contributing to hepatic VLDL-TG overproduction and the development of dyslipidemia. |
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Formal Description Interaction-ID: 4022 |
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| Comment | In insulin states, an increased FFA flux into the liver, resulting from unrestrained fat mobilization in adipose tissue, augments apoB secretion, contributing to hepatic VLDL-TG overproduction and the development of dyslipidemia. |
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Formal Description Interaction-ID: 4024 |
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| Comment | In insulin states, an increased FFA flux into the liver, resulting from unrestrained fat mobilization in adipose tissue, augments apoB secretion, contributing to hepatic VLDL-TG overproduction and the development of dyslipidemia. |
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Formal Description Interaction-ID: 4025 |
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| Comment | In insulin states, an increased FFA flux into the liver, resulting from unrestrained fat mobilization in adipose tissue, augments apoB secretion, contributing to hepatic VLDL-TG overproduction and the development of dyslipidemia. |
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Formal Description Interaction-ID: 4026 |
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| Comment | In insulin states, an increased FFA flux into the liver, resulting from unrestrained fat mobilization in adipose tissue, augments apoB secretion, contributing to hepatic VLDL-TG overproduction and the development of dyslipidemia. |
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Formal Description Interaction-ID: 4027 |
disease Insulin resistance increases_activity of process VLDL secretion |
| Comment | In insulin states, an increased FFA flux into the liver, resulting from unrestrained fat mobilization in adipose tissue, augments apoB secretion, contributing to hepatic VLDL-TG overproduction and the development of dyslipidemia. |
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Formal Description Interaction-ID: 4029 |
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| Comment | Increased lipid infiltration into the liver induces ER stress which inhibits hepatic apoB secretion and instigates lipid accumulation, contributing to the development of steatosis. |
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Formal Description Interaction-ID: 4030 |
decreases_activity of gene/protein |
| Comment | Increased lipid infiltration into the liver induces ER stress which inhibits hepatic apoB secretion and instigates lipid accumulation, contributing to the development of steatosis. |
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Formal Description Interaction-ID: 4031 |
increases_activity of disease Fatty liver disease, nonalcoholic |
| Comment | In the absence of insulin, FoxO1 resides in the nucleus and binds as a trans-activator to IRE, enhancint promoter activity. In response to insulin, FoxO1 is phosphorylated through the PIK2-dependent pathway, resulting in its nuclear exclusion and inhibition of target gene expression. |
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Formal Description Interaction-ID: 4033 |
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| Comment | In the absence of insulin, FoxO1 resides in the nucleus and binds as a trans-activator to IRE, enhancint promoter activity. In response to insulin, FoxO1 is phosphorylated through the PIK2-dependent pathway, resulting in its nuclear exclusion and inhibition of target gene expression. |
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Formal Description Interaction-ID: 4035 |
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| Comment | In cultured HepG2 cells MTP production is stimulated by FoxO1 and inhibited by insulin. |
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Formal Description Interaction-ID: 4036 |
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| Drugbank entries | Show/Hide entries for MTTP |
| Comment | In cultured HepG2 cells MTP production is stimulated by FoxO1 and inhibited by insulin. |
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Formal Description Interaction-ID: 4037 |
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| Drugbank entries | Show/Hide entries for MTTP |
| Comment | As a result of insulin resistance, FoxO1 is preferentially localized in the nucleus due to the inability of FoxO1 to undergo insulin-dependent phosphorylation and nuclear exclusion, this effect augments FoxO1 transcriptional activity in promoting hepatic MTP and VLDL-TG overproduction. |
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Formal Description Interaction-ID: 4038 |
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| Comment | Enhanced FoxO1 activity is associated with non-alcoholic steatohepatitis in humans. |
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Formal Description Interaction-ID: 4039 |
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| Comment | FoxO1 mediates the inhibitory effect of insulin on the expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), two key enzymes in hepatic gluconeogenesis. |
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Formal Description Interaction-ID: 4040 |
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| Drugbank entries | Show/Hide entries for PCK1 |
| Comment | FoxO1 mediates the inhibitory effect of insulin on the expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), two key enzymes in hepatic gluconeogenesis. |
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Formal Description Interaction-ID: 4041 |
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| Drugbank entries | Show/Hide entries for PCK1 |
| Comment | FoxO1 mediates the inhibitory effect of insulin on the expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), two key enzymes in hepatic gluconeogenesis. |
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Formal Description Interaction-ID: 4042 |
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| Comment | FoxO1 mediates the inhibitory effect of insulin on the expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), two key enzymes in hepatic gluconeogenesis. |
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Formal Description Interaction-ID: 4043 |
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| Comment | FoxO1 mediates the inhibitory effect of insulin on the expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), two key enzymes in hepatic gluconeogenesis. |
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Formal Description Interaction-ID: 4044 |
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| Comment | FoxO1 mediates the inhibitory effect of insulin on the expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), two key enzymes in hepatic gluconeogenesis. |
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Formal Description Interaction-ID: 4045 |
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| Comment | FoxO1 mediates the inhibitory effect of insulin on the expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), two key enzymes in hepatic gluconeogenesis. |
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Formal Description Interaction-ID: 4046 |
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| Drugbank entries | Show/Hide entries for PCK1 |
| Comment | Under fasting conditions, FoxO1 expression along with its nuclear distribution is increased, accounting for its augmented transcriptional activity to promote hepatic gluconeogenesis. Under fed conditions, FoxO1 is phosphorylated and translocated to the cytoplasm, resulting in inhibition of gluconeogenesis in the liver. These two reciprocal mechanisms play a critical role in maintaining blood glucose levels within a narrow physiological range in different metabolic states. |
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Formal Description Interaction-ID: 4084 |
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| Comment | FoxO1 integrates insulin signaling to hepatic glucose and VLDL production. Hepatic insulin signaling bifurcates at FoxO1 to target different sets of genes in glucose and lipid metabolism. Loss of insulin inhibition of FoxO1 activity in insulin resistant livers results in excessive production of both glucose and VLDL-TG, contributing to the dual pathogenesis of hyperglycemia and hypertriglyceridemia in diabetes. |
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Formal Description Interaction-ID: 4085 |
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| Comment | An increased FFA flux into the liver stimulates hepatic lipogenesis and promotes VLDL-TG overproduction, contributing to the pathogenesis of hypertriglyceridemia. |
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Formal Description Interaction-ID: 13064 |
phenotype increased liver free fatty acid level increases_activity of process VLDL secretion |
| Comment | An increased FFA flux into the liver stimulates hepatic lipogenesis and promotes VLDL-TG overproduction, contributing to the pathogenesis of hypertriglyceridemia. |
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Formal Description Interaction-ID: 13065 |
phenotype increased liver free fatty acid level increases_activity of phenotype |
| Comment | Hepatic MTP overproduction results in excessive VLDL-TG secretion and significantly elevated plasma TG levels. |
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Formal Description Interaction-ID: 13066 |
gene/protein affects_activity of phenotype |
| Drugbank entries | Show/Hide entries for MTTP |
| Comment | Under fasting conditions, FoxO1 expression along with its nuclear distribution is increased, accounting for its augmented transcriptional activity to promote hepatic gluconeogenesis. Under fed conditions, FoxO1 is phosphorylated and translocated to the cytoplasm, resulting in inhibition of gluconeogenesis in the liver. These two reciprocal mechanisms play a critical role in maintaining blood glucose levels within a narrow physiological range in different metabolic states. |
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Formal Description Interaction-ID: 13067 |
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| Comment | Under fasting conditions, FoxO1 expression along with its nuclear distribution is increased, accounting for its augmented transcriptional activity to promote hepatic gluconeogenesis. Under fed conditions, FoxO1 is phosphorylated and translocated to the cytoplasm, resulting in inhibition of gluconeogenesis in the liver. These two reciprocal mechanisms play a critical role in maintaining blood glucose levels within a narrow physiological range in different metabolic states. |
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Formal Description Interaction-ID: 13068 |
environment fasting increases_activity of process |
| Comment | Under fasting conditions, FoxO1 expression along with its nuclear distribution is increased, accounting for its augmented transcriptional activity to promote hepatic gluconeogenesis. Under fed conditions, FoxO1 is phosphorylated and translocated to the cytoplasm, resulting in inhibition of gluconeogenesis in the liver. These two reciprocal mechanisms play a critical role in maintaining blood glucose levels within a narrow physiological range in different metabolic states. |
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Formal Description Interaction-ID: 13069 |
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| Comment | Under fasting conditions, FoxO1 expression along with its nuclear distribution is increased, accounting for its augmented transcriptional activity to promote hepatic gluconeogenesis. Under fed conditions, FoxO1 is phosphorylated and translocated to the cytoplasm, resulting in inhibition of gluconeogenesis in the liver. These two reciprocal mechanisms play a critical role in maintaining blood glucose levels within a narrow physiological range in different metabolic states. |
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Formal Description Interaction-ID: 13070 |
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| Comment | Under fasting conditions, FoxO1 expression along with its nuclear distribution is increased, accounting for its augmented transcriptional activity to promote hepatic gluconeogenesis. Under fed conditions, FoxO1 is phosphorylated and translocated to the cytoplasm, resulting in inhibition of gluconeogenesis in the liver. These two reciprocal mechanisms play a critical role in maintaining blood glucose levels within a narrow physiological range in different metabolic states. |
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Formal Description Interaction-ID: 13071 |
environment feeding decreases_activity of process |
| Comment | FoxO1 integrates insulin signaling to hepatic glucose and VLDL production. Hepatic insulin signaling bifurcates at FoxO1 to target different sets of genes in glucose and lipid metabolism. Loss of insulin inhibition of FoxO1 activity in insulin resistant livers results in excessive production of both glucose and VLDL-TG, contributing to the dual pathogenesis of hyperglycemia and hypertriglyceridemia in diabetes. |
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Formal Description Interaction-ID: 13072 |
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| Comment | FoxO1 integrates insulin signaling to hepatic glucose and VLDL production. Hepatic insulin signaling bifurcates at FoxO1 to target different sets of genes in glucose and lipid metabolism. Loss of insulin inhibition of FoxO1 activity in insulin resistant livers results in excessive production of both glucose and VLDL-TG, contributing to the dual pathogenesis of hyperglycemia and hypertriglyceridemia in diabetes. |
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Formal Description Interaction-ID: 13073 |
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| Comment | FoxO1 integrates insulin signaling to hepatic glucose and VLDL production. Hepatic insulin signaling bifurcates at FoxO1 to target different sets of genes in glucose and lipid metabolism. Loss of insulin inhibition of FoxO1 activity in insulin resistant livers results in excessive production of both glucose and VLDL-TG, contributing to the dual pathogenesis of hyperglycemia and hypertriglyceridemia in diabetes. |
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Formal Description Interaction-ID: 13074 |
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| Comment | FoxO1 integrates insulin signaling to hepatic glucose and VLDL production. Hepatic insulin signaling bifurcates at FoxO1 to target different sets of genes in glucose and lipid metabolism. Loss of insulin inhibition of FoxO1 activity in insulin resistant livers results in excessive production of both glucose and VLDL-TG, contributing to the dual pathogenesis of hyperglycemia and hypertriglyceridemia in diabetes. |
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Formal Description Interaction-ID: 13075 |
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| Comment | FoxO1 integrates insulin signaling to hepatic glucose and VLDL production. Hepatic insulin signaling bifurcates at FoxO1 to target different sets of genes in glucose and lipid metabolism. Loss of insulin inhibition of FoxO1 activity in insulin resistant livers results in excessive production of both glucose and VLDL-TG, contributing to the dual pathogenesis of hyperglycemia and hypertriglyceridemia in diabetes. |
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Formal Description Interaction-ID: 13076 |
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