General 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.
Formal Description
Interaction-ID: 3956

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.
Formal Description
Interaction-ID: 3957

disease

Insulin resistance

increases_quantity of

drug/chemical compound

Fatty acid

in blood
Comment An increased FFA flux into the liver stimulates hepatic lipogenesis and promotes VLDL-TG overproduction, contributing to the pathogenesis of hypertriglyceridemia.
Formal Description
Interaction-ID: 3960

phenotype

increased liver free fatty acid level

increases_activity of

in liver
Comment Under fasting conditions, hepatic VLDL production is induced, resulting in increased VLDL secretion into the blood.
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.
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.
Formal Description
Interaction-ID: 3971

gene/protein

MTTP

affects_activity of

in liver
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.
Formal Description
Interaction-ID: 3972

gene/protein

MTTP

is localized in

cellular component

endoplasmic reticulum membrane

in liver
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.
Formal Description
Interaction-ID: 3973

gene/protein

MTTP

interacts (colocalizes) with

gene/protein

PDI

in endoplasmic reticulum membrane
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.
Formal Description
Interaction-ID: 3976

gene/protein

MTTP

affects_activity of

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.
Formal Description
Interaction-ID: 3977

organism model

MTTP+/- heterozygous mouse

increases_activity of

Comment MTP haploinsufficiency is associated with increased hepatic fat deposition due to markedly reduced VLDL secretion in MTP+/- heterozygous mice.
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.
Formal Description
Interaction-ID: 3980

gene/protein

MTTP

affects_activity of

process

VLDL secretion

if MTTP is overexpressed
Drugbank entries Show/Hide entries for MTTP
Comment MTP gene expression is negatively regulated by insulin in cultured HepG2 cells.
Formal Description
Interaction-ID: 3982

complex/PPI

Insulin

decreases_expression of

gene/protein

MTTP

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.
Formal Description
Interaction-ID: 3983

disease

Insulin resistance

increases_expression of

gene/protein

MTTP

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.
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.
Formal Description
Interaction-ID: 3989

complex/PPI

FOXA2-PGC-1beta complex

increases_expression of

gene/protein

MTTP

in liver
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.
Formal Description
Interaction-ID: 3991

complex/PPI

Insulin

increases_phosphorylation of

gene/protein

FOXA2

Comment In response to insulin action, Foxa2 is phosphorylated and dissociated from PGC-1beta, contributing to the reduction in hepatic MTP and VLDL production.
Formal Description
Interaction-ID: 3992

complex/PPI

Insulin

decreases_activity of

complex/PPI

FOXA2-PGC-1beta complex

via dissociation of phosphorylated FOXA2 from 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.
Formal Description
Interaction-ID: 3994

gene/protein

FOXA2

NOT affects_expression of

gene/protein

MTTP

in response to hyperinsulinemia
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.
Formal Description
Interaction-ID: 3995

gene/protein

PPARA

increases_expression of

gene/protein

MTTP

in liver
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.
Formal Description
Interaction-ID: 3996

drug/chemical compound

Fibric acid derivative

increases_activity of

gene/protein

PPARA

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.
Formal Description
Interaction-ID: 3997

drug/chemical compound

Fibric acid derivative

decreases_activity of

gene/protein

MTTP

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.
Formal Description
Interaction-ID: 3998

complex/PPI

Insulin

decreases_expression of

gene/protein

APOB

in liver
Comment Insulin suppresses apoB expression and promotes proteasome-mediated apoB degradation in cultured HepG2 cells, primary rat hepatocytes and, and perfused rat livers.
Formal Description
Interaction-ID: 3999

complex/PPI

Insulin

decreases_quantity of

gene/protein

APOB

in liver; via proteasome-mediated apoB degradation
Comment Insulin has been shown to restrain FFA mobilization from adipose tissue by inhibiting the hormone-sensitive lipase.
Formal Description
Interaction-ID: 4015

complex/PPI

Insulin

decreases_activity of

in adipose tissue
Comment Insulin has been shown to restrain FFA mobilization from adipose tissue by inhibiting the hormone-sensitive lipase.
Formal Description
Interaction-ID: 4020

complex/PPI

Insulin

decreases_activity of

gene/protein

LIPE

in adipose tissue
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.
Formal Description
Interaction-ID: 4021

disease

Insulin resistance

increases_activity of

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.
Formal Description
Interaction-ID: 4022

disease

Insulin resistance

increases_quantity of

drug/chemical compound

Fatty acid

in liver
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.
Formal Description
Interaction-ID: 4024

increases_quantity of

drug/chemical compound

Fatty acid

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.
Formal Description
Interaction-ID: 4025

disease

Insulin resistance

increases_quantity of

gene/protein

APOB

in liver
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.
Formal Description
Interaction-ID: 4026

drug/chemical compound

Fatty acid

increases_quantity of

gene/protein

APOB

in liver
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.
Formal Description
Interaction-ID: 4027

disease

Insulin resistance

increases_activity of

process

VLDL secretion

in liver
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.
Formal Description
Interaction-ID: 4029

gene/protein

APOB

increases_activity of

process

VLDL secretion

in liver
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.
Formal Description
Interaction-ID: 4030

decreases_activity of

gene/protein

APOB

in liver; if ER stress is lipid-induced
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.
Formal Description
Interaction-ID: 4031

increases_activity of

disease

Fatty liver disease, nonalcoholic

in liver; if ER stress is lipid-induced
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.
Formal Description
Interaction-ID: 4033

complex/PPI

Insulin

decreases_activity of

gene/protein

FOXO1

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.
Formal Description
Interaction-ID: 4035

complex/PPI

Insulin

increases_phosphorylation of

gene/protein

FOXO1

via PI3K-dependent pathway
Comment In cultured HepG2 cells MTP production is stimulated by FoxO1 and inhibited by insulin.
Formal Description
Interaction-ID: 4036

gene/protein

FOXO1

increases_expression of

gene/protein

MTTP

in liver
Drugbank entries Show/Hide entries for MTTP
Comment In cultured HepG2 cells MTP production is stimulated by FoxO1 and inhibited by insulin.
Formal Description
Interaction-ID: 4037

complex/PPI

Insulin

decreases_expression of

gene/protein

MTTP

in liver
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.
Formal Description
Interaction-ID: 4038

disease

Insulin resistance

increases_activity of

gene/protein

FOXO1

Comment Enhanced FoxO1 activity is associated with non-alcoholic steatohepatitis in humans.
Formal Description
Interaction-ID: 4039

gene/protein

FOXO1

affects_activity of

disease

Fatty liver disease, nonalcoholic

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.
Formal Description
Interaction-ID: 4040

complex/PPI

Insulin

decreases_activity of

gene/protein

PCK1

via FoxO1 inhibition
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.
Formal Description
Interaction-ID: 4041

gene/protein

FOXO1

increases_expression of

gene/protein

PCK1

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.
Formal Description
Interaction-ID: 4042

complex/PPI

Insulin

decreases_activity of

gene/protein

G6PC

via FoxO1 inhibition
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.
Formal Description
Interaction-ID: 4043

gene/protein

FOXO1

increases_expression of

gene/protein

G6PC

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.
Formal Description
Interaction-ID: 4044

complex/PPI

Insulin

decreases_activity of

process

gluconeogenesis

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.
Formal Description
Interaction-ID: 4045

gene/protein

G6PC

increases_activity of

process

gluconeogenesis

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.
Formal Description
Interaction-ID: 4046

gene/protein

PCK1

increases_activity of

process

gluconeogenesis

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.
Formal Description
Interaction-ID: 4084

environment

fasting

increases_expression of

gene/protein

FOXO1

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.
Formal Description
Interaction-ID: 4085

decreases_activity of

gene/protein

FOXO1

in liver
Comment An increased FFA flux into the liver stimulates hepatic lipogenesis and promotes VLDL-TG overproduction, contributing to the pathogenesis of hypertriglyceridemia.
Formal Description
Interaction-ID: 13064

phenotype

increased liver free fatty acid level

increases_activity of

process

VLDL secretion

in liver
Comment An increased FFA flux into the liver stimulates hepatic lipogenesis and promotes VLDL-TG overproduction, contributing to the pathogenesis of hypertriglyceridemia.
Formal Description
Interaction-ID: 13065

phenotype

increased liver free fatty acid level

increases_activity of

in liver
Comment Hepatic MTP overproduction results in excessive VLDL-TG secretion and significantly elevated plasma TG levels.
Formal Description
Interaction-ID: 13066

gene/protein

MTTP

affects_activity of

if MTTP is overexpressed
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.
Formal Description
Interaction-ID: 13067

environment

fasting

increases_transport of

gene/protein

FOXO1

into the nucleus
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.
Formal Description
Interaction-ID: 13068

environment

fasting

increases_activity of

process

gluconeogenesis

via increased nuclear level of FOXO1
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.
Formal Description
Interaction-ID: 13069

environment

feeding

increases_phosphorylation of

gene/protein

FOXO1

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.
Formal Description
Interaction-ID: 13070

environment

feeding

increases_transport of

gene/protein

FOXO1

into the cytoplasm
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.
Formal Description
Interaction-ID: 13071

environment

feeding

decreases_activity of

process

gluconeogenesis

via increased cytoplasmic level of FOXO1
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.
Formal Description
Interaction-ID: 13072

gene/protein

FOXO1

increases_activity of

process

gluconeogenesis

in liver
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.
Formal Description
Interaction-ID: 13073

disease

Insulin resistance

increases_activity of

gene/protein

FOXO1

in liver
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.
Formal Description
Interaction-ID: 13074

gene/protein

FOXO1

increases_activity of

process

VLDL secretion

in liver
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.
Formal Description
Interaction-ID: 13075

gene/protein

FOXO1

affects_activity of

phenotype

hyperglycemia

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.
Formal Description
Interaction-ID: 13076

gene/protein

FOXO1

affects_activity of