General Information:

Id: 459
Diseases: Diabetes mellitus, type II - [OMIM]
Insulin resistance
Peutz-Jeghers syndrome - [OMIM]
Mus musculus
male
adenovirus-mediated deletion of LKB1 in liver
article
Reference: Shaw RJ et al.(2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310: 1642-1646 [PMID: 16308421]

Interaction Information:

Comment The deletion of LKB1 in the liver resulted in a proportional decrease of AMPK phosphorylation at Thr172, suggesting that in this tissue, LKB1 accounts for most of the phosphorylation of AMPK. There was no effect of LKB1 loss on the amount of total AMPK-alpha.
Formal Description
Interaction-ID: 2029

gene/protein

STK11

affects_phosphorylation of

complex/PPI

AMPK

at Thr172 of AMPK alpha chain
Comment The deletion of LKB1 in the liver resulted in a proportional decrease of AMPK phosphorylation at Thr172, suggesting that in this tissue, LKB1 accounts for most of the phosphorylation of AMPK. There was no effect of LKB1 loss on the amount of total AMPK-alpha.
Formal Description
Interaction-ID: 2031

gene/protein

STK11

NOT affects_quantity of

gene/protein

AMPK alpha chain

Comment LKB1 deletion in liver causes severe hyperglycemia.
Formal Description
Interaction-ID: 2032

gene/protein

STK11

affects_activity of

phenotype

hyperglycemia

Comment Mice lacking hepatic LKB1 had impaired ability to maintain normal blood glucose concentrations after injection of glucose. However, these animals showed a normal reduction in blood glucose in response to insulin injection, suggesting that peripheral glucose uptake was not impaired in these animals.
Formal Description
Interaction-ID: 2033

gene/protein

STK11

decreases_activity of

in blood
Comment The increase in blood glucose in mice lacking liver LKB1 was accompanied over time by compensatory increases in blood insulin levels, as expected for mice with normal pancreatic function.
Formal Description
Interaction-ID: 2034

gene/protein

STK11

affects_activity of

Comment Despite these changes in blood glucose and insulin profiles, mice lacking LKB1 in the liver did not demonstrate increased body weight compared with their control littermates, even when placed on a high-fat diet for 2 months.
Formal Description
Interaction-ID: 2035

gene/protein

STK11

NOT affects_activity of

Comment LKB1 loss results in increased gluconeogenetic and lipogenic gene expression.
Formal Description
Interaction-ID: 2036

gene/protein

STK11

affects_activity of

process

gluconeogenesis

Comment LKB1 loss results in increased gluconeogenetic and lipogenic gene expression.
Formal Description
Interaction-ID: 2037

gene/protein

STK11

affects_activity of

Comment The expression of G6Pase and PGC1-alpha mRNA was increased in LKB1-deficient livers, whereas no change was observed in the expression of hexokinase mRNA.
Formal Description
Interaction-ID: 2038

gene/protein

STK11

affects_expression of

gene/protein

G6PC

in liver
Comment The expression of G6Pase and PGC1-alpha mRNA was increased in LKB1-deficient livers, whereas no change was observed in the expression of hexokinase mRNA.
Formal Description
Interaction-ID: 2039

gene/protein

STK11

affects_expression of

gene/protein

PPARGC1A

in liver
Comment The expression of G6Pase and PGC1-alpha mRNA was increased in LKB1-deficient livers, whereas no change was observed in the expression of hexokinase mRNA.
Formal Description
Interaction-ID: 2040

gene/protein

STK11

NOT affects_expression of

gene/protein

GCK

in liver
Drugbank entries Show/Hide entries for GCK
Comment In fasting LKB1-deficient mice, the amounts of PGC1-alpha protein are increased.
Formal Description
Interaction-ID: 2041

gene/protein

STK11

affects_quantity of

gene/protein

PPARGC1A

in fasting mice
Comment Amounts of mRNA encoding the critical lipogenic transcription factor sterol regulatory element-binding protein 1 (SREBP-1) were increased in LKB1-deficient livers along with those several well-described targets of SREBP-1 and the carbohydrate response element binding protein (ChREBP), which include the following: fatty acid synthase (FAS), acetyl CoA carboxylase (ACC1), and liver pyruvate kinase (L-PK). In contrast, marginal effects were observed on transcription of the ChREBP transcription factor itself. Protein levels of FAS and ACC1 were similarly increased in LKB1-deficient livers.
Formal Description
Interaction-ID: 2042

gene/protein

STK11

affects_expression of

gene/protein

SREBF1

in liver
Comment Amounts of mRNA encoding the critical lipogenic transcription factor sterol regulatory element-binding protein 1 (SREBP-1) were increased in LKB1-deficient livers along with those several well-described targets of SREBP-1 and the carbohydrate response element binding protein (ChREBP), which include the following: fatty acid synthase (FAS), acetyl CoA carboxylase (ACC1), and liver pyruvate kinase (L-PK). In contrast, marginal effects were observed on transcription of the ChREBP transcription factor itself. Protein levels of FAS and ACC1 were similarly increased in LKB1-deficient livers.
Formal Description
Interaction-ID: 2043

gene/protein

STK11

affects_expression of

gene/protein

FASN

in liver
Drugbank entries Show/Hide entries for FASN
Comment Amounts of mRNA encoding the critical lipogenic transcription factor sterol regulatory element-binding protein 1 (SREBP-1) were increased in LKB1-deficient livers along with those several well-described targets of SREBP-1 and the carbohydrate response element binding protein (ChREBP), which include the following: fatty acid synthase (FAS), acetyl CoA carboxylase (ACC1), and liver pyruvate kinase (L-PK). In contrast, marginal effects were observed on transcription of the ChREBP transcription factor itself. Protein levels of FAS and ACC1 were similarly increased in LKB1-deficient livers.
Formal Description
Interaction-ID: 2044

gene/protein

STK11

affects_expression of

gene/protein

ACACB

in liver
Drugbank entries Show/Hide entries for ACACB
Comment Amounts of mRNA encoding the critical lipogenic transcription factor sterol regulatory element-binding protein 1 (SREBP-1) were increased in LKB1-deficient livers along with those several well-described targets of SREBP-1 and the carbohydrate response element binding protein (ChREBP), which include the following: fatty acid synthase (FAS), acetyl CoA carboxylase (ACC1), and liver pyruvate kinase (L-PK). In contrast, marginal effects were observed on transcription of the ChREBP transcription factor itself. Protein levels of FAS and ACC1 were similarly increased in LKB1-deficient livers.
Formal Description
Interaction-ID: 2045

gene/protein

STK11

affects_expression of

gene/protein

PKLR

in liver
Drugbank entries Show/Hide entries for PKLR
Comment Amounts of mRNA encoding the critical lipogenic transcription factor sterol regulatory element-binding protein 1 (SREBP-1) were increased in LKB1-deficient livers along with those several well-described targets of SREBP-1 and the carbohydrate response element binding protein (ChREBP), which include the following: fatty acid synthase (FAS), acetyl CoA carboxylase (ACC1), and liver pyruvate kinase (L-PK). In contrast, marginal effects were observed on transcription of the ChREBP transcription factor itself. Protein levels of FAS and ACC1 were similarly increased in LKB1-deficient livers.
Formal Description
Interaction-ID: 2046

gene/protein

STK11

NOT affects_expression of

gene/protein

MLXIPL

in liver
Comment Amounts of mRNA encoding the critical lipogenic transcription factor sterol regulatory element-binding protein 1 (SREBP-1) were increased in LKB1-deficient livers along with those several well-described targets of SREBP-1 and the carbohydrate response element binding protein (ChREBP), which include the following: fatty acid synthase (FAS), acetyl CoA carboxylase (ACC1), and liver pyruvate kinase (L-PK). In contrast, marginal effects were observed on transcription of the ChREBP transcription factor itself. Protein levels of FAS and ACC1 were similarly increased in LKB1-deficient livers.
Formal Description
Interaction-ID: 2047

gene/protein

STK11

affects_quantity of

gene/protein

FASN

in liver
Drugbank entries Show/Hide entries for FASN
Comment Amounts of mRNA encoding the critical lipogenic transcription factor sterol regulatory element-binding protein 1 (SREBP-1) were increased in LKB1-deficient livers along with those several well-described targets of SREBP-1 and the carbohydrate response element binding protein (ChREBP), which include the following: fatty acid synthase (FAS), acetyl CoA carboxylase (ACC1), and liver pyruvate kinase (L-PK). In contrast, marginal effects were observed on transcription of the ChREBP transcription factor itself. Protein levels of FAS and ACC1 were similarly increased in LKB1-deficient livers.
Formal Description
Interaction-ID: 2048

gene/protein

STK11

affects_quantity of

gene/protein

ACACB

in liver
Drugbank entries Show/Hide entries for ACACB
Comment TORC2 is deregulated in LKB1-deficient livers and drives gluconeogenesis.
Formal Description
Interaction-ID: 2049

gene/protein

STK11

affects_activity of

gene/protein

CRTC2

Comment TORC2 from untreated wild-type livers was predominantly phosphorylated, whereas much of the TORC2 from LKB1-deficient liver exhibited a faster mobility, consistent with the absence of Ser171 phosphorylation.
Formal Description
Interaction-ID: 2050

gene/protein

STK11

affects_phosphorylation of

gene/protein

CRTC2

in liver
Comment TORC2 was predominantly nuclear in LKB1-/- livers, whereas in wild-type mice, TORC2 was predominantly cytoplasmic.
Formal Description
Interaction-ID: 2051

gene/protein

CRTC2

is localized in

cellular component

cytoplasm

Comment Metformin requires hepatic LKB1 to lower blood glucose.
Formal Description
Interaction-ID: 2052

gene/protein

STK11

affects_activity of

drug/chemical compound

Metformin

Drugbank entries Show/Hide entries for
Comment AMPK phosphorylation was increased in livers from wild-type mice injected with metformin, but not in livers deficient in LKB1.
Formal Description
Interaction-ID: 2053

drug/chemical compound

Metformin

increases_phosphorylation of

complex/PPI

AMPK

in liver; if STK11 is present
Drugbank entries Show/Hide entries for Metformin
Comment Metformin treatment reduced blood glucose by more than 50% in the wild-type mice on a high-fat diet. Metformin treatment also lowered blood glucose in the ob/ob mice by 40%. However, there was no reduction in blood glucose in the mice in which LKB1 had been deleted in the liver.
Formal Description
Interaction-ID: 2054

drug/chemical compound

Metformin

decreases_quantity of

drug/chemical compound

Glucose

in blood; in wild-type mice on high-fat diet, in ob/ob mice
Drugbank entries Show/Hide entries for Metformin
Comment The LKB1 tumor suppressor is the major upstream activating kinase for AMPK in liver.
Formal Description
Interaction-ID: 2055

gene/protein

STK11

increases_phosphorylation of

complex/PPI

AMPK

in liver
Comment The activation of an upstream kinase (LKB1) in turn regulates downstream kinases (AMPK and SIK) that phosphorylate a transcriptional coactivator (TORC2), resulting in its inactivation through sequestration in the cytoplasm. This pathway normally integrates cellular (AMPK) and hormonal (SIK) inputs to negatively regulate transcriptional events that promote synthesis of gluconeogenic enzymes. In the absence of LKB1, no kinase is active to phosphorylate TORC2, and gluconeogenesis occurs without these metabolic checkpoints.
Formal Description
Interaction-ID: 2057

gene/protein

STK11

increases_activity of

complex/PPI

AMPK

Comment AMPK activation is absolutely required for the glucose-lowering action of metformin in intact animals. The deletion of LKB1 in the liver did not impair AMPK activation in muscle, yet it eliminated the effect of metformin on serum glucose levels. This result suggests that in mice, metformin primarily decreases blood glucose concentrations by decreasing hepatic gluconeogenesis.
Formal Description
Interaction-ID: 2059

complex/PPI

AMPK

affects_activity of

drug/chemical compound

Metformin

Drugbank entries Show/Hide entries for
Comment TORC2 is deregulated in LKB1-deficient livers and drives gluconeogenesis.
Formal Description
Interaction-ID: 12749

gene/protein

CRTC2

affects_activity of

process

gluconeogenesis

Comment The activation of an upstream kinase (LKB1) in turn regulates downstream kinases (AMPK and SIK) that phosphorylate a transcriptional coactivator (TORC2), resulting in its inactivation through sequestration in the cytoplasm. This pathway normally integrates cellular (AMPK) and hormonal (SIK) inputs to negatively regulate transcriptional events that promote synthesis of gluconeogenic enzymes. In the absence of LKB1, no kinase is active to phosphorylate TORC2, and gluconeogenesis occurs without these metabolic checkpoints.
Formal Description
Interaction-ID: 12750

gene/protein

STK11

increases_activity of

gene/protein

SIK

Comment The activation of an upstream kinase (LKB1) in turn regulates downstream kinases (AMPK and SIK) that phosphorylate a transcriptional coactivator (TORC2), resulting in its inactivation through sequestration in the cytoplasm. This pathway normally integrates cellular (AMPK) and hormonal (SIK) inputs to negatively regulate transcriptional events that promote synthesis of gluconeogenic enzymes. In the absence of LKB1, no kinase is active to phosphorylate TORC2, and gluconeogenesis occurs without these metabolic checkpoints.
Formal Description
Interaction-ID: 12751

complex/PPI

AMPK

decreases_activity of

gene/protein

CRTC2

Comment The activation of an upstream kinase (LKB1) in turn regulates downstream kinases (AMPK and SIK) that phosphorylate a transcriptional coactivator (TORC2), resulting in its inactivation through sequestration in the cytoplasm. This pathway normally integrates cellular (AMPK) and hormonal (SIK) inputs to negatively regulate transcriptional events that promote synthesis of gluconeogenic enzymes. In the absence of LKB1, no kinase is active to phosphorylate TORC2, and gluconeogenesis occurs without these metabolic checkpoints.
Formal Description
Interaction-ID: 12752

gene/protein

SIK

decreases_activity of

gene/protein

CRTC2

Comment AMPK activation is absolutely required for the glucose-lowering action of metformin in intact animals. The deletion of LKB1 in the liver did not impair AMPK activation in muscle, yet it eliminated the effect of metformin on serum glucose levels. This result suggests that in mice, metformin primarily decreases blood glucose concentrations by decreasing hepatic gluconeogenesis.
Formal Description
Interaction-ID: 12753

drug/chemical compound

Metformin

decreases_activity of

process

gluconeogenesis

in liver
Drugbank entries Show/Hide entries for Metformin