General Information:

Id: 824 (click here to show other Interactions for entry)
Diseases: Diabetes mellitus, type II - [OMIM]
Insulin resistance
Obesity - [OMIM]
Mammalia
review
Reference: Sugden MC et al.(2010) PPAR control: its SIRTainly as easy as PGC J. Endocrinol. 2: 93-104 [PMID: 19770177]

Interaction Information:

Comment Induction of PPAR-alpha gene targets requires the interaction of PPAR-alpha and PGC-1, often in complex with other enzymes and coactivators.
Formal Description
Interaction-ID: 4788

gene/protein

PPARA

interacts (colocalizes) with

gene/protein

PPARGC1A

Drugbank entries Show/Hide entries for PPARA
Comment SIRT1-mediated deacetylation activates PGC-1alpha, while acetylation by GCN5 inhibits PGC-1alpha-directed gene expression.
Formal Description
Interaction-ID: 4790

gene/protein

SIRT1

decreases_acetylation of

gene/protein

PPARGC1A

Comment SIRT1-mediated deacetylation activates PGC-1alpha, while acetylation by GCN5 inhibits PGC-1alpha-directed gene expression.
Formal Description
Interaction-ID: 4791

gene/protein

SIRT1

increases_activity of

gene/protein

PPARGC1A

Comment SIRT1-mediated deacetylation activates PGC-1alpha, while acetylation by GCN5 inhibits PGC-1alpha-directed gene expression.
Formal Description
Interaction-ID: 4792

gene/protein

KAT2A

increases_acetylation of

gene/protein

PPARGC1A

Drugbank entries Show/Hide entries for KAT2A
Comment SIRT1-mediated deacetylation activates PGC-1alpha, while acetylation by GCN5 inhibits PGC-1alpha-directed gene expression.
Formal Description
Interaction-ID: 4793

gene/protein

KAT2A

decreases_activity of

gene/protein

PPARGC1A

Drugbank entries Show/Hide entries for KAT2A
Comment In skeletal muscle, phosphorylation by AMPK and p38 MAPK increases stabilization of PGC-1alpha.
Formal Description
Interaction-ID: 4794

complex/PPI

AMPK

increases_phosphorylation of

gene/protein

PPARGC1A

in skeletal muscle
Comment In skeletal muscle, phosphorylation by AMPK and p38 MAPK increases stabilization of PGC-1alpha.
Formal Description
Interaction-ID: 4795

gene/protein

p38 MAPK

increases_phosphorylation of

gene/protein

PPARGC1A

in skeletal muscle
Comment In skeletal muscle, phosphorylation by AMPK and p38 MAPK increases stabilization of PGC-1alpha.
Formal Description
Interaction-ID: 4797

complex/PPI

AMPK

increases_quantity of

gene/protein

PPARGC1A

in skeletal muscle; via decreased degradation of PPARGC1A
Comment In skeletal muscle, phosphorylation by AMPK and p38 MAPK increases stabilization of PGC-1alpha.
Formal Description
Interaction-ID: 4799

gene/protein

p38 MAPK

increases_quantity of

gene/protein

PPARGC1A

in skeletal muscle; via decreased degradation of PPARGC1A
Comment AKT/PKB-mediated phosphorylation facilitates degradation of hepatic PGC-1alpha.
Formal Description
Interaction-ID: 4800

gene/protein

AKT1

increases_phosphorylation of

gene/protein

PPARGC1A

in liver
Drugbank entries Show/Hide entries for AKT1
Comment AKT/PKB-mediated phosphorylation facilitates degradation of hepatic PGC-1alpha.
Formal Description
Interaction-ID: 4802

gene/protein

AKT1

decreases_quantity of

gene/protein

PPARGC1A

in liver; via increased degradation of PPARGC1A
Drugbank entries Show/Hide entries for AKT1
Comment PRMT1 also activates PGC-1alpha through methylation at several arginine residues.
Formal Description
Interaction-ID: 4803

gene/protein

PRMT1

increases_methylation of

gene/protein

PPARGC1A

at several Arg residues
Drugbank entries Show/Hide entries for PRMT1
Comment PRMT1 also activates PGC-1alpha through methylation at several arginine residues.
Formal Description
Interaction-ID: 4804

gene/protein

PRMT1

increases_activity of

gene/protein

PPARGC1A

Drugbank entries Show/Hide entries for PRMT1
Comment The PGC-1s are a small family of transcriptional coactivators that play a critical role in the control of glucose, lipid, and energy metabolism. There are three known isoforms of PGC-1: PGC-1alpha (PPARGC1A); PGC-1beta (PPARGC1B); PGC-1-related coactivator (PRC or PPRC1).
Formal Description
Interaction-ID: 4805

gene/protein

PPARGC1A

affects_activity of

via regulation of a transcription factor
Comment Both PGC-1alpha and PGC-1beta are found in complex with GCN5, an acetyl transferase which acetylates PGC-1 at several lysine residues and inhibits its transcriptional activity.
Formal Description
Interaction-ID: 4812

gene/protein

PPARGC1A

interacts (colocalizes) with

gene/protein

KAT2A

Drugbank entries Show/Hide entries for KAT2A
Comment Expression of PGC-1 coactivators in the liver is relatively low in the fed state; however, in parallel with effects of fasting to increase PPAR-alpha signaling, hepatic PGC-1alpha mRNA expression is elevated after starvation and plays a critical role in the regulation of hepatic gluconeogenesis and fatty acid oxidation.
Formal Description
Interaction-ID: 4840

environment

fasting

increases_expression of

gene/protein

PPARGC1A

in liver
Comment Expression of PGC-1 coactivators in the liver is relatively low in the fed state; however, in parallel with effects of fasting to increase PPAR-alpha signaling, hepatic PGC-1alpha mRNA expression is elevated after starvation and plays a critical role in the regulation of hepatic gluconeogenesis and fatty acid oxidation.
Formal Description
Interaction-ID: 4841

gene/protein

PPARGC1A

affects_activity of

process

gluconeogenesis

in liver
Comment Expression of PGC-1 coactivators in the liver is relatively low in the fed state; however, in parallel with effects of fasting to increase PPAR-alpha signaling, hepatic PGC-1alpha mRNA expression is elevated after starvation and plays a critical role in the regulation of hepatic gluconeogenesis and fatty acid oxidation.
Formal Description
Interaction-ID: 4843

gene/protein

PPARGC1A

affects_activity of

in liver
Comment Increased expression of PGC-1alpha in liver via adenovirus vector enhances hepatic glucose production.
Formal Description
Interaction-ID: 4844

gene/protein

PPARGC1A

increases_activity of

process

gluconeogenesis

in liver; if PPARGC1A is overexpressed
Comment The rise in glucagon levels on fasting is associated with the dephosphorylation and translocation of the CREB-regulated transcription coactivator (TORC2 or CRTC2) to the nucleus, where it coactivates CREB, a transcription factor present on the PGC-1alpha gene promoter, leading to induction of PGC-1alpha.
Formal Description
Interaction-ID: 4850

gene/protein

CREB1

increases_activity of

gene/protein

PPARGC1A

in liver
Drugbank entries Show/Hide entries for CREB1
Comment PGC-1alpha subsequently coactivates and forms complexes with FoxO1, the GR and HNF-4alpha, which (as well as PPAR-alpha) are essential for expression of the key gluconeogenic genes PCK1 and/or G6Pase.
Formal Description
Interaction-ID: 4852

gene/protein

PPARGC1A

increases_activity of

gene/protein

FOXO1

in liver
Comment PGC-1alpha subsequently coactivates and forms complexes with FoxO1, the GR and HNF-4alpha, which (as well as PPAR-alpha) are essential for expression of the key gluconeogenic genes PCK1 and/or G6Pase.
Formal Description
Interaction-ID: 4854

gene/protein

PPARGC1A

increases_activity of

gene/protein

NR3C1

in liver
Drugbank entries Show/Hide entries for NR3C1
Comment PGC-1alpha subsequently coactivates and forms complexes with FoxO1, the GR and HNF-4alpha, which (as well as PPAR-alpha) are essential for expression of the key gluconeogenic genes PCK1 and/or G6Pase.
Formal Description
Interaction-ID: 4855

gene/protein

PPARGC1A

increases_activity of

gene/protein

HNF4A

in liver
Drugbank entries Show/Hide entries for HNF4A
Comment Activation of AKT by insulin elicits phosphorylation of both TORC2 and PGC-1alpha leading to their degradation.
Formal Description
Interaction-ID: 4862

gene/protein

AKT1

increases_phosphorylation of

gene/protein

PPARGC1A

in liver
Drugbank entries Show/Hide entries for AKT1
Comment Activation of AKT by insulin elicits phosphorylation of both TORC2 and PGC-1alpha leading to their degradation.
Formal Description
Interaction-ID: 4864

gene/protein

AKT1

decreases_quantity of

gene/protein

PPARGC1A

in liver; via increased degradation of PPARGC1A
Drugbank entries Show/Hide entries for AKT1
Comment Activation of AKT by insulin elicits phosphorylation of both TORC2 and PGC-1alpha leading to their degradation.
Formal Description
Interaction-ID: 4867

gene/protein

AKT1

decreases_activity of

gene/protein

PPARGC1A

in liver
Drugbank entries Show/Hide entries for AKT1
Comment PGC-1alpha target genes for fatty acid (FA) oxidation are induced in skeletal muscle by SIRT1 and inhibited by GCN5.
Formal Description
Interaction-ID: 4869

gene/protein

SIRT1

increases_activity of

gene/protein

PPARGC1A

in skeletal muscle
Comment PGC-1alpha target genes for fatty acid (FA) oxidation are induced in skeletal muscle by SIRT1 and inhibited by GCN5.
Formal Description
Interaction-ID: 4870

gene/protein

KAT2A

decreases_activity of

gene/protein

PPARGC1A

in skeletal muscle
Drugbank entries Show/Hide entries for KAT2A
Comment PGC-1alpha target genes for fatty acid (FA) oxidation are induced in skeletal muscle by SIRT1 and inhibited by GCN5.
Formal Description
Interaction-ID: 4871

gene/protein

PPARGC1A

increases_activity of

in skeletal muscle
Comment TORC2 induces PGC-1alpha, while knockdown of lipin-1 decreases PGC-1alpha mRNA levels.
Formal Description
Interaction-ID: 4903

gene/protein

CRTC2

increases_expression of

gene/protein

PPARGC1A

Comment TORC2 induces PGC-1alpha, while knockdown of lipin-1 decreases PGC-1alpha mRNA levels.
Formal Description
Interaction-ID: 4904

gene/protein

LPIN1

increases_expression of

gene/protein

PPARGC1A

Comment Normal pancreatic islets express both PGC-1alpha and SIRT1 at low levels. As in liver, fasting for 24 h increases PGC-1alpha mRNA expression in islets, an effect reversed by 24 h of refeeding.
Formal Description
Interaction-ID: 4909

environment

fasting

increases_expression of

gene/protein

PPARGC1A

in pancreas, in pancreatic islets
Comment PGC-1alpha mRNA and protein expression have been reported to be elevated in islets from animal models of diabetes, including the ob/ob mouse and ZDF rats.
Formal Description
Interaction-ID: 4910

increases_expression of

gene/protein

PPARGC1A

in pancreas, in pancreatic islets
Comment Overexpression of PGC-1alpha in islets substantially reduces the expression of the beta-cell glucose sensors for glucose-stimulated insulin secretion (GSIS), GLUT2, and glucokinase, and also impairs GSIS, suggesting it can precipitate beta-cell dysfunction.
Formal Description
Interaction-ID: 4911

gene/protein

PPARGC1A

decreases_expression of

gene/protein

SLC2A2

in pancreas, in pancreatic islets
Drugbank entries Show/Hide entries for SLC2A2
Comment Overexpression of PGC-1alpha in islets substantially reduces the expression of the beta-cell glucose sensors for glucose-stimulated insulin secretion (GSIS), GLUT2, and glucokinase, and also impairs GSIS, suggesting it can precipitate beta-cell dysfunction.
Formal Description
Interaction-ID: 4912

gene/protein

PPARGC1A

decreases_expression of

gene/protein

GCK

in pancreas, in pancreatic islets
Drugbank entries Show/Hide entries for GCK
Comment Chronic hyperlipidemia and hyperglycemia, which together cause adverse effects on beta-cell function via glucolipotoxicity, also affect PGC-1alpha gene expression.
Formal Description
Interaction-ID: 4913

phenotype

hyperlipidemia

affects_expression of

gene/protein

PPARGC1A

in pancreas, in pancreatic islets
Comment Chronic hyperlipidemia and hyperglycemia, which together cause adverse effects on beta-cell function via glucolipotoxicity, also affect PGC-1alpha gene expression.
Formal Description
Interaction-ID: 4914

phenotype

hyperglycemia

affects_expression of

gene/protein

PPARGC1A

in pancreas, in pancreatic islets
Comment GLP-1 increases islet PGC-1alpha mRNA expression which leads to repression of genes involved in beta-cell glucose sensing with a marked inhibition of GSIS.
Formal Description
Interaction-ID: 4915

increases_expression of

gene/protein

PPARGC1A

in pancreas, in pancreatic islets
Comment GLP-1 increases islet PGC-1alpha mRNA expression which leads to repression of genes involved in beta-cell glucose sensing with a marked inhibition of GSIS.
Formal Description
Interaction-ID: 4916

gene/protein

PPARGC1A

decreases_activity of

in pancreas, in pancreatic islets
Comment Both PGC-1beta and SREBP-1c, but not PGC-1alpha, are induced in liver in response to acute (24-48 h) high (58%) dietary saturated fat (mainly hydrogenated coconut oil), the increases in PGC-1beta and SREBP-1c in response to dietary saturated fat were specific to liver and not replicated in skeletal muscle or white adipose tissue, while dietary cholesterol intake had little impact on hepatic PGC-1beta expression.
Formal Description
Interaction-ID: 4970

environment

high-saturated-fat diet

NOT increases_expression of

gene/protein

PPARGC1A

Comment Ectopic expression of PGC-1alpha in white adipocytes increases the expression of UCP1, genes encoding respiratory chain proteins (cytochrome c-oxidase subunits COX II and IV) and enzymes of FA oxidation and causes white adipocytes to acquire features of brown adipocytes.
Formal Description
Interaction-ID: 5035

gene/protein

PPARGC1A

affects_expression of

gene/protein

UCP1

Comment In ob/ob mice, the expression of transcripts encoding mitochondrial proteins decreases with the development of obesity. TZD treatment in ob/ob mice increases PGC-1alpha expression and increases mitochondrial mass and energy expenditure.
Formal Description
Interaction-ID: 5041

drug/chemical compound

Thiazolidinedione

increases_expression of

gene/protein

PPARGC1A

Comment Hepatic PGC-1alpha is increased in rodent models of type 2 diabetes mellitus (T2DM) which may lead to induction of gluconeogenesis and hyperglycemia, while at least two clinical studies have identified a correlation between mutations of the PPARGC1A gene (previously known as the PGC-1alpha gene) and insulin resistance or diabetes.
Formal Description
Interaction-ID: 5092

gene/protein

PPARGC1A

affects_activity of

Comment Hepatic PGC-1alpha is increased in rodent models of type 2 diabetes mellitus (T2DM) which may lead to induction of gluconeogenesis and hyperglycemia, while at least two clinical studies have identified a correlation between mutations of the PPARGC1A gene (previously known as the PGC-1alpha gene) and insulin resistance or diabetes.
Formal Description
Interaction-ID: 5104

gene/protein

PPARGC1A

affects_activity of

disease

Insulin resistance

Comment Overexpression of PGC-1alpha in cultures of primary rat skeletal muscle cells induces increased expression of the mammalian tribbles homolog TRB3, an inhibitor of AKT signaling, highlighting the potential of PGC-1alpha to cause insulin resistance.
Formal Description
Interaction-ID: 5105

gene/protein

PPARGC1A

increases_expression of

gene/protein

TRIB3

in skeletal muscle
Comment A study undertook a genome-wide promoter analysis of DNA methylation, screening for genes differentially methylated in T2DM, which identified cytosine hypermethylation of PGC-1alpha in diabetic subjects. Hypermethylation of the PGC-1alpha promoter was associated with reduced PGC-1alpha expression.
Formal Description
Interaction-ID: 5125

decreases_expression of

gene/protein

PPARGC1A

via hypermethylation of the PPARGC1A promoter
Comment Treatment of high-fat-fed mice with resveratrol elicits PGC-1alpha deacetylation and activation, opposes weight gain, and enhances insulin sensitivity.
Formal Description
Interaction-ID: 5132

drug/chemical compound

Resveratrol

decreases_acetylation of

gene/protein

PPARGC1A

in high-fat fed mice
Drugbank entries Show/Hide entries for Resveratrol
Comment Treatment of high-fat-fed mice with resveratrol elicits PGC-1alpha deacetylation and activation, opposes weight gain, and enhances insulin sensitivity.
Formal Description
Interaction-ID: 5133

drug/chemical compound

Resveratrol

increases_activity of

gene/protein

PPARGC1A

in high-fat fed mice
Drugbank entries Show/Hide entries for Resveratrol
Comment The observation that, in liver, TRIB3 is a target for PPAR-alpha and that knockdown of hepatic TRIB3 expression improves glucose tolerance, whereas hepatic overexpression of TRIB3 reverses the insulin-sensitive phenotype of PGC-1-deficient mice has led to the suggestion that TRIB3 inhibitors may have a potential role in the treatment of T2DM. However, chronic reduction of hepatic PGC-1alpha expression has been shown to impair hepatic insulin sensitivity.
Formal Description
Interaction-ID: 13113

gene/protein

PPARGC1A

affects_activity of

in liver
Comment Unlike classic PPAR-gamma-target genes such as aP2 (which is constitutively associated with coactivators), the glycerol kinase gene is targeted by NR corepressors. TZDs trigger the dismissal of corepressor HDAC complexes and the recruitment of coactivators to the glycerol kinase gene. They also induce PGC-1alpha, whose recruitment to the glycerol kinase gene is sufficient to release the corepressors.
Formal Description
Interaction-ID: 13117

drug/chemical compound

Thiazolidinedione

affects_activity of

gene/protein

PPARGC1A

Comment Ectopic expression of PGC-1alpha in white adipocytes increases the expression of UCP1, genes encoding respiratory chain proteins (cytochrome c-oxidase subunits COX II and IV) and enzymes of FA oxidation and causes white adipocytes to acquire features of brown adipocytes.
Formal Description
Interaction-ID: 13128

gene/protein

PPARGC1A

affects_expression of

gene/protein

MT-CO2

Drugbank entries Show/Hide entries for MT-CO2
Comment Ectopic expression of PGC-1alpha in white adipocytes increases the expression of UCP1, genes encoding respiratory chain proteins (cytochrome c-oxidase subunits COX II and IV) and enzymes of FA oxidation and causes white adipocytes to acquire features of brown adipocytes.
Formal Description
Interaction-ID: 13129

gene/protein

PPARGC1A

affects_expression of

gene/protein

COX4

Comment Ectopic expression of PGC-1alpha in white adipocytes increases the expression of UCP1, genes encoding respiratory chain proteins (cytochrome c-oxidase subunits COX II and IV) and enzymes of FA oxidation and causes white adipocytes to acquire features of brown adipocytes.
Formal Description
Interaction-ID: 13130

gene/protein

PPARGC1A

increases_activity of

complex/PPI

Mitochondrial respiratory chain

Comment Ectopic expression of PGC-1alpha in white adipocytes increases the expression of UCP1, genes encoding respiratory chain proteins (cytochrome c-oxidase subunits COX II and IV) and enzymes of FA oxidation and causes white adipocytes to acquire features of brown adipocytes.
Formal Description
Interaction-ID: 13131

gene/protein

PPARGC1A

affects_activity of