General Information:

Id: 5,241
Diseases: Diabetes mellitus, type II - [OMIM]
Insulin resistance
Mammalia
review
Reference: Dominy JE Jr et al.(2010) Nutrient-dependent regulation of PGC-1alphas acetylation state and metabolic function through the enzymatic activities of Sirt1/GCN5 Biochim. Biophys. Acta 1804: 1676-1683 [PMID: 20005308]

Interaction Information:

Comment When a mammal is deprived of food, its body undergoes both quantitative and qualitative changes in the way in which stored macronutrients are mobilized and metabolized as fuel. These changes constitute a homeostatic response that ultimately aids in the preservation of a constant supply of circulating blood glucose for those tissues that exclusively require it and in the reduction of overall energy expenditure. Part of this response includes switching to the utilization of free fatty acids as the major macronutrient fuel in peripheral tissues such as muscle as well as increasing the rate of glucose synthesis in the liver and kidney. The coordinated initiation and subsequent maintenance of this change in fuel utilization is a highly complicated process that requires the integration of many hormonal, transcriptional, translational, and allosteric signals.
Formal Description
Interaction-ID: 51038

environment

fasting

increases_activity of

in skeletal muscle
Comment When a mammal is deprived of food, its body undergoes both quantitative and qualitative changes in the way in which stored macronutrients are mobilized and metabolized as fuel. These changes constitute a homeostatic response that ultimately aids in the preservation of a constant supply of circulating blood glucose for those tissues that exclusively require it and in the reduction of overall energy expenditure. Part of this response includes switching to the utilization of free fatty acids as the major macronutrient fuel in peripheral tissues such as muscle as well as increasing the rate of glucose synthesis in the liver and kidney. The coordinated initiation and subsequent maintenance of this change in fuel utilization is a highly complicated process that requires the integration of many hormonal, transcriptional, translational, and allosteric signals.
Formal Description
Interaction-ID: 51039

environment

fasting

increases_activity of

process

gluconeogenesis

in liver, in kidneys
Comment The list of transcription factors to which proliferator-activated receptor gamma-coactivator-1 alpha (PGC-1alpha) is known to bind includes PPARgamma, PPARalpha, glucocorticoid receptor, hepatic nuclear factor-4alpha, members of the estrogen related receptor (ERR) family, myocyte enhancer factor 2, nuclear respiratory factors 1 and 2, FoxO1, and YY1.
Formal Description
Interaction-ID: 51040

gene/protein

PPARGC1A

interacts (colocalizes) with

gene/protein

PPARG

Drugbank entries Show/Hide entries for PPARG
Comment The list of transcription factors to which proliferator-activated receptor gamma-coactivator-1 alpha (PGC-1alpha) is known to bind includes PPARgamma, PPARalpha, glucocorticoid receptor, hepatic nuclear factor-4alpha, members of the estrogen related receptor (ERR) family, myocyte enhancer factor 2, nuclear respiratory factors 1 and 2, FoxO1, and YY1.
Formal Description
Interaction-ID: 51041

gene/protein

PPARGC1A

interacts (colocalizes) with

gene/protein

PPARA

Drugbank entries Show/Hide entries for PPARA
Comment The list of transcription factors to which proliferator-activated receptor gamma-coactivator-1 alpha (PGC-1alpha) is known to bind includes PPARgamma, PPARalpha, glucocorticoid receptor, hepatic nuclear factor-4alpha, members of the estrogen related receptor (ERR) family, myocyte enhancer factor 2, nuclear respiratory factors 1 and 2, FoxO1, and YY1.
Formal Description
Interaction-ID: 51042

gene/protein

PPARGC1A

interacts (colocalizes) with

gene/protein

NR3C1

Drugbank entries Show/Hide entries for NR3C1
Comment The list of transcription factors to which proliferator-activated receptor gamma-coactivator-1 alpha (PGC-1alpha) is known to bind includes PPARgamma, PPARalpha, glucocorticoid receptor, hepatic nuclear factor-4alpha, members of the estrogen related receptor (ERR) family, myocyte enhancer factor 2, nuclear respiratory factors 1 and 2, FoxO1, and YY1.
Formal Description
Interaction-ID: 51043

gene/protein

PPARGC1A

interacts (colocalizes) with

gene/protein

HNF4A

Drugbank entries Show/Hide entries for HNF4A
Comment The list of transcription factors to which proliferator-activated receptor gamma-coactivator-1 alpha (PGC-1alpha) is known to bind includes PPARgamma, PPARalpha, glucocorticoid receptor, hepatic nuclear factor-4alpha, members of the estrogen related receptor (ERR) family, myocyte enhancer factor 2, nuclear respiratory factors 1 and 2, FoxO1, and YY1.
Formal Description
Interaction-ID: 51044

gene/protein

PPARGC1A

interacts (colocalizes) with

gene/protein

ESRRA

Drugbank entries Show/Hide entries for ESRRA
Comment The list of transcription factors to which proliferator-activated receptor gamma-coactivator-1 alpha (PGC-1alpha) is known to bind includes PPARgamma, PPARalpha, glucocorticoid receptor, hepatic nuclear factor-4alpha, members of the estrogen related receptor (ERR) family, myocyte enhancer factor 2, nuclear respiratory factors 1 and 2, FoxO1, and YY1.
Formal Description
Interaction-ID: 51045

gene/protein

PPARGC1A

interacts (colocalizes) with

gene/protein

ESRRG

Drugbank entries Show/Hide entries for ESRRG
Comment The list of transcription factors to which proliferator-activated receptor gamma-coactivator-1 alpha (PGC-1alpha) is known to bind includes PPARgamma, PPARalpha, glucocorticoid receptor, hepatic nuclear factor-4alpha, members of the estrogen related receptor (ERR) family, myocyte enhancer factor 2, nuclear respiratory factors 1 and 2, FoxO1, and YY1.
Formal Description
Interaction-ID: 51046

gene/protein

PPARGC1A

interacts (colocalizes) with

gene/protein

MEF2

Comment The list of transcription factors to which proliferator-activated receptor gamma-coactivator-1 alpha (PGC-1alpha) is known to bind includes PPARgamma, PPARalpha, glucocorticoid receptor, hepatic nuclear factor-4alpha, members of the estrogen related receptor (ERR) family, myocyte enhancer factor 2, nuclear respiratory factors 1 and 2, FoxO1, and YY1.
Formal Description
Interaction-ID: 51047

gene/protein

PPARGC1A

interacts (colocalizes) with

gene/protein

NRF1

Comment The list of transcription factors to which proliferator-activated receptor gamma-coactivator-1 alpha (PGC-1alpha) is known to bind includes PPARgamma, PPARalpha, glucocorticoid receptor, hepatic nuclear factor-4alpha, members of the estrogen related receptor (ERR) family, myocyte enhancer factor 2, nuclear respiratory factors 1 and 2, FoxO1, and YY1.
Formal Description
Interaction-ID: 51048

gene/protein

PPARGC1A

interacts (colocalizes) with

complex/PPI

GA binding protein transcription factor alpha

Comment The list of transcription factors to which proliferator-activated receptor gamma-coactivator-1 alpha (PGC-1alpha) is known to bind includes PPARgamma, PPARalpha, glucocorticoid receptor, hepatic nuclear factor-4alpha, members of the estrogen related receptor (ERR) family, myocyte enhancer factor 2, nuclear respiratory factors 1 and 2, FoxO1, and YY1.
Formal Description
Interaction-ID: 51049

gene/protein

PPARGC1A

interacts (colocalizes) with

gene/protein

FOXO1

Comment The list of transcription factors to which proliferator-activated receptor gamma-coactivator-1 alpha (PGC-1alpha) is known to bind includes PPARgamma, PPARalpha, glucocorticoid receptor, hepatic nuclear factor-4alpha, members of the estrogen related receptor (ERR) family, myocyte enhancer factor 2, nuclear respiratory factors 1 and 2, FoxO1, and YY1.
Formal Description
Interaction-ID: 51051

gene/protein

PPARGC1A

interacts (colocalizes) with

gene/protein

YY1

Comment Although they enhance the activity of PGC-1alpha, SRC-1 and CBP/p300 do not acetylate PGC-1alpha.
Formal Description
Interaction-ID: 51052

gene/protein

NCOA1

increases_activity of

gene/protein

PPARGC1A

Drugbank entries Show/Hide entries for NCOA1
Comment Although they enhance the activity of PGC-1alpha, SRC-1 and CBP/p300 do not acetylate PGC-1alpha.
Formal Description
Interaction-ID: 51053

gene/protein

EP300

increases_activity of

gene/protein

PPARGC1A

Comment Although they enhance the activity of PGC-1alpha, SRC-1 and CBP/p300 do not acetylate PGC-1alpha.
Formal Description
Interaction-ID: 51054

gene/protein

CREBBP

increases_activity of

gene/protein

PPARGC1A

Drugbank entries Show/Hide entries for CREBBP
Comment It should be noted that although PGC-1alpha is a co-activator it is not merely a blunt instrument for effecting a wholesale change in the transcriptional activity of its binding partners - its co-activational properties can apparently be selectively tuned for different promoters even when coupled to the same transcription factor. The UCP-1 and aP2 genes, for instance, contain conserved PPARgamma binding sites within their promoters but it is only the gene expression of UCP-1 that changes in response to levels of PGC-1alpha.
Formal Description
Interaction-ID: 51055

gene/protein

PPARGC1A

affects_expression of

gene/protein

UCP1

Comment It should be noted that although PGC-1alpha is a co-activator it is not merely a blunt instrument for effecting a wholesale change in the transcriptional activity of its binding partners - its co-activational properties can apparently be selectively tuned for different promoters even when coupled to the same transcription factor. The UCP-1 and aP2 genes, for instance, contain conserved PPARgamma binding sites within their promoters but it is only the gene expression of UCP-1 that changes in response to levels of PGC-1alpha.
Formal Description
Interaction-ID: 51056

gene/protein

PPARGC1A

NOT affects_expression of

gene/protein

FABP4

Comment From a physiological standpoint, the co-activation of a litany of cognate transcription factors by PGC-1alpha has important metabolic repercussions; collectively, the set of transcription factors to which PGC-1alpha binds controls the expression of genes involved in gluconeogenesis, glycolysis, lipogenesis, peroxisomal and mitochondrial fatty acid oxidation, and mitochondrial respiration efficiency. Thus, PGC-1alpha can single handedly coordinate the gene expression of multiple energy pathways. This point is underscored by the PGC-1alpha knock-out mouse, which shows a reduced respiratory capacity, diminished hepatic TCA cycle flux, reduced rates of hepatic gluconeogenesis and beta-oxidation, hepatic steatosis under fasting conditions, and hypoglycemia.
Formal Description
Interaction-ID: 51057

gene/protein

PPARGC1A

affects_activity of

Comment From a physiological standpoint, the co-activation of a litany of cognate transcription factors by PGC-1alpha has important metabolic repercussions; collectively, the set of transcription factors to which PGC-1alpha binds controls the expression of genes involved in gluconeogenesis, glycolysis, lipogenesis, peroxisomal and mitochondrial fatty acid oxidation, and mitochondrial respiration efficiency. Thus, PGC-1alpha can single handedly coordinate the gene expression of multiple energy pathways. This point is underscored by the PGC-1alpha knock-out mouse, which shows a reduced respiratory capacity, diminished hepatic TCA cycle flux, reduced rates of hepatic gluconeogenesis and beta-oxidation, hepatic steatosis under fasting conditions, and hypoglycemia.
Formal Description
Interaction-ID: 51058

gene/protein

PPARGC1A

affects_activity of

Comment From a physiological standpoint, the co-activation of a litany of cognate transcription factors by PGC-1alpha has important metabolic repercussions; collectively, the set of transcription factors to which PGC-1alpha binds controls the expression of genes involved in gluconeogenesis, glycolysis, lipogenesis, peroxisomal and mitochondrial fatty acid oxidation, and mitochondrial respiration efficiency. Thus, PGC-1alpha can single handedly coordinate the gene expression of multiple energy pathways. This point is underscored by the PGC-1alpha knock-out mouse, which shows a reduced respiratory capacity, diminished hepatic TCA cycle flux, reduced rates of hepatic gluconeogenesis and beta-oxidation, hepatic steatosis under fasting conditions, and hypoglycemia.
Formal Description
Interaction-ID: 51059

gene/protein

PPARGC1A

affects_activity of

Comment From a physiological standpoint, the co-activation of a litany of cognate transcription factors by PGC-1alpha has important metabolic repercussions; collectively, the set of transcription factors to which PGC-1alpha binds controls the expression of genes involved in gluconeogenesis, glycolysis, lipogenesis, peroxisomal and mitochondrial fatty acid oxidation, and mitochondrial respiration efficiency. Thus, PGC-1alpha can single handedly coordinate the gene expression of multiple energy pathways. This point is underscored by the PGC-1alpha knock-out mouse, which shows a reduced respiratory capacity, diminished hepatic TCA cycle flux, reduced rates of hepatic gluconeogenesis and beta-oxidation, hepatic steatosis under fasting conditions, and hypoglycemia.
Formal Description
Interaction-ID: 51062

gene/protein

PPARGC1A

affects_activity of

Comment From a physiological standpoint, the co-activation of a litany of cognate transcription factors by PGC-1alpha has important metabolic repercussions; collectively, the set of transcription factors to which PGC-1alpha binds controls the expression of genes involved in gluconeogenesis, glycolysis, lipogenesis, peroxisomal and mitochondrial fatty acid oxidation, and mitochondrial respiration efficiency. Thus, PGC-1alpha can single handedly coordinate the gene expression of multiple energy pathways. This point is underscored by the PGC-1alpha knock-out mouse, which shows a reduced respiratory capacity, diminished hepatic TCA cycle flux, reduced rates of hepatic gluconeogenesis and beta-oxidation, hepatic steatosis under fasting conditions, and hypoglycemia.
Formal Description
Interaction-ID: 51064

gene/protein

PPARGC1A

affects_activity of

disease

Fatty liver disease, nonalcoholic

Comment The maintenance of the gluconeogenic response through prolonged fasting is thought to be mediated by PGC-1alpha and its cognate transcription factors. Hepatic levels of PGC-1alpha protein significantly increase under fasting conditions, driven in part by an increase in transcription caused by CRTC2 activation and in part by an increase in the half-life of the protein induced by an attenuation of insulin signaling. The elevated levels of PGC-1alpha facilitate increased hepatic glucose output by promoting the expression of gluconeogenic genes such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, most likely through the co-activation of HNF4alpha and FoxO1. Whereas the increase in Sirt1 activity that accompanies prolonged fasting attenuates CRTC2 signaling, it actually improves PGC-1alpha's ability to increase hepatic gluconeogenesis.
Formal Description
Interaction-ID: 51065

environment

fasting

increases_quantity of

gene/protein

PPARGC1A

in liver
Comment The maintenance of the gluconeogenic response through prolonged fasting is thought to be mediated by PGC-1alpha and its cognate transcription factors. Hepatic levels of PGC-1alpha protein significantly increase under fasting conditions, driven in part by an increase in transcription caused by CRTC2 activation and in part by an increase in the half-life of the protein induced by an attenuation of insulin signaling. The elevated levels of PGC-1alpha facilitate increased hepatic glucose output by promoting the expression of gluconeogenic genes such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, most likely through the co-activation of HNF4alpha and FoxO1. Whereas the increase in Sirt1 activity that accompanies prolonged fasting attenuates CRTC2 signaling, it actually improves PGC-1alpha's ability to increase hepatic gluconeogenesis.
Formal Description
Interaction-ID: 51070

gene/protein

PPARGC1A

increases_expression of

gene/protein

PCK1

in liver
Drugbank entries Show/Hide entries for PCK1
Comment The maintenance of the gluconeogenic response through prolonged fasting is thought to be mediated by PGC-1alpha and its cognate transcription factors. Hepatic levels of PGC-1alpha protein significantly increase under fasting conditions, driven in part by an increase in transcription caused by CRTC2 activation and in part by an increase in the half-life of the protein induced by an attenuation of insulin signaling. The elevated levels of PGC-1alpha facilitate increased hepatic glucose output by promoting the expression of gluconeogenic genes such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, most likely through the co-activation of HNF4alpha and FoxO1. Whereas the increase in Sirt1 activity that accompanies prolonged fasting attenuates CRTC2 signaling, it actually improves PGC-1alpha's ability to increase hepatic gluconeogenesis.
Formal Description
Interaction-ID: 51071

gene/protein

PPARGC1A

increases_expression of

gene/protein

G6PC

in liver
Comment In skeletal muscle during fasting, induction of PGC-1alpha helps to orchestrate a series of metabolic changes that results in muscle tissue using less glucose and more fatty acids for oxidative phosphorylation. PGC-1alpha has been shown to increase the expression of the glucose transporters GLUT1 and GLUT4 in muscle tissue. In the case of GLUT4, this effect is dependent upon the transcription factor MEF-2c.
Formal Description
Interaction-ID: 51072

gene/protein

PPARGC1A

increases_expression of

gene/protein

SLC2A1

in skeletal muscle
Comment In skeletal muscle during fasting, induction of PGC-1alpha helps to orchestrate a series of metabolic changes that results in muscle tissue using less glucose and more fatty acids for oxidative phosphorylation. PGC-1alpha has been shown to increase the expression of the glucose transporters GLUT1 and GLUT4 in muscle tissue. In the case of GLUT4, this effect is dependent upon the transcription factor MEF-2c.
Formal Description
Interaction-ID: 51073

gene/protein

PPARGC1A

increases_expression of

gene/protein

SLC2A4

in skeletal muscle; via transcription factor MEF2C
Comment Although PGC-1alpha can induce glucose transporter expression, net utilization of glucose by skeletal myocytes is significantly mitigated by an increase in PGC-1alpha activity. The mechanism by which this occurs involves at least two different processes. The first mechanism is a PGC-1alpha-induced decrease in the expression of phosphofructokinase and an accompanying diminution in glycolytic flux. The second proposed mechanism involves a PGC-1alpha-induced increase in the expression of pyruvate dehydrogenase kinase-4, a negative regulator of pyruvate dehydrogenase, which abates the entry of glucose-derived pyruvate into the TCA cycle. PGC-1alpha's coactivation of ERRalpha is responsible for increased PDK4 expression.
Formal Description
Interaction-ID: 51074

gene/protein

PPARGC1A

decreases_expression of

gene/protein

PFKM

in skeletal muscle
Comment Although PGC-1alpha can induce glucose transporter expression, net utilization of glucose by skeletal myocytes is significantly mitigated by an increase in PGC-1alpha activity. The mechanism by which this occurs involves at least two different processes. The first mechanism is a PGC-1alpha-induced decrease in the expression of phosphofructokinase and an accompanying diminution in glycolytic flux. The second proposed mechanism involves a PGC-1alpha-induced increase in the expression of pyruvate dehydrogenase kinase-4, a negative regulator of pyruvate dehydrogenase, which abates the entry of glucose-derived pyruvate into the TCA cycle. PGC-1alpha's coactivation of ERRalpha is responsible for increased PDK4 expression.
Formal Description
Interaction-ID: 51075

gene/protein

PPARGC1A

decreases_activity of

in skeletal muscle; via decreased expression of PFKM
Comment Although PGC-1alpha can induce glucose transporter expression, net utilization of glucose by skeletal myocytes is significantly mitigated by an increase in PGC-1alpha activity. The mechanism by which this occurs involves at least two different processes. The first mechanism is a PGC-1alpha-induced decrease in the expression of phosphofructokinase and an accompanying diminution in glycolytic flux. The second proposed mechanism involves a PGC-1alpha-induced increase in the expression of pyruvate dehydrogenase kinase-4, a negative regulator of pyruvate dehydrogenase, which abates the entry of glucose-derived pyruvate into the TCA cycle. PGC-1alpha's coactivation of ERRalpha is responsible for increased PDK4 expression.
Formal Description
Interaction-ID: 51076

gene/protein

PPARGC1A

increases_expression of

gene/protein

PDK4

in skeletal muscle; via transcription factor ESRRA
Drugbank entries Show/Hide entries for PDK4
Comment Although PGC-1alpha can induce glucose transporter expression, net utilization of glucose by skeletal myocytes is significantly mitigated by an increase in PGC-1alpha activity. The mechanism by which this occurs involves at least two different processes. The first mechanism is a PGC-1alpha-induced decrease in the expression of phosphofructokinase and an accompanying diminution in glycolytic flux. The second proposed mechanism involves a PGC-1alpha-induced increase in the expression of pyruvate dehydrogenase kinase-4, a negative regulator of pyruvate dehydrogenase, which abates the entry of glucose-derived pyruvate into the TCA cycle. PGC-1alpha's coactivation of ERRalpha is responsible for increased PDK4 expression.
Formal Description
Interaction-ID: 51077

gene/protein

PDK4

decreases_activity of

complex/PPI

Pyruvate dehydrogenase complex

in skeletal muscle
Drugbank entries Show/Hide entries for PDK4
Comment Although PGC-1alpha can induce glucose transporter expression, net utilization of glucose by skeletal myocytes is significantly mitigated by an increase in PGC-1alpha activity. The mechanism by which this occurs involves at least two different processes. The first mechanism is a PGC-1alpha-induced decrease in the expression of phosphofructokinase and an accompanying diminution in glycolytic flux. The second proposed mechanism involves a PGC-1alpha-induced increase in the expression of pyruvate dehydrogenase kinase-4, a negative regulator of pyruvate dehydrogenase, which abates the entry of glucose-derived pyruvate into the TCA cycle. PGC-1alpha's coactivation of ERRalpha is responsible for increased PDK4 expression.
Formal Description
Interaction-ID: 51078

gene/protein

PPARGC1A

decreases_activity of

in skeletal muscle; via increased PDK4 expression
Comment From a physiological standpoint, the co-activation of a litany of cognate transcription factors by PGC-1alpha has important metabolic repercussions; collectively, the set of transcription factors to which PGC-1alpha binds controls the expression of genes involved in gluconeogenesis, glycolysis, lipogenesis, peroxisomal and mitochondrial fatty acid oxidation, and mitochondrial respiration efficiency. Thus, PGC-1alpha can single handedly coordinate the gene expression of multiple energy pathways. This point is underscored by the PGC-1alpha knock-out mouse, which shows a reduced respiratory capacity, diminished hepatic TCA cycle flux, reduced rates of hepatic gluconeogenesis and beta-oxidation, hepatic steatosis under fasting conditions, and hypoglycemia.
Formal Description
Interaction-ID: 51079

gene/protein

PPARGC1A

affects_activity of

process

gluconeogenesis

Comment Higher levels of PGC-1alpha also permit muscle cells to oxidize more fatty acids. PGC-1alpha facilitates the delivery of free fatty acids across the cell membrane by increasing the expression of the integral membrane protein CD36, which is capable of binding to long-chain fatty acids and mediates their internalization into the cytosol.
Formal Description
Interaction-ID: 51080

gene/protein

PPARGC1A

increases_expression of

gene/protein

CD36

in skeletal muscle
Comment Higher levels of PGC-1alpha also permit muscle cells to oxidize more fatty acids. PGC-1alpha facilitates the delivery of free fatty acids across the cell membrane by increasing the expression of the integral membrane protein CD36, which is capable of binding to long-chain fatty acids and mediates their internalization into the cytosol.
Formal Description
Interaction-ID: 51081

gene/protein

CD36

increases_activity of

into the cytosol, in skeletal muscle
Comment Transport of free fatty acids from the cytoplasm across the outer mitochondrial membrane is facilitated by PGC-1alpha by an increase in the expression of the free fatty acid transporter carnitine palmitoyltransferase 1 (CPT-1).
Formal Description
Interaction-ID: 51082

gene/protein

PPARGC1A

increases_expression of

gene/protein

CPT1B

in skeletal muscle
Comment Transport of free fatty acids from the cytoplasm across the outer mitochondrial membrane is facilitated by PGC-1alpha by an increase in the expression of the free fatty acid transporter carnitine palmitoyltransferase 1 (CPT-1).
Formal Description
Interaction-ID: 51083

gene/protein

CPT1B

increases_activity of

across the outer mitochondrial membrane, in skeletal muscle
Comment The complete oxidation of fatty acids and its coupling to ATP production within the mitochondria are facilitated by PGC-1alpha by an increase in the levels of medium chain acyl CoA dehydrogenase (MCAD), cytochrome oxidases II and IV, isocitrate dehydrogenase 3A, beta-ATP synthase, and cytochrome c.
Formal Description
Interaction-ID: 51084

gene/protein

PPARGC1A

increases_expression of

gene/protein

ACADM

in skeletal muscle
Drugbank entries Show/Hide entries for ACADM
Comment The complete oxidation of fatty acids and its coupling to ATP production within the mitochondria are facilitated by PGC-1alpha by an increase in the levels of medium chain acyl CoA dehydrogenase (MCAD), cytochrome oxidases II and IV, isocitrate dehydrogenase 3A, beta-ATP synthase, and cytochrome c.
Formal Description
Interaction-ID: 51085

gene/protein

PPARGC1A

increases_expression of

gene/protein

MT-CO2

in skeletal muscle
Drugbank entries Show/Hide entries for MT-CO2
Comment The complete oxidation of fatty acids and its coupling to ATP production within the mitochondria are facilitated by PGC-1alpha by an increase in the levels of medium chain acyl CoA dehydrogenase (MCAD), cytochrome oxidases II and IV, isocitrate dehydrogenase 3A, beta-ATP synthase, and cytochrome c.
Formal Description
Interaction-ID: 51086

gene/protein

PPARGC1A

increases_expression of

gene/protein

COX4I1

in skeletal muscle
Drugbank entries Show/Hide entries for COX4I1
Comment The complete oxidation of fatty acids and its coupling to ATP production within the mitochondria are facilitated by PGC-1alpha by an increase in the levels of medium chain acyl CoA dehydrogenase (MCAD), cytochrome oxidases II and IV, isocitrate dehydrogenase 3A, beta-ATP synthase, and cytochrome c.
Formal Description
Interaction-ID: 51087

gene/protein

PPARGC1A

increases_expression of

gene/protein

IDH3A

in skeletal muscle
Drugbank entries Show/Hide entries for IDH3A
Comment The complete oxidation of fatty acids and its coupling to ATP production within the mitochondria are facilitated by PGC-1alpha by an increase in the levels of medium chain acyl CoA dehydrogenase (MCAD), cytochrome oxidases II and IV, isocitrate dehydrogenase 3A, beta-ATP synthase, and cytochrome c.
Formal Description
Interaction-ID: 51088

gene/protein

PPARGC1A

increases_expression of

gene/protein

ATP5F1B

in skeletal muscle
Comment The complete oxidation of fatty acids and its coupling to ATP production within the mitochondria are facilitated by PGC-1alpha by an increase in the levels of medium chain acyl CoA dehydrogenase (MCAD), cytochrome oxidases II and IV, isocitrate dehydrogenase 3A, beta-ATP synthase, and cytochrome c.
Formal Description
Interaction-ID: 51089

gene/protein

PPARGC1A

increases_expression of

gene/protein

CYCS

in skeletal muscle
Drugbank entries Show/Hide entries for CYCS
Comment Under high nutrient conditions and low intracellular NAD+ concentrations, PGC-1alpha is hyperacetylated by GCN5 and located within punctate nuclear bodies along with its transcription factor binding partners. In this state, the PGC-1alpha complex is effectively transcriptionally inactive. As cells are confronted with low nutrient availability, however, intracellular NAD+ levels increase and lead to an increase in the rate at which PGC-1alpha is deacetylated by Sirt1. The change in PGC-1alpha acetylation coincides with an increased occupancy of PGC-1alpha at the promoters of its target genes and an increase in transcriptional activation by remodeling of the local chromatin environment, by proteins such as p300, and greater interaction with general transcriptional machinery, facilitated by proteins such as the TRAP/Mediator complex.
Formal Description
Interaction-ID: 51090

gene/protein

KAT2A

decreases_activity of

gene/protein

PPARGC1A

via hyperacetylation
Drugbank entries Show/Hide entries for KAT2A
Comment Under high nutrient conditions and low intracellular NAD+ concentrations, PGC-1alpha is hyperacetylated by GCN5 and located within punctate nuclear bodies along with its transcription factor binding partners. In this state, the PGC-1alpha complex is effectively transcriptionally inactive. As cells are confronted with low nutrient availability, however, intracellular NAD+ levels increase and lead to an increase in the rate at which PGC-1alpha is deacetylated by Sirt1. The change in PGC-1alpha acetylation coincides with an increased occupancy of PGC-1alpha at the promoters of its target genes and an increase in transcriptional activation by remodeling of the local chromatin environment, by proteins such as p300, and greater interaction with general transcriptional machinery, facilitated by proteins such as the TRAP/Mediator complex.
Formal Description
Interaction-ID: 51091

gene/protein

SIRT1

increases_activity of

gene/protein

PPARGC1A

via deacetylation
Comment The hepatic overexpression of GCN5 during fasting resulted in a suppression of the gluconeogenic genes PEPCK and glucose-6-phosphatase as well as in a reduction of de novo synthesis of glucose from pyruvate.
Formal Description
Interaction-ID: 51092

gene/protein

KAT2A

decreases_expression of

gene/protein

PCK1

via decreased PPARGC1A activity
Drugbank entries Show/Hide entries for KAT2A or PCK1
Comment The hepatic overexpression of GCN5 during fasting resulted in a suppression of the gluconeogenic genes PEPCK and glucose-6-phosphatase as well as in a reduction of de novo synthesis of glucose from pyruvate.
Formal Description
Interaction-ID: 51093

gene/protein

KAT2A

decreases_expression of

gene/protein

G6PC

via decreased PPARGC1A activity
Drugbank entries Show/Hide entries for KAT2A
Comment The hepatic overexpression of GCN5 during fasting resulted in a suppression of the gluconeogenic genes PEPCK and glucose-6-phosphatase as well as in a reduction of de novo synthesis of glucose from pyruvate.
Formal Description
Interaction-ID: 51094

gene/protein

KAT2A

decreases_activity of

process

gluconeogenesis

via decreased PPARGC1A activity
Drugbank entries Show/Hide entries for KAT2A
Comment SRC-3 positively regulates the activity of GCN5 in mammalian cells.
Formal Description
Interaction-ID: 51095

gene/protein

NCOA3

increases_activity of

gene/protein

KAT2A

Drugbank entries Show/Hide entries for KAT2A
Comment Sirtuin 1 (Sirt1) is a NAD+-dependent protein deacetylase that has been implicated in a panoply of physiological processes in mammals, including control of lipolytic rates in white adipose tissue, modulation of insulin secretion from pancreatic beta-cells, control of cytoplasmic and mitochondrial acetyl-CoA synthetase activity, regulation of the circadian clock, and regulation of the genetic response to various stressors such as heat shock, genotoxicity, and hypoxia. To this long list of biological functions, one can also add the regulation of PGC-1alpha acetylation state. Sirt1 has thus far been the only identified protein capable of binding to PGC-1alpha and deacetylating it both in vivo and in vitro. Sirt1 binds to a region of PGC-1alpha that is contained within amino acid residues 200–400 and deacetylates the protein in a NAD+-dependent manner.
Formal Description
Interaction-ID: 51096

drug/chemical compound

NAD+

increases_activity of

gene/protein

SIRT1

Comment Sirtuin 1 (Sirt1) is a NAD+-dependent protein deacetylase that has been implicated in a panoply of physiological processes in mammals, including control of lipolytic rates in white adipose tissue, modulation of insulin secretion from pancreatic beta-cells, control of cytoplasmic and mitochondrial acetyl-CoA synthetase activity, regulation of the circadian clock, and regulation of the genetic response to various stressors such as heat shock, genotoxicity, and hypoxia. To this long list of biological functions, one can also add the regulation of PGC-1alpha acetylation state. Sirt1 has thus far been the only identified protein capable of binding to PGC-1alpha and deacetylating it both in vivo and in vitro. Sirt1 binds to a region of PGC-1alpha that is contained within amino acid residues 200–400 and deacetylates the protein in a NAD+-dependent manner.
Formal Description
Interaction-ID: 51097

gene/protein

SIRT1

affects_activity of

in white adipose tissue
Comment Sirtuin 1 (Sirt1) is a NAD+-dependent protein deacetylase that has been implicated in a panoply of physiological processes in mammals, including control of lipolytic rates in white adipose tissue, modulation of insulin secretion from pancreatic beta-cells, control of cytoplasmic and mitochondrial acetyl-CoA synthetase activity, regulation of the circadian clock, and regulation of the genetic response to various stressors such as heat shock, genotoxicity, and hypoxia. To this long list of biological functions, one can also add the regulation of PGC-1alpha acetylation state. Sirt1 has thus far been the only identified protein capable of binding to PGC-1alpha and deacetylating it both in vivo and in vitro. Sirt1 binds to a region of PGC-1alpha that is contained within amino acid residues 200–400 and deacetylates the protein in a NAD+-dependent manner.
Formal Description
Interaction-ID: 51098

gene/protein

SIRT1

affects_activity of

in pancreas, in pancreatic beta cells
Comment Sirtuin 1 (Sirt1) is a NAD+-dependent protein deacetylase that has been implicated in a panoply of physiological processes in mammals, including control of lipolytic rates in white adipose tissue, modulation of insulin secretion from pancreatic beta-cells, control of cytoplasmic and mitochondrial acetyl-CoA synthetase activity, regulation of the circadian clock, and regulation of the genetic response to various stressors such as heat shock, genotoxicity, and hypoxia. To this long list of biological functions, one can also add the regulation of PGC-1alpha acetylation state. Sirt1 has thus far been the only identified protein capable of binding to PGC-1alpha and deacetylating it both in vivo and in vitro. Sirt1 binds to a region of PGC-1alpha that is contained within amino acid residues 200–400 and deacetylates the protein in a NAD+-dependent manner.
Formal Description
Interaction-ID: 51099

gene/protein

SIRT1

affects_activity of

gene/protein

ACSS1

Drugbank entries Show/Hide entries for ACSS1
Comment Sirtuin 1 (Sirt1) is a NAD+-dependent protein deacetylase that has been implicated in a panoply of physiological processes in mammals, including control of lipolytic rates in white adipose tissue, modulation of insulin secretion from pancreatic beta-cells, control of cytoplasmic and mitochondrial acetyl-CoA synthetase activity, regulation of the circadian clock, and regulation of the genetic response to various stressors such as heat shock, genotoxicity, and hypoxia. To this long list of biological functions, one can also add the regulation of PGC-1alpha acetylation state. Sirt1 has thus far been the only identified protein capable of binding to PGC-1alpha and deacetylating it both in vivo and in vitro. Sirt1 binds to a region of PGC-1alpha that is contained within amino acid residues 200–400 and deacetylates the protein in a NAD+-dependent manner.
Formal Description
Interaction-ID: 51101

gene/protein

SIRT1

affects_activity of

gene/protein

ACSS2

Drugbank entries Show/Hide entries for ACSS2
Comment Sirtuin 1 (Sirt1) is a NAD+-dependent protein deacetylase that has been implicated in a panoply of physiological processes in mammals, including control of lipolytic rates in white adipose tissue, modulation of insulin secretion from pancreatic beta-cells, control of cytoplasmic and mitochondrial acetyl-CoA synthetase activity, regulation of the circadian clock, and regulation of the genetic response to various stressors such as heat shock, genotoxicity, and hypoxia. To this long list of biological functions, one can also add the regulation of PGC-1alpha acetylation state. Sirt1 has thus far been the only identified protein capable of binding to PGC-1alpha and deacetylating it both in vivo and in vitro. Sirt1 binds to a region of PGC-1alpha that is contained within amino acid residues 200–400 and deacetylates the protein in a NAD+-dependent manner.
Formal Description
Interaction-ID: 51102

gene/protein

SIRT1

affects_activity of

Comment Sirtuin 1 (Sirt1) is a NAD+-dependent protein deacetylase that has been implicated in a panoply of physiological processes in mammals, including control of lipolytic rates in white adipose tissue, modulation of insulin secretion from pancreatic beta-cells, control of cytoplasmic and mitochondrial acetyl-CoA synthetase activity, regulation of the circadian clock, and regulation of the genetic response to various stressors such as heat shock, genotoxicity, and hypoxia. To this long list of biological functions, one can also add the regulation of PGC-1alpha acetylation state. Sirt1 has thus far been the only identified protein capable of binding to PGC-1alpha and deacetylating it both in vivo and in vitro. Sirt1 binds to a region of PGC-1alpha that is contained within amino acid residues 200–400 and deacetylates the protein in a NAD+-dependent manner.
Formal Description
Interaction-ID: 51104

gene/protein

SIRT1

affects_activity of

Comment Sirtuin 1 (Sirt1) is a NAD+-dependent protein deacetylase that has been implicated in a panoply of physiological processes in mammals, including control of lipolytic rates in white adipose tissue, modulation of insulin secretion from pancreatic beta-cells, control of cytoplasmic and mitochondrial acetyl-CoA synthetase activity, regulation of the circadian clock, and regulation of the genetic response to various stressors such as heat shock, genotoxicity, and hypoxia. To this long list of biological functions, one can also add the regulation of PGC-1alpha acetylation state. Sirt1 has thus far been the only identified protein capable of binding to PGC-1alpha and deacetylating it both in vivo and in vitro. Sirt1 binds to a region of PGC-1alpha that is contained within amino acid residues 200–400 and deacetylates the protein in a NAD+-dependent manner.
Formal Description
Interaction-ID: 51105

gene/protein

SIRT1

affects_activity of

Comment Sirtuin 1 (Sirt1) is a NAD+-dependent protein deacetylase that has been implicated in a panoply of physiological processes in mammals, including control of lipolytic rates in white adipose tissue, modulation of insulin secretion from pancreatic beta-cells, control of cytoplasmic and mitochondrial acetyl-CoA synthetase activity, regulation of the circadian clock, and regulation of the genetic response to various stressors such as heat shock, genotoxicity, and hypoxia. To this long list of biological functions, one can also add the regulation of PGC-1alpha acetylation state. Sirt1 has thus far been the only identified protein capable of binding to PGC-1alpha and deacetylating it both in vivo and in vitro. Sirt1 binds to a region of PGC-1alpha that is contained within amino acid residues 200–400 and deacetylates the protein in a NAD+-dependent manner.
Formal Description
Interaction-ID: 51107

gene/protein

SIRT1

affects_activity of

Comment Activation of endogenous Sirt1 activity by resveratrol in cultures of C2C12 myotubes was able to induce the deacetylation of overexpressed PGC-1alpha protein and potentiate the effects of PGC-1alpha on MCAD, ERRalpha, and cytochrome c. Resveratrol, however, was not able to enhance the activity of PGC-1alpha when all 13 of the known acetylated lysine residues were mutated to an arginine.
Formal Description
Interaction-ID: 51108

drug/chemical compound

Resveratrol

increases_activity of

gene/protein

SIRT1

Drugbank entries Show/Hide entries for Resveratrol
Comment Activation of endogenous Sirt1 activity by resveratrol in cultures of C2C12 myotubes was able to induce the deacetylation of overexpressed PGC-1alpha protein and potentiate the effects of PGC-1alpha on MCAD, ERRalpha, and cytochrome c. Resveratrol, however, was not able to enhance the activity of PGC-1alpha when all 13 of the known acetylated lysine residues were mutated to an arginine.
Formal Description
Interaction-ID: 51110

drug/chemical compound

Resveratrol

increases_activity of

gene/protein

PPARGC1A

via SIRT1 activation
Drugbank entries Show/Hide entries for Resveratrol
Comment Overexpression of Sirt1 in the liver significantly increased the expression of PEPCK and glucose-6-phosphatase in a PGC-1alpha-dependent manner.
Formal Description
Interaction-ID: 51115

gene/protein

SIRT1

increases_expression of

gene/protein

PCK1

via PPARGC1A
Drugbank entries Show/Hide entries for PCK1
Comment Overexpression of Sirt1 in the liver significantly increased the expression of PEPCK and glucose-6-phosphatase in a PGC-1alpha-dependent manner.
Formal Description
Interaction-ID: 51118

gene/protein

SIRT1

increases_expression of

gene/protein

G6PC

via PPARGC1A
Comment Levels of Sirt1 have been reported to change in response to nutrients. Some investigators have found that Sirt1 transcription is inversely responsive to changes in nutrient load by a mechanism that is dependent upon either the transcription factor Foxo3a or the transcriptional co-repressor CtBp and its binding partner Hypermethylated In Cancer. Others, however, report that there are increases in Sirt1 protein caused by nutrient deprivation in both cultured cells and mice, but are not accompanied by changes in the rates of transcription or in steady-state mRNA levels. Among these reports there is disagreement as to whether Sirt1 actually increases in the liver. From this body of work, it is clear that additional studies need to be done to establish the exact mechanism by which Sirt1 protein is controlled by nutriture and if this control is cell autonomous or tissue specific.
Formal Description
Interaction-ID: 51121

environment

feeding

affects_quantity of

gene/protein

SIRT1

Comment Levels of NAD+ are known to change in response to nutrient availability. NAD+ is a necessary co-substrate for the deacetylase activity of sirtuin proteins.
Formal Description
Interaction-ID: 51123

environment

feeding

affects_quantity of

drug/chemical compound

NAD+

Comment One of the outstanding mysteries in mammalian NAD+ biology is how changes in dietary intake cause the intracellular NAD+ concentration of tissues to change. Intracellular concentrations of liver and muscle NAD+ have been shown to increase in rodents during fasting. Nevertheless, under these circumstances, it is not clear if cells are responding to a change in a particular macronutrient such as glucose or fatty acids, one of their respective downstream metabolites, or perhaps a hormonal signal. Because cultured cells show an increase in intracellular NAD+ following the withdrawal of glucose in culture medium, however, it is possible that tissues in vivo are also altering intracellular NAD+ based on glucose availability.
Formal Description
Interaction-ID: 51124

environment

fasting

increases_quantity of

drug/chemical compound

NAD+

in liver, in skeletal muscle