CIDeRplusGeneral Information:
| Id: | 824 |
| 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 204: 93-104 [PMID: 19770177] |
Interaction Information:
| Comment | Ligand binding to PPAR-alpha causes PPAR-alpha to heterodimerize with the RXR and recruit coactivators to activate a program of lipid-induced activation of genes encoding proteins involved in fatty acid uptake, activation, and oxidation. |
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Formal Description Interaction-ID: 4766 |
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| Drugbank entries | Show/Hide entries for PPARA |
| Comment | Ligand binding to PPAR-alpha causes PPAR-alpha to heterodimerize with the RXR and recruit coactivators to activate a program of lipid-induced activation of genes encoding proteins involved in fatty acid uptake, activation, and oxidation. |
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Formal Description Interaction-ID: 4771 |
complex/PPI PPARA-RXR complex affects_activity of process |
| Comment | PPAR-alpha target genes include carnitine palmitoyltransferase I (CPT I), involved in the transport of long-chain fatty acyl goups into the mitochondria, medium-chain acyl-CoA dehydrogenase (involved in beta-oxidation) and, specifically in liver, mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (the rate limiting enzyme of ketogenesis), peroxisomal acyl-CoA oxidase (peroxisomal beta-oxidation), and microsomal cytochrome P450 (CYP) FA omega-hydroxylases. |
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Formal Description Interaction-ID: 4773 |
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| Drugbank entries | Show/Hide entries for PPARA or CPT1A |
| Comment | PPAR-alpha target genes include carnitine palmitoyltransferase I (CPT I), involved in the transport of long-chain fatty acyl goups into the mitochondria, medium-chain acyl-CoA dehydrogenase (involved in beta-oxidation) and, specifically in liver, mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (the rate limiting enzyme of ketogenesis), peroxisomal acyl-CoA oxidase (peroxisomal beta-oxidation), and microsomal cytochrome P450 (CYP) FA omega-hydroxylases. |
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Formal Description Interaction-ID: 4777 |
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| Drugbank entries | Show/Hide entries for PPARA or ACADM |
| Comment | PPAR-alpha target genes include carnitine palmitoyltransferase I (CPT I), involved in the transport of long-chain fatty acyl goups into the mitochondria, medium-chain acyl-CoA dehydrogenase (involved in beta-oxidation) and, specifically in liver, mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (the rate limiting enzyme of ketogenesis), peroxisomal acyl-CoA oxidase (peroxisomal beta-oxidation), and microsomal cytochrome P450 (CYP) FA omega-hydroxylases. |
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Formal Description Interaction-ID: 4778 |
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| Drugbank entries | Show/Hide entries for PPARA |
| Comment | PPAR-alpha target genes include carnitine palmitoyltransferase I (CPT I), involved in the transport of long-chain fatty acyl goups into the mitochondria, medium-chain acyl-CoA dehydrogenase (involved in beta-oxidation) and, specifically in liver, mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (the rate limiting enzyme of ketogenesis), peroxisomal acyl-CoA oxidase (peroxisomal beta-oxidation), and microsomal cytochrome P450 (CYP) FA omega-hydroxylases. |
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Formal Description Interaction-ID: 4780 |
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| Drugbank entries | Show/Hide entries for PPARA |
| Comment | PPAR-alpha target genes include carnitine palmitoyltransferase I (CPT I), involved in the transport of long-chain fatty acyl goups into the mitochondria, medium-chain acyl-CoA dehydrogenase (involved in beta-oxidation) and, specifically in liver, mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (the rate limiting enzyme of ketogenesis), peroxisomal acyl-CoA oxidase (peroxisomal beta-oxidation), and microsomal cytochrome P450 (CYP) FA omega-hydroxylases. |
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Formal Description Interaction-ID: 4783 |
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| Drugbank entries | Show/Hide entries for PPARA |
| Comment | PPAR-alpha target genes include carnitine palmitoyltransferase I (CPT I), involved in the transport of long-chain fatty acyl goups into the mitochondria, medium-chain acyl-CoA dehydrogenase (involved in beta-oxidation) and, specifically in liver, mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (the rate limiting enzyme of ketogenesis), peroxisomal acyl-CoA oxidase (peroxisomal beta-oxidation), and microsomal cytochrome P450 (CYP) FA omega-hydroxylases. |
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Formal Description Interaction-ID: 4784 |
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| Drugbank entries | Show/Hide entries for PPARA |
| Comment | PPAR-alpha target genes include carnitine palmitoyltransferase I (CPT I), involved in the transport of long-chain fatty acyl goups into the mitochondria, medium-chain acyl-CoA dehydrogenase (involved in beta-oxidation) and, specifically in liver, mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (the rate limiting enzyme of ketogenesis), peroxisomal acyl-CoA oxidase (peroxisomal beta-oxidation), and microsomal cytochrome P450 (CYP) FA omega-hydroxylases. |
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Formal Description Interaction-ID: 4785 |
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| Drugbank entries | Show/Hide entries for PPARA |
| Comment | PPAR-alpha plays a critical role in maintenance of lipid homeostasis (oxidation and production). |
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Formal Description Interaction-ID: 4786 |
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| Drugbank entries | Show/Hide entries for PPARA |
| Comment | Exposure of insulin-sensitive tissues (in particular liver and skeletal muscle) to excess nonesterified fatty acids (FA) and circulating triglycerides (triacylglycerol, TAG) induces insulin resistance that can be corrected by the administration of PPAR-alpha activators by actions to promote removal of intracellular lipid through tissue FA oxidation. |
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Formal Description Interaction-ID: 4787 |
gene/protein decreases_activity of disease Insulin resistance |
| Drugbank entries | Show/Hide entries for PPARA |
| Comment | Induction of PPAR-alpha gene targets requires the interaction of PPAR-alpha and PGC-1, often in complex with other enzymes and coactivators. |
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Formal Description Interaction-ID: 4788 |
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| Drugbank entries | Show/Hide entries for PPARA |
| Comment | SIRT1-mediated deacetylation activates PGC-1alpha, while acetylation by GCN5 inhibits PGC-1alpha-directed gene expression. |
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Formal Description Interaction-ID: 4790 |
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| Comment | SIRT1-mediated deacetylation activates PGC-1alpha, while acetylation by GCN5 inhibits PGC-1alpha-directed gene expression. |
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Formal Description Interaction-ID: 4791 |
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| Comment | SIRT1-mediated deacetylation activates PGC-1alpha, while acetylation by GCN5 inhibits PGC-1alpha-directed gene expression. |
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Formal Description Interaction-ID: 4792 |
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| Drugbank entries | Show/Hide entries for KAT2A |
| Comment | SIRT1-mediated deacetylation activates PGC-1alpha, while acetylation by GCN5 inhibits PGC-1alpha-directed gene expression. |
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Formal Description Interaction-ID: 4793 |
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| Drugbank entries | Show/Hide entries for KAT2A |
| Comment | In skeletal muscle, phosphorylation by AMPK and p38 MAPK increases stabilization of PGC-1alpha. |
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Formal Description Interaction-ID: 4794 |
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| Comment | In skeletal muscle, phosphorylation by AMPK and p38 MAPK increases stabilization of PGC-1alpha. |
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Formal Description Interaction-ID: 4795 |
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| Comment | In skeletal muscle, phosphorylation by AMPK and p38 MAPK increases stabilization of PGC-1alpha. |
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Formal Description Interaction-ID: 4797 |
complex/PPI AMPK increases_quantity of gene/protein |
| Comment | In skeletal muscle, phosphorylation by AMPK and p38 MAPK increases stabilization of PGC-1alpha. |
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Formal Description Interaction-ID: 4799 |
gene/protein p38 MAPK increases_quantity of gene/protein |
| Comment | AKT/PKB-mediated phosphorylation facilitates degradation of hepatic PGC-1alpha. |
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Formal Description Interaction-ID: 4800 |
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| Drugbank entries | Show/Hide entries for AKT1 |
| Comment | AKT/PKB-mediated phosphorylation facilitates degradation of hepatic PGC-1alpha. |
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Formal Description Interaction-ID: 4802 |
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| Drugbank entries | Show/Hide entries for AKT1 |
| Comment | PRMT1 also activates PGC-1alpha through methylation at several arginine residues. |
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Formal Description Interaction-ID: 4803 |
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| Drugbank entries | Show/Hide entries for PRMT1 |
| Comment | PRMT1 also activates PGC-1alpha through methylation at several arginine residues. |
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Formal Description Interaction-ID: 4804 |
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| 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). |
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Formal Description Interaction-ID: 4805 |
gene/protein affects_activity of process |
| Comment | PGC-1 coactivators functionally interact with transcription factors, in particular with members of the NR superfamily such as PPAR-gamma and PPAR-alpha, ERR, LXR, and HNF-4alpha, but also with non-NR transcription factors and regulatory elements including cAMP response element-binding protein (CREB), the lipogenic transcription factor sterol regulatory element-binding protein-1c (SREBP-1c or SREBF1), and forkhead box O1 (FOXO1), abnormalities in which have been implicated in the development of diabetes. |
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Formal Description Interaction-ID: 4806 |
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| Drugbank entries | Show/Hide entries for PPARG |
| Comment | HAT enzymes (histone acetyl transferases) such as p300, CBP, and SRC-1 bind to the amino terminal of PGC-1, where they function to acetylate and remodel chromatin, leading to modified access to target genes by transcriptional machinery. |
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Formal Description Interaction-ID: 4807 |
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| Comment | HAT enzymes (histone acetyl transferases) such as p300, CBP, and SRC-1 bind to the amino terminal of PGC-1, where they function to acetylate and remodel chromatin, leading to modified access to target genes by transcriptional machinery. |
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Formal Description Interaction-ID: 4808 |
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| Drugbank entries | Show/Hide entries for CREBBP |
| Comment | HAT enzymes (histone acetyl transferases) such as p300, CBP, and SRC-1 bind to the amino terminal of PGC-1, where they function to acetylate and remodel chromatin, leading to modified access to target genes by transcriptional machinery. |
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Formal Description Interaction-ID: 4809 |
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| Drugbank entries | Show/Hide entries for NCOA1 |
| Comment | HAT enzymes (histone acetyl transferases) such as p300, CBP, and SRC-1 bind to the amino terminal of PGC-1, where they function to acetylate and remodel chromatin, leading to modified access to target genes by transcriptional machinery. |
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Formal Description Interaction-ID: 4810 |
complex/PPI HAT-PPARGC1 complex increases_acetylation of complex/PPI Chromatin |
| Comment | HAT enzymes (histone acetyl transferases) such as p300, CBP, and SRC-1 bind to the amino terminal of PGC-1, where they function to acetylate and remodel chromatin, leading to modified access to target genes by transcriptional machinery. |
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Formal Description Interaction-ID: 4811 |
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| 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. |
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Formal Description Interaction-ID: 4812 |
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| Drugbank entries | Show/Hide entries for KAT2A |
| 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. |
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Formal Description Interaction-ID: 4813 |
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| Drugbank entries | Show/Hide entries for KAT2A |
| 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. |
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Formal Description Interaction-ID: 4814 |
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| Drugbank entries | Show/Hide entries for KAT2A |
| 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. |
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Formal Description Interaction-ID: 4815 |
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| Drugbank entries | Show/Hide entries for KAT2A |
| Comment | Protein deacetylase SIRT1 (the mammalian Sir2 ortholog) deacetylates a number of nonhistone targets including PGC-1alpha and PGC-1beta, with activation of both cofactors. |
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Formal Description Interaction-ID: 4816 |
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| Comment | Protein deacetylase SIRT1 (the mammalian Sir2 ortholog) deacetylates a number of nonhistone targets including PGC-1alpha and PGC-1beta, with activation of both cofactors. |
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Formal Description Interaction-ID: 4817 |
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| Comment | SIRT1, located in the cell nucleus, requires NAD(+) as a cofactor and is negatively regulated by either NADH or the deacetylation product nicotinamide. |
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Formal Description Interaction-ID: 4818 |
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| Comment | Nonobese diabetic Goto-Kakizaki rats, a rodent model of diabetes, have decreased hepatic PRMT activity associated with impaired arginine methylation, and transfection with PRMT siRNA attenuates insulin signaling to gluconeogenic gene expression. |
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Formal Description Interaction-ID: 4819 |
organism model non-obese diabetic Goto-Kakizaki rat decreases_activity of gene/protein |
| Drugbank entries | Show/Hide entries for PRMT1 |
| 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. |
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Formal Description Interaction-ID: 4840 |
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| 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. |
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Formal Description Interaction-ID: 4841 |
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| 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. |
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Formal Description Interaction-ID: 4842 |
environment fasting increases_activity of |
| 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. |
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Formal Description Interaction-ID: 4843 |
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| Comment | Increased expression of PGC-1alpha in liver via adenovirus vector enhances hepatic glucose production. |
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Formal Description Interaction-ID: 4844 |
gene/protein increases_activity of process |
| 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. |
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Formal Description Interaction-ID: 4845 |
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| 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. |
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Formal Description Interaction-ID: 4847 |
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| 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. |
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Formal Description Interaction-ID: 4849 |
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| Drugbank entries | Show/Hide entries for CREB1 |
| 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. |
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Formal Description Interaction-ID: 4850 |
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| 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. |
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Formal Description Interaction-ID: 4852 |
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| 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. |
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Formal Description Interaction-ID: 4854 |
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| 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. |
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Formal Description Interaction-ID: 4855 |
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| Drugbank entries | Show/Hide entries for HNF4A |
| 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. |
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Formal Description Interaction-ID: 4856 |
complex/PPI PPARGC1A-NR3C1-FOXO1-HNF4A-PPARA complex increases_expression of gene/protein |
| 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. |
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Formal Description Interaction-ID: 4857 |
complex/PPI PPARGC1A-NR3C1-FOXO1-HNF4A-PPARA complex increases_expression of gene/protein |
| Drugbank entries | Show/Hide entries for PCK1 |
| 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. |
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Formal Description Interaction-ID: 4858 |
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| 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. |
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Formal Description Interaction-ID: 4859 |
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| Drugbank entries | Show/Hide entries for PCK1 |
| Comment | Activation of AKT by insulin elicits phosphorylation of both TORC2 and PGC-1alpha leading to their degradation. |
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Formal Description Interaction-ID: 4860 |
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| 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. |
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Formal Description Interaction-ID: 4861 |
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| 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. |
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Formal Description Interaction-ID: 4862 |
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| 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. |
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Formal Description Interaction-ID: 4863 |
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| 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. |
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Formal Description Interaction-ID: 4864 |
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| 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. |
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Formal Description Interaction-ID: 4866 |
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| 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. |
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Formal Description Interaction-ID: 4867 |
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| Drugbank entries | Show/Hide entries for AKT1 |
| Comment | PGC-1alpha is deacetylated by SIRT1, induction of PGC-1alpha being associated with coactivation of FOXO1 and HNF-4alpha and induction of gluconeogenic gene expression, this pathway is not activated by classical gluconeogenic stimuli, including the GCs and glucagon, but this pathway is inhibited by GCN5. |
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Formal Description Interaction-ID: 4868 |
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| 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. |
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Formal Description Interaction-ID: 4869 |
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| Comment | PGC-1alpha target genes for fatty acid (FA) oxidation are induced in skeletal muscle by SIRT1 and inhibited by GCN5. |
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Formal Description Interaction-ID: 4870 |
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| 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. |
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Formal Description Interaction-ID: 4871 |
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| Comment | In the cytoplasm, lipin-1 promotes TAG accumulation and phospholipid synthesis by functioning as a Mg2+-dependent phosphatidate phosphatase (phosphatidic acid phosphatase-1 (PAP-1). PAP-1 converts phosphatidate to diacylglycerol (DAG), the immediate precursor of TAG and neutral phospholipids. |
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Formal Description Interaction-ID: 4878 |
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| Comment | In the cytoplasm, lipin-1 promotes TAG accumulation and phospholipid synthesis by functioning as a Mg2+-dependent phosphatidate phosphatase (phosphatidic acid phosphatase-1 (PAP-1). PAP-1 converts phosphatidate to diacylglycerol (DAG), the immediate precursor of TAG and neutral phospholipids. |
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Formal Description Interaction-ID: 4882 |
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| Comment | In the nucleus, lipin-1 acts as a transcriptional coativator linked to FA oxidation. |
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Formal Description Interaction-ID: 4893 |
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| Comment | Lipin-1 induces PPAR-alpha gene expression as well as forming an interactive complex with PPAR-alpha and PGC-1alpha leading to induction of FA oxidation genes including CPT1. |
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Formal Description Interaction-ID: 4894 |
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| Drugbank entries | Show/Hide entries for PPARA |
| Comment | Lipin-1 induces PPAR-alpha gene expression as well as forming an interactive complex with PPAR-alpha and PGC-1alpha leading to induction of FA oxidation genes including CPT1. |
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Formal Description Interaction-ID: 4895 |
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| Drugbank entries | Show/Hide entries for CPT1A |
| Comment | The lipogenic transcription factor SREBP-1 is involved in the regulation of lipin-1 expression and lipin-1 protein is induced by sterol depletion. |
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Formal Description Interaction-ID: 4896 |
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| Comment | Lipin-1 gene expression is induced by T0901317, an activating ligand for the LXR. |
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Formal Description Interaction-ID: 4897 |
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| Comment | Lipin-1 is induced by TORC2, a key coactivator of gluconeogenic gene expression, which leads to increased levels of DAG and consequent activation of protein kinase C. This, in turn, leads to inhibition of Akt signaling and insulin resistance. |
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Formal Description Interaction-ID: 4898 |
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| Comment | Lipin-1 is induced by TORC2, a key coactivator of gluconeogenic gene expression, which leads to increased levels of DAG and consequent activation of protein kinase C. This, in turn, leads to inhibition of Akt signaling and insulin resistance. |
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Formal Description Interaction-ID: 4899 |
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| Comment | Lipin-1 is induced by TORC2, a key coactivator of gluconeogenic gene expression, which leads to increased levels of DAG and consequent activation of protein kinase C. This, in turn, leads to inhibition of Akt signaling and insulin resistance. |
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Formal Description Interaction-ID: 4900 |
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| Comment | Lipin-1 is induced by TORC2, a key coactivator of gluconeogenic gene expression, which leads to increased levels of DAG and consequent activation of protein kinase C. This, in turn, leads to inhibition of Akt signaling and insulin resistance. |
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Formal Description Interaction-ID: 4901 |
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| Comment | Lipin-1 is induced by TORC2, a key coactivator of gluconeogenic gene expression, which leads to increased levels of DAG and consequent activation of protein kinase C. This, in turn, leads to inhibition of Akt signaling and insulin resistance. |
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Formal Description Interaction-ID: 4902 |
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| Comment | TORC2 induces PGC-1alpha, while knockdown of lipin-1 decreases PGC-1alpha mRNA levels. |
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Formal Description Interaction-ID: 4903 |
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| Comment | TORC2 induces PGC-1alpha, while knockdown of lipin-1 decreases PGC-1alpha mRNA levels. |
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Formal Description Interaction-ID: 4904 |
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| Comment | SIRT1 has been reported to deacetylate TORC2 leading to its ubiquitin-mediated degradation and inhibition of gluconeogenic gene expression. |
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Formal Description Interaction-ID: 4905 |
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| Comment | SIRT1 has been reported to deacetylate TORC2 leading to its ubiquitin-mediated degradation and inhibition of gluconeogenic gene expression. |
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Formal Description Interaction-ID: 4906 |
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| Comment | SIRT1 has been reported to deacetylate TORC2 leading to its ubiquitin-mediated degradation and inhibition of gluconeogenic gene expression. |
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Formal Description Interaction-ID: 4907 |
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| Comment | SIRT1 acts on targets in a signal-specific manner, deacetylating PGC-1alpha only in response to nutrient signaling but not glucagon. |
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Formal Description Interaction-ID: 4908 |
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| 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. |
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Formal Description Interaction-ID: 4909 |
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| 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. |
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Formal Description Interaction-ID: 4910 |
disease increases_expression of gene/protein |
| 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. |
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Formal Description Interaction-ID: 4911 |
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| 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. |
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Formal Description Interaction-ID: 4912 |
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| 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. |
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Formal Description Interaction-ID: 4913 |
phenotype affects_expression of gene/protein |
| Comment | Chronic hyperlipidemia and hyperglycemia, which together cause adverse effects on beta-cell function via glucolipotoxicity, also affect PGC-1alpha gene expression. |
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Formal Description Interaction-ID: 4914 |
phenotype affects_expression of gene/protein |
| 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. |
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Formal Description Interaction-ID: 4915 |
gene/protein increases_expression of gene/protein |
| 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. |
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Formal Description Interaction-ID: 4916 |
gene/protein decreases_activity of process |
| Comment | Increased SIRT1 expression specifically in pancreatic beta-cells, which would be predicted to induce PPAR-alpha signaling through deacetylation and induction of PGC-1alpha, improves glucose tolerance and enhances insulin secretion, in particular first-phase insulin secretion in response to glucose. |
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Formal Description Interaction-ID: 4917 |
gene/protein increases_activity of phenotype |
| Comment | Increased SIRT1 expression specifically in pancreatic beta-cells, which would be predicted to induce PPAR-alpha signaling through deacetylation and induction of PGC-1alpha, improves glucose tolerance and enhances insulin secretion, in particular first-phase insulin secretion in response to glucose. |
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Formal Description Interaction-ID: 4918 |
gene/protein increases_activity of process |
| Comment | The expression of Ucp2 and the prolactin receptor gene (Prlr), both of which significantly influence beta-cell function, were downregulated by SIRT1 overexpression. |
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Formal Description Interaction-ID: 4919 |
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| Comment | The expression of Ucp2 and the prolactin receptor gene (Prlr), both of which significantly influence beta-cell function, were downregulated by SIRT1 overexpression. |
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Formal Description Interaction-ID: 4920 |
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| Drugbank entries | Show/Hide entries for PRLR |
| Comment | LXRs alpha and beta, like the PPARs, are a second family of nutrient-responsive nuclear receptors that heterodimerize with RXR to influence gene expression. LXR-beta (NR1H2) is ubiquitously expressed. LXR-alpha (NR1H3) is abundant in liver and also in adipose tissue, intestine, kidney, and spleen. |
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Formal Description Interaction-ID: 4921 |
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| Drugbank entries | Show/Hide entries for NR1H2 |
| Comment | As well as acting as sensors of cellular cholesterol and modulating the expression of genes concerned with cellular cholesterol handling, the LXRs enhance expression of genes involved in fatty acid biosynthesis and TAG secretion. |
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Formal Description Interaction-ID: 4922 |
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| Comment | As well as acting as sensors of cellular cholesterol and modulating the expression of genes concerned with cellular cholesterol handling, the LXRs enhance expression of genes involved in fatty acid biosynthesis and TAG secretion. |
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Formal Description Interaction-ID: 4923 |
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| Comment | As well as acting as sensors of cellular cholesterol and modulating the expression of genes concerned with cellular cholesterol handling, the LXRs enhance expression of genes involved in fatty acid biosynthesis and TAG secretion. |
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Formal Description Interaction-ID: 4924 |
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| Comment | As in liver, LXR activation in adipocytes stimulates lipid accumulation. |
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Formal Description Interaction-ID: 4925 |
gene/protein NR1H increases_quantity of drug/chemical compound |
| Comment | LXR-alpha gene expression is increased in adipose tissue from obese human subjects. |
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Formal Description Interaction-ID: 4926 |
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| Drugbank entries | Show/Hide entries for NR1H3 |
| Comment | LXR increases the synthesis of FA and TAG by upregulating SREBP-1c. |
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Formal Description Interaction-ID: 4933 |
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| Comment | A carbohydrate response element-binding protein (ChREBP or MLXIPL), a glucose-sensitive transcription factor that enhances hepatic conversion of excess carbohydrate to lipid, is a hepatic LXR target which stimulates lipogenic genes independent of SREBP-1c. |
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Formal Description Interaction-ID: 4935 |
gene/protein increases_activity of process |
| Comment | LXRs are acetylated at Lys432 in LXR-alpha and Lys433 in LXR-beta, and deacetylation regulates LXR transcriptional activity. |
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Formal Description Interaction-ID: 4950 |
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| Drugbank entries | Show/Hide entries for NR1H2 |
| Comment | SIRT1 deacetylates and thus positively regulates LXR. |
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Formal Description Interaction-ID: 4951 |
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| Comment | SIRT1 deacetylates and thus positively regulates LXR. |
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Formal Description Interaction-ID: 4952 |
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| Comment | Adenoviral-mediated overexpression of hepatic PGC-1beta in rats leads to increased TAG synthesis and VLDL secretion and consequent hypertriglyceridemia and hypercholesterolemia. |
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Formal Description Interaction-ID: 4953 |
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| Comment | Adenoviral-mediated overexpression of hepatic PGC-1beta in rats leads to increased TAG synthesis and VLDL secretion and consequent hypertriglyceridemia and hypercholesterolemia. |
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Formal Description Interaction-ID: 4954 |
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| Comment | Adenoviral-mediated overexpression of hepatic PGC-1beta in rats leads to increased TAG synthesis and VLDL secretion and consequent hypertriglyceridemia and hypercholesterolemia. |
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Formal Description Interaction-ID: 4955 |
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| Comment | Adenoviral-mediated overexpression of hepatic PGC-1beta in rats leads to increased TAG synthesis and VLDL secretion and consequent hypertriglyceridemia and hypercholesterolemia. |
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Formal Description Interaction-ID: 4957 |
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| Comment | PGC-1beta induces hepatic lipogenesis through coactivation of both LXR and SREBP-1. |
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Formal Description Interaction-ID: 4959 |
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| Comment | PGC-1beta induces hepatic lipogenesis through coactivation of both LXR and SREBP-1. |
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Formal Description Interaction-ID: 4960 |
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| Comment | PGC-1beta is induced in liver in response to high dietary saturated fat and fructose. |
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Formal Description Interaction-ID: 4961 |
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| Comment | PGC-1beta coactivates SREBP-1c and increases the expression of genes involved in the synthesis of FA, TAG and cholesterol, including FAS, SCD-1, HMG-CoA reductase, DGAT and GPAT. |
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Formal Description Interaction-ID: 4962 |
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| Drugbank entries | Show/Hide entries for FASN |
| Comment | PGC-1beta coactivates SREBP-1c and increases the expression of genes involved in the synthesis of FA, TAG and cholesterol, including FAS, SCD-1, HMG-CoA reductase, DGAT and GPAT. |
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Formal Description Interaction-ID: 4964 |
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| Comment | PGC-1beta coactivates SREBP-1c and increases the expression of genes involved in the synthesis of FA, TAG and cholesterol, including FAS, SCD-1, HMG-CoA reductase, DGAT and GPAT. |
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Formal Description Interaction-ID: 4965 |
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| Drugbank entries | Show/Hide entries for HMGCR |
| Comment | PGC-1beta coactivates SREBP-1c and increases the expression of genes involved in the synthesis of FA, TAG and cholesterol, including FAS, SCD-1, HMG-CoA reductase, DGAT and GPAT. |
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Formal Description Interaction-ID: 4966 |
complex/PPI PPARGC1B-SREBF1c complex increases_expression of gene/protein DGAT |
| Comment | PGC-1beta coactivates SREBP-1c and increases the expression of genes involved in the synthesis of FA, TAG and cholesterol, including FAS, SCD-1, HMG-CoA reductase, DGAT and GPAT. |
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Formal Description Interaction-ID: 4967 |
complex/PPI PPARGC1B-SREBF1c complex increases_expression of gene/protein GPAT |
| 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. |
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Formal Description Interaction-ID: 4968 |
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| 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. |
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Formal Description Interaction-ID: 4969 |
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| 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. |
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Formal Description Interaction-ID: 4970 |
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| 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. |
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Formal Description Interaction-ID: 4995 |
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| Comment | While SREBP overexpression alone increases lipogenic gene expression and heptic lipid levels, hypertriglyceridemia does not occur, probably as a result of parallel upregulation of hepatic low-density lipoprotein receptor (LDLR) levels. In contrast, PGC-1beta fails to stimulate LDLR expression, but does stimulate VLDL secretion, possibly via augmenting activation of LXRalpha, leading to hypertriglyceridemia and accumulation of cholesterol in VLDL, the precursor to LDL cholesterol. |
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Formal Description Interaction-ID: 4997 |
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| Comment | PPAR-gamma activation promotes lipid synthesis and storage in white adipose tisue, as well as preadipocyte differentiation to mature adipocytes. |
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Formal Description Interaction-ID: 5002 |
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| Drugbank entries | Show/Hide entries for PPARG |
| Comment | PPAR-gamma activation promotes lipid synthesis and storage in white adipose tisue, as well as preadipocyte differentiation to mature adipocytes. |
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Formal Description Interaction-ID: 5004 |
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| Drugbank entries | Show/Hide entries for PPARG |
| Comment | PPAR-gamma activation promotes lipid synthesis and storage in white adipose tisue, as well as preadipocyte differentiation to mature adipocytes. |
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Formal Description Interaction-ID: 5005 |
gene/protein increases_activity of process |
| Drugbank entries | Show/Hide entries for PPARG |
| Comment | Wnt/beta-catenin signaling maintains preadipocytes in an undifferentiated state in part through inhibition of PPAR-gamma. |
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Formal Description Interaction-ID: 5007 |
process decreases_activity of process |
| Comment | Wnt/beta-catenin signaling maintains preadipocytes in an undifferentiated state in part through inhibition of PPAR-gamma. |
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Formal Description Interaction-ID: 5010 |
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| Drugbank entries | Show/Hide entries for PPARG |
| Comment | Rev-erb-alpha acts downstream of PPAR-gamma by facilitating gene expression of PPAR-gamma target genes, including that encoding C/EBP-alpha (important for the acquisition of insulin sensitivity) and acts as a repressor of anti-adipogenic genes. |
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Formal Description Interaction-ID: 5015 |
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| Drugbank entries | Show/Hide entries for PPARG |
| Comment | Rev-erb-alpha acts downstream of PPAR-gamma by facilitating gene expression of PPAR-gamma target genes, including that encoding C/EBP-alpha (important for the acquisition of insulin sensitivity) and acts as a repressor of anti-adipogenic genes. |
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Formal Description Interaction-ID: 5018 |
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| Comment | PPAR-delta, also expressed in adipose tissue, is not involved in preadipocyte differentiation directly, but is implicated in the control of preadipocyte proliferation and PPAR-gamma gene expression. |
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Formal Description Interaction-ID: 5021 |
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| Drugbank entries | Show/Hide entries for PPARD |
| Comment | PPAR-delta, also expressed in adipose tissue, is not involved in preadipocyte differentiation directly, but is implicated in the control of preadipocyte proliferation and PPAR-gamma gene expression. |
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Formal Description Interaction-ID: 5024 |
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| Drugbank entries | Show/Hide entries for PPARD or PPARG |
| Comment | Certain PPAR-gamma target genes that are normally expressed only at low levels in mature adipocytes are dramatically upregulated by thiazolidinediones (TZDs), among these the enzyme glycerol kinase. Glycerol kinase allows glycerol 3-phosphate production from glycerol, thereby enhancing the capacity for FA esterification to TAG. |
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Formal Description Interaction-ID: 5026 |
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| 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. |
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Formal Description Interaction-ID: 5031 |
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| 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. |
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Formal Description Interaction-ID: 5035 |
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| 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. |
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Formal Description Interaction-ID: 5041 |
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| Comment | In mature adipocytes, SIRT1 binds and represses PPAR-gamma in association with mobilization of fat stores during food deprivation. |
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Formal Description Interaction-ID: 5076 |
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| Drugbank entries | Show/Hide entries for PPARG |
| Comment | In mature adipocytes, SIRT1 binds and represses PPAR-gamma in association with mobilization of fat stores during food deprivation. |
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Formal Description Interaction-ID: 5078 |
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| Drugbank entries | Show/Hide entries for PPARG |
| Comment | In mature adipocytes, SIRT1 binds and represses PPAR-gamma in association with mobilization of fat stores during food deprivation. |
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Formal Description Interaction-ID: 5080 |
gene/protein increases_activity of process fat reserve metabolic process |
| Comment | Lipin-1 promotes adipocyte TAG storage, it physically interacts with PPAR-gamma and is recruited to PPAR-gamma response element upstream of the PEP carboxykinase (PEPCK) gene. PEPCK is involved in glycerogenesis in white adipose tissue. |
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Formal Description Interaction-ID: 5082 |
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| Drugbank entries | Show/Hide entries for PPARG |
| Comment | Lipin-1 promotes adipocyte TAG storage, it physically interacts with PPAR-gamma and is recruited to PPAR-gamma response element upstream of the PEP carboxykinase (PEPCK) gene. PEPCK is involved in glycerogenesis in white adipose tissue. |
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Formal Description Interaction-ID: 5083 |
gene/protein increases_activity of |
| Comment | Lipin-1 promotes adipocyte TAG storage, it physically interacts with PPAR-gamma and is recruited to PPAR-gamma response element upstream of the PEP carboxykinase (PEPCK) gene. PEPCK is involved in glycerogenesis in white adipose tissue. |
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Formal Description Interaction-ID: 5088 |
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| Drugbank entries | Show/Hide entries for PCK1 |
| Comment | Lipin-1 overexpression in adipocytes promotes increased TAG content and obesity. |
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Formal Description Interaction-ID: 5089 |
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| Comment | Lipin-1 overexpression in adipocytes promotes increased TAG content and obesity. |
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Formal Description Interaction-ID: 5090 |
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| Comment | In the mouse, lipin-1 deficiency is associated with insulin resistance, whereas transgenic overexpression of lipin-1 in adipose tissue promotes insulin sensitivity, even though the mice have increased adiposity. |
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Formal Description Interaction-ID: 5091 |
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| 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. |
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Formal Description Interaction-ID: 5092 |
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| 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. |
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Formal Description Interaction-ID: 5104 |
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| 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. |
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Formal Description Interaction-ID: 5105 |
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| 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. |
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Formal Description Interaction-ID: 5107 |
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| 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. |
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Formal Description Interaction-ID: 5110 |
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| Drugbank entries | Show/Hide entries for PPARA |
| Comment | Epigenetic modification, including DNA methylation, represents a molecular mechanism linking environmental events to altered gene expression and the development of disease states, including T2DM. |
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Formal Description Interaction-ID: 5112 |
affects_activity of disease |
| 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. |
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Formal Description Interaction-ID: 5125 |
disease decreases_expression of gene/protein |
| Comment | Overexpression in liver of the long form of lipin-1 (lipin-1beta, the predominant form in liver) increases the expression of PPAR-alpha and PPAR-alpha target genes involved in FA uptake and utilization. |
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Formal Description Interaction-ID: 5126 |
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| Drugbank entries | Show/Hide entries for PPARA |
| Comment | Alterations in lipin-1 function in adipose tissue are likely to impact the efficacy of the TZDs in the treatment of insulin resistance. The expression of the lipin-1 isoform found in mature adipocytes (lipin-1beta) increases following TZD treatment, which causes weight gain. |
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Formal Description Interaction-ID: 5127 |
drug/chemical compound Thiazolidinedione increases_expression of mRNA/protein variant |
| Comment | Alterations in lipin-1 function in adipose tissue are likely to impact the efficacy of the TZDs in the treatment of insulin resistance. The expression of the lipin-1 isoform found in mature adipocytes (lipin-1beta) increases following TZD treatment, which causes weight gain. |
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Formal Description Interaction-ID: 5128 |
drug/chemical compound Thiazolidinedione increases_activity of phenotype |
| Comment | Alterations in lipin-1 function in adipose tissue are likely to impact the efficacy of the TZDs in the treatment of insulin resistance. The expression of the lipin-1 isoform found in mature adipocytes (lipin-1beta) increases following TZD treatment, which causes weight gain. |
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Formal Description Interaction-ID: 5129 |
mRNA/protein variant increases_activity of phenotype |
| Comment | The suitability of agonists of lipin-1 as pharmaceutical candidates is confounded given its links with PGC-1alpha and its reported ability to induce synthesis of DAG, TAG, and VLDL. It seems likely that the opposing actions of lipin-1 occur in response to different physiological stimuli and therefore further studies are required to establish which lipin-1-directed pathway is dysregulated during the onset of metabolic disease. |
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Formal Description Interaction-ID: 5130 |
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| Comment | Resveratrol, a polyphenol found in red wine, activates SIRTs. |
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Formal Description Interaction-ID: 5131 |
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| 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. |
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Formal Description Interaction-ID: 5132 |
drug/chemical compound decreases_acetylation of gene/protein |
| 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. |
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Formal Description Interaction-ID: 5133 |
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| 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. |
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Formal Description Interaction-ID: 5134 |
drug/chemical compound decreases_activity of phenotype |
| 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. |
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Formal Description Interaction-ID: 5135 |
drug/chemical compound decreases_activity of disease Insulin resistance |
| Drugbank entries | Show/Hide entries for Resveratrol |
| Comment | Small molecular weight molecules, including SRT1460 and SRT1720, that selectively activate SIRT1 and are 1000-fold more potent activators than (and structurally unrelated to) resveratrol have been identified. The therapeutic potential of SIRT1 activators to treat insulin resistance and diabetes has been examined in vivo in models of T2DM. SRT1720 opposes hyperinsulinemia and the impairment in glucose tolerance introduced by high-fat feeding in mice to an extent similar to that achieved with rosiglitazone. |
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Formal Description Interaction-ID: 5136 |
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| Comment | Small molecular weight molecules, including SRT1460 and SRT1720, that selectively activate SIRT1 and are 1000-fold more potent activators than (and structurally unrelated to) resveratrol have been identified. The therapeutic potential of SIRT1 activators to treat insulin resistance and diabetes has been examined in vivo in models of T2DM. SRT1720 opposes hyperinsulinemia and the impairment in glucose tolerance introduced by high-fat feeding in mice to an extent similar to that achieved with rosiglitazone. |
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Formal Description Interaction-ID: 5137 |
drug/chemical compound SRT1720 decreases_activity of disease Insulin resistance |
| Comment | Small molecular weight molecules, including SRT1460 and SRT1720, that selectively activate SIRT1 and are 1000-fold more potent activators than (and structurally unrelated to) resveratrol have been identified. The therapeutic potential of SIRT1 activators to treat insulin resistance and diabetes has been examined in vivo in models of T2DM. SRT1720 opposes hyperinsulinemia and the impairment in glucose tolerance introduced by high-fat feeding in mice to an extent similar to that achieved with rosiglitazone. |
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Formal Description Interaction-ID: 5138 |
drug/chemical compound SRT1720 decreases_activity of phenotype |
| Comment | While SREBP overexpression alone increases lipogenic gene expression and heptic lipid levels, hypertriglyceridemia does not occur, probably as a result of parallel upregulation of hepatic low-density lipoprotein receptor (LDLR) levels. In contrast, PGC-1beta fails to stimulate LDLR expression, but does stimulate VLDL secretion, possibly via augmenting activation of LXRalpha, leading to hypertriglyceridemia and accumulation of cholesterol in VLDL, the precursor to LDL cholesterol. |
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Formal Description Interaction-ID: 13085 |
gene/protein SREBF NOT affects_activity of phenotype |
| Comment | While SREBP overexpression alone increases lipogenic gene expression and heptic lipid levels, hypertriglyceridemia does not occur, probably as a result of parallel upregulation of hepatic low-density lipoprotein receptor (LDLR) levels. In contrast, PGC-1beta fails to stimulate LDLR expression, but does stimulate VLDL secretion, possibly via augmenting activation of LXRalpha, leading to hypertriglyceridemia and accumulation of cholesterol in VLDL, the precursor to LDL cholesterol. |
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Formal Description Interaction-ID: 13086 |
|
| Drugbank entries | Show/Hide entries for LDLR |
| Comment | While SREBP overexpression alone increases lipogenic gene expression and heptic lipid levels, hypertriglyceridemia does not occur, probably as a result of parallel upregulation of hepatic low-density lipoprotein receptor (LDLR) levels. In contrast, PGC-1beta fails to stimulate LDLR expression, but does stimulate VLDL secretion, possibly via augmenting activation of LXRalpha, leading to hypertriglyceridemia and accumulation of cholesterol in VLDL, the precursor to LDL cholesterol. |
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Formal Description Interaction-ID: 13087 |
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| Drugbank entries | Show/Hide entries for LDLR |
| Comment | While SREBP overexpression alone increases lipogenic gene expression and heptic lipid levels, hypertriglyceridemia does not occur, probably as a result of parallel upregulation of hepatic low-density lipoprotein receptor (LDLR) levels. In contrast, PGC-1beta fails to stimulate LDLR expression, but does stimulate VLDL secretion, possibly via augmenting activation of LXRalpha, leading to hypertriglyceridemia and accumulation of cholesterol in VLDL, the precursor to LDL cholesterol. |
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Formal Description Interaction-ID: 13088 |
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| 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. |
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Formal Description Interaction-ID: 13089 |
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| 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. |
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Formal Description Interaction-ID: 13111 |
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| 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. |
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Formal Description Interaction-ID: 13113 |
|
| 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. |
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Formal Description Interaction-ID: 13117 |
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| 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. |
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Formal Description Interaction-ID: 13128 |
|
| 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. |
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Formal Description Interaction-ID: 13129 |
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| 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. |
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Formal Description Interaction-ID: 13130 |
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| 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. |
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Formal Description Interaction-ID: 13131 |
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| 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). |
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Formal Description Interaction-ID: 45966 |
gene/protein affects_activity of process |
| 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). |
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Formal Description Interaction-ID: 45967 |
gene/protein affects_activity of process |
| Comment | PGC-1 coactivators functionally interact with transcription factors, in particular with members of the NR superfamily such as PPAR-gamma and PPAR-alpha, ERR, LXR, and HNF-4alpha, but also with non-NR transcription factors and regulatory elements including cAMP response element-binding protein (CREB), the lipogenic transcription factor sterol regulatory element-binding protein-1c (SREBP-1c or SREBF1), and forkhead box O1 (FOXO1), abnormalities in which have been implicated in the development of diabetes. |
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Formal Description Interaction-ID: 45968 |
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| Drugbank entries | Show/Hide entries for PPARA |
| Comment | PGC-1 coactivators functionally interact with transcription factors, in particular with members of the NR superfamily such as PPAR-gamma and PPAR-alpha, ERR, LXR, and HNF-4alpha, but also with non-NR transcription factors and regulatory elements including cAMP response element-binding protein (CREB), the lipogenic transcription factor sterol regulatory element-binding protein-1c (SREBP-1c or SREBF1), and forkhead box O1 (FOXO1), abnormalities in which have been implicated in the development of diabetes. |
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Formal Description Interaction-ID: 45969 |
gene/protein PPARGC1 affects_activity of gene/protein ESRR |
| Comment | PGC-1 coactivators functionally interact with transcription factors, in particular with members of the NR superfamily such as PPAR-gamma and PPAR-alpha, ERR, LXR, and HNF-4alpha, but also with non-NR transcription factors and regulatory elements including cAMP response element-binding protein (CREB), the lipogenic transcription factor sterol regulatory element-binding protein-1c (SREBP-1c or SREBF1), and forkhead box O1 (FOXO1), abnormalities in which have been implicated in the development of diabetes. |
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Formal Description Interaction-ID: 45970 |
gene/protein PPARGC1 affects_activity of gene/protein NR1H |
| Comment | PGC-1 coactivators functionally interact with transcription factors, in particular with members of the NR superfamily such as PPAR-gamma and PPAR-alpha, ERR, LXR, and HNF-4alpha, but also with non-NR transcription factors and regulatory elements including cAMP response element-binding protein (CREB), the lipogenic transcription factor sterol regulatory element-binding protein-1c (SREBP-1c or SREBF1), and forkhead box O1 (FOXO1), abnormalities in which have been implicated in the development of diabetes. |
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Formal Description Interaction-ID: 45971 |
|
| Drugbank entries | Show/Hide entries for HNF4A |
| Comment | PGC-1 coactivators functionally interact with transcription factors, in particular with members of the NR superfamily such as PPAR-gamma and PPAR-alpha, ERR, LXR, and HNF-4alpha, but also with non-NR transcription factors and regulatory elements including cAMP response element-binding protein (CREB), the lipogenic transcription factor sterol regulatory element-binding protein-1c (SREBP-1c or SREBF1), and forkhead box O1 (FOXO1), abnormalities in which have been implicated in the development of diabetes. |
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Formal Description Interaction-ID: 45972 |
|
| Drugbank entries | Show/Hide entries for CREB1 |
| Comment | PGC-1 coactivators functionally interact with transcription factors, in particular with members of the NR superfamily such as PPAR-gamma and PPAR-alpha, ERR, LXR, and HNF-4alpha, but also with non-NR transcription factors and regulatory elements including cAMP response element-binding protein (CREB), the lipogenic transcription factor sterol regulatory element-binding protein-1c (SREBP-1c or SREBF1), and forkhead box O1 (FOXO1), abnormalities in which have been implicated in the development of diabetes. |
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Formal Description Interaction-ID: 45973 |
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| Comment | PGC-1 coactivators functionally interact with transcription factors, in particular with members of the NR superfamily such as PPAR-gamma and PPAR-alpha, ERR, LXR, and HNF-4alpha, but also with non-NR transcription factors and regulatory elements including cAMP response element-binding protein (CREB), the lipogenic transcription factor sterol regulatory element-binding protein-1c (SREBP-1c or SREBF1), and forkhead box O1 (FOXO1), abnormalities in which have been implicated in the development of diabetes. |
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Formal Description Interaction-ID: 45974 |
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| Comment | LXRs alpha and beta, like the PPARs, are a second family of nutrient-responsive nuclear receptors that heterodimerize with RXR to influence gene expression. LXR-beta (NR1H2) is ubiquitously expressed. LXR-alpha (NR1H3) is abundant in liver and also in adipose tissue, intestine, kidney, and spleen. |
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Formal Description Interaction-ID: 45975 |
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| Drugbank entries | Show/Hide entries for NR1H3 |
| Comment | LXRs are acetylated at Lys432 in LXR-alpha and Lys433 in LXR-beta, and deacetylation regulates LXR transcriptional activity. |
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Formal Description Interaction-ID: 45976 |
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| Drugbank entries | Show/Hide entries for NR1H3 |