CIDeRGeneral Information:
| Id: | 947 (click here to show other Interactions for entry) |
| Diseases: |
Diabetes mellitus, type II
- [OMIM]
Fatty liver disease, nonalcoholic Insulin resistance |
| Mus musculus | |
| SIRT1 LKO: liver-specific SIRT1 knockout mouse on the C57BL/6 background | |
| article | |
| Reference: | Purushotham A et al.(2009) Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation Cell Metab. 9: 327-338 [PMID: 19356714] |
Interaction Information:
| Comment | Hepatic deletion of SIRT1 alters PPAR-alpha signaling. |
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Formal Description Interaction-ID: 5731 |
gene/protein affects_activity of process peroxisome proliferator activated receptor alpha signaling pathway |
| Comment | Quantitative real-time PCR (qPCR) confirmed decreased expression of several PPAR-alpha targets, including medium chain acyl-CoA dehydrogenase (MCAD), liver bifunctional enzyme (Ehhadh), palmitoyl acyl-CoA carboxylase (AOX), fatty acid transporter (CD36), and microsomal cytochrome P450 enzymes involved in the omega-oxidation of fatty acids (Cyp4A10 and Cyp4A14), in SIRT1 LKO mice compared to Lox controls. In contrast, the mRNA level of SPOT14, a gene known to be negatively regulated by PPAR-alpha, was significantly higher in the SIRT1 LKO mice. |
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Formal Description Interaction-ID: 5742 |
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| Drugbank entries | Show/Hide entries for ACADM |
| Comment | Quantitative real-time PCR (qPCR) confirmed decreased expression of several PPAR-alpha targets, including medium chain acyl-CoA dehydrogenase (MCAD), liver bifunctional enzyme (Ehhadh), palmitoyl acyl-CoA carboxylase (AOX), fatty acid transporter (CD36), and microsomal cytochrome P450 enzymes involved in the omega-oxidation of fatty acids (Cyp4A10 and Cyp4A14), in SIRT1 LKO mice compared to Lox controls. In contrast, the mRNA level of SPOT14, a gene known to be negatively regulated by PPAR-alpha, was significantly higher in the SIRT1 LKO mice. |
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Formal Description Interaction-ID: 5746 |
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| Drugbank entries | Show/Hide entries for EHHADH |
| Comment | Quantitative real-time PCR (qPCR) confirmed decreased expression of several PPAR-alpha targets, including medium chain acyl-CoA dehydrogenase (MCAD), liver bifunctional enzyme (Ehhadh), palmitoyl acyl-CoA carboxylase (AOX), fatty acid transporter (CD36), and microsomal cytochrome P450 enzymes involved in the omega-oxidation of fatty acids (Cyp4A10 and Cyp4A14), in SIRT1 LKO mice compared to Lox controls. In contrast, the mRNA level of SPOT14, a gene known to be negatively regulated by PPAR-alpha, was significantly higher in the SIRT1 LKO mice. |
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Formal Description Interaction-ID: 5747 |
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| Drugbank entries | Show/Hide entries for ACOX1 |
| Comment | Quantitative real-time PCR (qPCR) confirmed decreased expression of several PPAR-alpha targets, including medium chain acyl-CoA dehydrogenase (MCAD), liver bifunctional enzyme (Ehhadh), palmitoyl acyl-CoA carboxylase (AOX), fatty acid transporter (CD36), and microsomal cytochrome P450 enzymes involved in the omega-oxidation of fatty acids (Cyp4A10 and Cyp4A14), in SIRT1 LKO mice compared to Lox controls. In contrast, the mRNA level of SPOT14, a gene known to be negatively regulated by PPAR-alpha, was significantly higher in the SIRT1 LKO mice. |
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Formal Description Interaction-ID: 5754 |
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| Comment | Quantitative real-time PCR (qPCR) confirmed decreased expression of several PPAR-alpha targets, including medium chain acyl-CoA dehydrogenase (MCAD), liver bifunctional enzyme (Ehhadh), palmitoyl acyl-CoA carboxylase (AOX), fatty acid transporter (CD36), and microsomal cytochrome P450 enzymes involved in the omega-oxidation of fatty acids (Cyp4A10 and Cyp4A14), in SIRT1 LKO mice compared to Lox controls. In contrast, the mRNA level of SPOT14, a gene known to be negatively regulated by PPAR-alpha, was significantly higher in the SIRT1 LKO mice. |
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Formal Description Interaction-ID: 5755 |
gene/protein affects_expression of gene/protein Cyp4A10 |
| Comment | Quantitative real-time PCR (qPCR) confirmed decreased expression of several PPAR-alpha targets, including medium chain acyl-CoA dehydrogenase (MCAD), liver bifunctional enzyme (Ehhadh), palmitoyl acyl-CoA carboxylase (AOX), fatty acid transporter (CD36), and microsomal cytochrome P450 enzymes involved in the omega-oxidation of fatty acids (Cyp4A10 and Cyp4A14), in SIRT1 LKO mice compared to Lox controls. In contrast, the mRNA level of SPOT14, a gene known to be negatively regulated by PPAR-alpha, was significantly higher in the SIRT1 LKO mice. |
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Formal Description Interaction-ID: 5756 |
gene/protein affects_expression of gene/protein Cyp4A14 |
| Comment | Quantitative real-time PCR (qPCR) confirmed decreased expression of several PPAR-alpha targets, including medium chain acyl-CoA dehydrogenase (MCAD), liver bifunctional enzyme (Ehhadh), palmitoyl acyl-CoA carboxylase (AOX), fatty acid transporter (CD36), and microsomal cytochrome P450 enzymes involved in the omega-oxidation of fatty acids (Cyp4A10 and Cyp4A14), in SIRT1 LKO mice compared to Lox controls. In contrast, the mRNA level of SPOT14, a gene known to be negatively regulated by PPAR-alpha, was significantly higher in the SIRT1 LKO mice. |
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Formal Description Interaction-ID: 5758 |
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| Comment | SIRT1 LKO mice displayed reduced expression of several PPAR-alpha target genes after overnight fasting: CPT1a, AOX, CD36, Cyp4A14, CytoC, and PGC-1a. Interestingly, the expression of PPAR-gamma co-activator 1-alpha (PGC-1alpha), a transcription co-factor known to activate PPAR-alpha, was also significantly lower in SIRT1 LKO mice. |
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Formal Description Interaction-ID: 5759 |
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| Drugbank entries | Show/Hide entries for CPT1A |
| Comment | SIRT1 LKO mice displayed reduced expression of several PPAR-alpha target genes after overnight fasting: CPT1a, AOX, CD36, Cyp4A14, CytoC, and PGC-1a. Interestingly, the expression of PPAR-gamma co-activator 1-alpha (PGC-1alpha), a transcription co-factor known to activate PPAR-alpha, was also significantly lower in SIRT1 LKO mice. |
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Formal Description Interaction-ID: 5763 |
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| Drugbank entries | Show/Hide entries for ACOX1 |
| Comment | SIRT1 LKO mice displayed reduced expression of several PPAR-alpha target genes after overnight fasting: CPT1a, AOX, CD36, Cyp4A14, CytoC, and PGC-1a. Interestingly, the expression of PPAR-gamma co-activator 1-alpha (PGC-1alpha), a transcription co-factor known to activate PPAR-alpha, was also significantly lower in SIRT1 LKO mice. |
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Formal Description Interaction-ID: 5764 |
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| Comment | SIRT1 LKO mice displayed reduced expression of several PPAR-alpha target genes after overnight fasting: CPT1a, AOX, CD36, Cyp4A14, CytoC, and PGC-1a. Interestingly, the expression of PPAR-gamma co-activator 1-alpha (PGC-1alpha), a transcription co-factor known to activate PPAR-alpha, was also significantly lower in SIRT1 LKO mice. |
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Formal Description Interaction-ID: 5765 |
gene/protein affects_expression of gene/protein Cyp4A14 |
| Comment | SIRT1 LKO mice displayed reduced expression of several PPAR-alpha target genes after overnight fasting: CPT1a, AOX, CD36, Cyp4A14, CytoC, and PGC-1a. Interestingly, the expression of PPAR-gamma co-activator 1-alpha (PGC-1alpha), a transcription co-factor known to activate PPAR-alpha, was also significantly lower in SIRT1 LKO mice. |
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Formal Description Interaction-ID: 5766 |
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| Drugbank entries | Show/Hide entries for CYCS |
| Comment | SIRT1 LKO mice displayed reduced expression of several PPAR-alpha target genes after overnight fasting: CPT1a, AOX, CD36, Cyp4A14, CytoC, and PGC-1a. Interestingly, the expression of PPAR-gamma co-activator 1-alpha (PGC-1alpha), a transcription co-factor known to activate PPAR-alpha, was also significantly lower in SIRT1 LKO mice. |
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Formal Description Interaction-ID: 5768 |
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| Comment | To elucidate the regulatory role of SIRT1 in PPAR-alpha signaling in liver, primary hepatocytes from Lox control or SIRT1 LKO mice were treated with a PPAR-alpha agonist WY14643. WY treatment induced the expression of several genes involved in fatty acid oxidation in control hepatocytes. However, the induction of these genes was significantly lower in the SIRT1 deficient (LKO) hepatocytes. |
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Formal Description Interaction-ID: 5777 |
gene/protein affects_activity of |
| Comment | SIRT1 directly regulates PPAR-alpha transactivation. |
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Formal Description Interaction-ID: 5780 |
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| Drugbank entries | Show/Hide entries for PPARA |
| Comment | SIRT1 interacts with PPAR-alpha and is required for the activation of PGC-1alpha. |
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Formal Description Interaction-ID: 5787 |
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| Drugbank entries | Show/Hide entries for PPARA |
| Comment | SIRT1 interacts with PPAR-alpha and is required for the activation of PGC-1alpha. |
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Formal Description Interaction-ID: 5788 |
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| Comment | Although SIRT1 LKO mice showed no body weight abnormality on a chow diet, they gained significantly more weight than control mice on the western diet. Consistent with diet-induced obesity, SIRT1 LKO mice showed greater lipid accumulation in the liver compared to control mice. Their serum free fatty acid levels were also significantly increased as compared to control mice. Additionally, serum beta-hydroxybutyrate, a marker for fatty acid oxidation and ketogenesis in the liver, was significantly lower in the SIRT1 LKO mice. |
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Formal Description Interaction-ID: 5793 |
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| Comment | Levels of PPAR-alpha targets known to regulate fatty acid oxidation were significantly lower in SIRT1 LKO mouse livers upon high-fat diet feeding: CPT1a, CPT2, ACAD, AOX, CD36, Cyp4A14, and Cyp4A10. |
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Formal Description Interaction-ID: 5796 |
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| Drugbank entries | Show/Hide entries for CPT1A |
| Comment | Levels of PPAR-alpha targets known to regulate fatty acid oxidation were significantly lower in SIRT1 LKO mouse livers upon high-fat diet feeding: CPT1a, CPT2, ACAD, AOX, CD36, Cyp4A14, and Cyp4A10. |
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Formal Description Interaction-ID: 5804 |
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| Drugbank entries | Show/Hide entries for CPT2 |
| Comment | Levels of PPAR-alpha targets known to regulate fatty acid oxidation were significantly lower in SIRT1 LKO mouse livers upon high-fat diet feeding: CPT1a, CPT2, ACAD, AOX, CD36, Cyp4A14, and Cyp4A10. |
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Formal Description Interaction-ID: 5805 |
gene/protein affects_expression of gene/protein ACAD |
| Comment | Levels of PPAR-alpha targets known to regulate fatty acid oxidation were significantly lower in SIRT1 LKO mouse livers upon high-fat diet feeding: CPT1a, CPT2, ACAD, AOX, CD36, Cyp4A14, and Cyp4A10. |
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Formal Description Interaction-ID: 5806 |
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| Drugbank entries | Show/Hide entries for ACOX1 |
| Comment | Levels of PPAR-alpha targets known to regulate fatty acid oxidation were significantly lower in SIRT1 LKO mouse livers upon high-fat diet feeding: CPT1a, CPT2, ACAD, AOX, CD36, Cyp4A14, and Cyp4A10. |
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Formal Description Interaction-ID: 5807 |
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| Comment | Levels of PPAR-alpha targets known to regulate fatty acid oxidation were significantly lower in SIRT1 LKO mouse livers upon high-fat diet feeding: CPT1a, CPT2, ACAD, AOX, CD36, Cyp4A14, and Cyp4A10. |
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Formal Description Interaction-ID: 5808 |
gene/protein affects_expression of gene/protein Cyp4A14 |
| Comment | Levels of PPAR-alpha targets known to regulate fatty acid oxidation were significantly lower in SIRT1 LKO mouse livers upon high-fat diet feeding: CPT1a, CPT2, ACAD, AOX, CD36, Cyp4A14, and Cyp4A10. |
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Formal Description Interaction-ID: 5809 |
gene/protein affects_expression of gene/protein Cyp4A10 |
| Comment | Levels of PPAR-alpha targets known to regulate fatty acid oxidation were significantly lower in SIRT1 LKO mouse livers upon high-fat diet feeding: CPT1a, CPT2, ACAD, AOX, CD36, Cyp4A14, and Cyp4A10. |
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Formal Description Interaction-ID: 5811 |
gene/protein affects_activity of process |
| Comment | Upon high-fat diet feeding a reduction in the expression of mitochondrial oxidative phosphorylation genes (Cytochrome C, Cox4 and Cox5b) was observed in livers of SIRT1 LKO mice. The decreased expression of the above-mentioned PPAR-alpha target genes was accompanied by a 40% decrease in the expression of PGC-1alpha mRNA. |
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Formal Description Interaction-ID: 5820 |
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| Drugbank entries | Show/Hide entries for CYCS |
| Comment | Upon high-fat diet feeding a reduction in the expression of mitochondrial oxidative phosphorylation genes (Cytochrome C, Cox4 and Cox5b) was observed in livers of SIRT1 LKO mice. The decreased expression of the above-mentioned PPAR-alpha target genes was accompanied by a 40% decrease in the expression of PGC-1alpha mRNA. |
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Formal Description Interaction-ID: 5821 |
gene/protein affects_expression of gene/protein COX4 |
| Comment | Upon high-fat diet feeding a reduction in the expression of mitochondrial oxidative phosphorylation genes (Cytochrome C, Cox4 and Cox5b) was observed in livers of SIRT1 LKO mice. The decreased expression of the above-mentioned PPAR-alpha target genes was accompanied by a 40% decrease in the expression of PGC-1alpha mRNA. |
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Formal Description Interaction-ID: 5843 |
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| Drugbank entries | Show/Hide entries for COX5B |
| Comment | Upon high-fat diet feeding a reduction in the expression of mitochondrial oxidative phosphorylation genes (Cytochrome C, Cox4 and Cox5b) was observed in livers of SIRT1 LKO mice. The decreased expression of the above-mentioned PPAR-alpha target genes was accompanied by a 40% decrease in the expression of PGC-1alpha mRNA. |
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Formal Description Interaction-ID: 5849 |
gene/protein affects_activity of process |
| Comment | Upon high-fat diet feeding a reduction in the expression of mitochondrial oxidative phosphorylation genes (Cytochrome C, Cox4 and Cox5b) was observed in livers of SIRT1 LKO mice. The decreased expression of the above-mentioned PPAR-alpha target genes was accompanied by a 40% decrease in the expression of PGC-1alpha mRNA. |
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Formal Description Interaction-ID: 5850 |
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| Comment | SIRT1 LKO mice on high-fat diet displayed significantly lower mRNA levels of mitochondrial glycerol-3-phosphate acyltransferase (mtGPAT), acyl coenzyme A: diacylglycerol acyltransferase 1 (DGAT1), and acyl coenzyme A: diacylglycerol acyltransferase 2 (DGAT2), genes involved in the esterification of fatty acids to glycerol for the synthesis of triglycerides, suggesting that the increase in liver free fatty acids in SIRT1 LKO mice may also be a consequence of impaired fatty acid esterification. |
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Formal Description Interaction-ID: 5851 |
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| Comment | SIRT1 LKO mice on high-fat diet displayed significantly lower mRNA levels of mitochondrial glycerol-3-phosphate acyltransferase (mtGPAT), acyl coenzyme A: diacylglycerol acyltransferase 1 (DGAT1), and acyl coenzyme A: diacylglycerol acyltransferase 2 (DGAT2), genes involved in the esterification of fatty acids to glycerol for the synthesis of triglycerides, suggesting that the increase in liver free fatty acids in SIRT1 LKO mice may also be a consequence of impaired fatty acid esterification. |
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Formal Description Interaction-ID: 5852 |
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| Comment | SIRT1 LKO mice on high-fat diet displayed significantly lower mRNA levels of mitochondrial glycerol-3-phosphate acyltransferase (mtGPAT), acyl coenzyme A: diacylglycerol acyltransferase 1 (DGAT1), and acyl coenzyme A: diacylglycerol acyltransferase 2 (DGAT2), genes involved in the esterification of fatty acids to glycerol for the synthesis of triglycerides, suggesting that the increase in liver free fatty acids in SIRT1 LKO mice may also be a consequence of impaired fatty acid esterification. |
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Formal Description Interaction-ID: 5853 |
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| Comment | SIRT1 LKO mice on high-fat diet displayed significantly lower mRNA levels of mitochondrial glycerol-3-phosphate acyltransferase (mtGPAT), acyl coenzyme A: diacylglycerol acyltransferase 1 (DGAT1), and acyl coenzyme A: diacylglycerol acyltransferase 2 (DGAT2), genes involved in the esterification of fatty acids to glycerol for the synthesis of triglycerides, suggesting that the increase in liver free fatty acids in SIRT1 LKO mice may also be a consequence of impaired fatty acid esterification. |
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Formal Description Interaction-ID: 5854 |
gene/protein affects_activity of |
| Comment | Cyp7A1, the rate-limiting enzyme involved in the conversion of cholesterol to bile acids, was decreased in SIRT1 LKO mice on high-fat diet, suggesting that the accumulation of hepatic cholesterol may be the result of diminished bile synthesis. |
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Formal Description Interaction-ID: 5855 |
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| Comment | Hepatic deletion of SIRT1 leads to hepatic inflammation and ER stress on the high-fat diet. |
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Formal Description Interaction-ID: 5857 |
gene/protein affects_activity of phenotype |
| Comment | Hepatic deletion of SIRT1 leads to hepatic inflammation and ER stress on the high-fat diet. |
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Formal Description Interaction-ID: 5858 |
gene/protein affects_activity of |
| Comment | ER stress provokes an ER transmembrane protein kinase, pancreatic ER kinase (PERK), to phosphorylate the alpha subunit of the translation initiation factor (eIF2-alpha) thus blocking cellular protein translation. Comparison of levels of phosphorylated eIF2-alpha in liver extracts of control and SIRT1 LKO mice revealed that SIRT1 LKO mice had a 2.2-fold increase in p-eIF2-alpha protein compared to Lox controls. |
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Formal Description Interaction-ID: 5862 |
gene/protein affects_quantity of protein modification EIF2S1-phos |
| Comment | Hyper-activation of c-Jun N-terminal kinase (JNK) through phosphorylation is another marker of ER stress. Phosphorylation of JNK (p-JNK) and its downstream target c-Jun (p-c-Jun) were significantly increased by 2.1-fold and 3.2-fold respectively in SIRT1 LKO mice compared to control mice. |
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Formal Description Interaction-ID: 5876 |
gene/protein affects_quantity of protein modification JUN-phos |
| Comment | Infiltration of macrophages into tissues is a hallmark of local inflammation. Analysis of mRNA from livers of SIRT1 LKO mice revealed a 70-80% increase in macrophage markers, including macrophage inflammation protein (MIP1a). |
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Formal Description Interaction-ID: 5884 |
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| Comment | Several proinflammatory molecules that are dramatically induced in PPAR-alpha deficient livers, such as vascular cell adhesion molecule (VCAM-1), serum amyloid A-1 (SAA-1), and interferon (IFN)-gamma inducible protein (CXCL10), were significantly higher in livers of SIRT1 LKO mice compared to Lox controls. |
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Formal Description Interaction-ID: 5885 |
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| Drugbank entries | Show/Hide entries for VCAM1 |
| Comment | Several proinflammatory molecules that are dramatically induced in PPAR-alpha deficient livers, such as vascular cell adhesion molecule (VCAM-1), serum amyloid A-1 (SAA-1), and interferon (IFN)-gamma inducible protein (CXCL10), were significantly higher in livers of SIRT1 LKO mice compared to Lox controls. |
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Formal Description Interaction-ID: 5887 |
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| Drugbank entries | Show/Hide entries for SAA1 |
| Comment | Several proinflammatory molecules that are dramatically induced in PPAR-alpha deficient livers, such as vascular cell adhesion molecule (VCAM-1), serum amyloid A-1 (SAA-1), and interferon (IFN)-gamma inducible protein (CXCL10), were significantly higher in livers of SIRT1 LKO mice compared to Lox controls. |
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Formal Description Interaction-ID: 5888 |
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| Drugbank entries | Show/Hide entries for CXCL10 |
| Comment | TNF-alpha and IL-1beta, two major proinflammatory cytokines induced by fat accumulation, were also significantly increased in the liver SIRT1 LKO mice. |
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Formal Description Interaction-ID: 5889 |
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| Drugbank entries | Show/Hide entries for TNF |
| Comment | TNF-alpha and IL-1beta, two major proinflammatory cytokines induced by fat accumulation, were also significantly increased in the liver SIRT1 LKO mice. |
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Formal Description Interaction-ID: 5890 |
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| Drugbank entries | Show/Hide entries for IL1B |
| Comment | After feeding with a high-fat diet, Ser473 phosphorylation of Akt, a key molecule in the insulin signaling pathway, was 80% lower in livers of SIRT1 LKO mice. |
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Formal Description Interaction-ID: 5891 |
gene/protein affects_quantity of protein modification AKT1-phosSer473 |
| Comment | To elucidate the regulatory role of SIRT1 in PPAR-alpha signaling in liver, primary hepatocytes from Lox control or SIRT1 LKO mice were treated with a PPAR-alpha agonist WY14643. WY treatment induced the expression of several genes involved in fatty acid oxidation in control hepatocytes. However, the induction of these genes was significantly lower in the SIRT1 deficient (LKO) hepatocytes. |
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Formal Description Interaction-ID: 13195 |
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| Comment | Although SIRT1 LKO mice showed no body weight abnormality on a chow diet, they gained significantly more weight than control mice on the western diet. Consistent with diet-induced obesity, SIRT1 LKO mice showed greater lipid accumulation in the liver compared to control mice. Their serum free fatty acid levels were also significantly increased as compared to control mice. Additionally, serum beta-hydroxybutyrate, a marker for fatty acid oxidation and ketogenesis in the liver, was significantly lower in the SIRT1 LKO mice. |
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Formal Description Interaction-ID: 13196 |
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| Comment | Although SIRT1 LKO mice showed no body weight abnormality on a chow diet, they gained significantly more weight than control mice on the western diet. Consistent with diet-induced obesity, SIRT1 LKO mice showed greater lipid accumulation in the liver compared to control mice. Their serum free fatty acid levels were also significantly increased as compared to control mice. Additionally, serum beta-hydroxybutyrate, a marker for fatty acid oxidation and ketogenesis in the liver, was significantly lower in the SIRT1 LKO mice. |
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Formal Description Interaction-ID: 13197 |
gene/protein affects_quantity of drug/chemical compound |
| Comment | Although SIRT1 LKO mice showed no body weight abnormality on a chow diet, they gained significantly more weight than control mice on the western diet. Consistent with diet-induced obesity, SIRT1 LKO mice showed greater lipid accumulation in the liver compared to control mice. Their serum free fatty acid levels were also significantly increased as compared to control mice. Additionally, serum beta-hydroxybutyrate, a marker for fatty acid oxidation and ketogenesis in the liver, was significantly lower in the SIRT1 LKO mice. |
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Formal Description Interaction-ID: 13198 |
gene/protein affects_quantity of drug/chemical compound |