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General Information:

Id:	368
Diseases:	Diabetes mellitus, type II - [OMIM] Fatty liver disease, nonalcoholic Insulin resistance Obesity - [OMIM]
Organism:	Mus musculus
Gender:	male
Organism Model:	ob/+ mouse, ob/ob mouse
Publication type:	article
Reference:	Kammoun HL et al.(2009) GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice J. Clin. Invest. 5: 1201-1215 [PMID: 19363290]

Interaction Information:

Comment	The mature form of SREBP-1c and proteins of the unfolded protein response (UPR) pathway are coinduced in the livers of insulin-resistant obese rodents.
Formal Description Interaction-ID: 1478	disease Insulin resistance increases_quantity of mRNA/protein variant SREBF1c in liver; in obese mice

Comment	Insig-2 mRNA and protein increased in ob/ob mice compared with ob/+ mice, indicating that in these animals insulin fails to inhibit Insig-2 expression.
Formal Description Interaction-ID: 1479	complex/PPI Insulin affects_expression of gene/protein INSIG2

Comment	Insig-1 mRNA increased in the livers of ob/ob mice compared with ob/+ mice, in agreement with the accumulation of nuclear SREBP-1c. Despite this increase, Insig-1 proteins were undetectable in the livers of ob/ob mice, suggesting that Insig-1 is not translated or is degraded.
Formal Description Interaction-ID: 1480	organism model ob/ob mouse affects_expression of gene/protein INSIG1 in liver

Comment	The expression of SCAP, another partner of the SREBP processing complex, was not modified in the livers of ob/ob mice.
Formal Description Interaction-ID: 1481	organism model ob/ob mouse NOT affects_expression of gene/protein SCAP in liver

Comment	X box-binding protein-1 (XBP-1) nuclear protein content was highly increased in the livers of obese (ob/ob mice) compared with lean (ob/+ mice) animals, indicating that the IRE1 branch of the UPR pathway was activated.
Formal Description Interaction-ID: 1482	organism model ob/ob mouse increases_quantity of gene/protein XBP1 in liver

Comment	GRP78, ATF4, TRB3, and EDEM mRNA, induced in response to the activation of ATF6 and PERK, were increased in the livers of ob/ob mice compared to ob/+ mice.
Formal Description Interaction-ID: 1483	organism model ob/ob mouse affects_expression of gene/protein HSPA5 in liver
Drugbank entries	Show/Hide entries for HSPA5
Drugbank DB00025	Antihemophilic Factor chaperone HSPA5

Comment	The mature nuclear forms of the UPR transcription factors ATF6 and XBP-1 accumulated in the livers of ob/ob mice compared with ob/+ mice. In contrast, the amount of ATF6 precursor was reduced in the livers of ob/ob mice compared to ob/+ mice, showing that ATF6 was processed in ob/ob mice. Adenovirally mediated overexpression of GRP78 caused a major increase in the protein content of GRP78 in ob/+ and ob/ob mice and a strong decrease in ATF6 and XBP nuclear forms in ob/ob mice, demonstrating that ER stress was reduced in the livers of these animals.
Formal Description Interaction-ID: 1498	organism model ob/ob mouse affects_expression of gene/protein ATF6 in liver

Comment	The overexpression of GRP78 resulted in a near-complete disappearance of nuclear SREBP-1c in ob/ob mice, a similar although less marked reduction was observed in ob/+ mice. The SREBP-1c precursor and SREBP-1c mRNA were also strongly reduced, which might result from the fact that SREBP-1c participates in the control of its own transcription.
Formal Description Interaction-ID: 1500	gene/protein HSPA5 affects_quantity of mRNA/protein variant SREBF1c
Drugbank entries	Show/Hide entries for HSPA5
Drugbank DB00025	Antihemophilic Factor chaperone HSPA5

Comment	ChREBP nuclear content and ChREBP mRNA were strongly diminished by GRP78 overexpression in the liver.
Formal Description Interaction-ID: 1502	gene/protein HSPA5 affects_quantity of gene/protein MLXIPL in liver
Drugbank entries	Show/Hide entries for HSPA5
Drugbank DB00025	Antihemophilic Factor chaperone HSPA5

Comment	As a consequence of the fall in hepatic SREBP-1c and ChREBP nuclear forms in ob/ob mice overexpressing GRP78 in the liver, the levels of FAS, SCD1, and malic enzyme mRNA, which are target genes of SREBP-1c and ChREBP, were strongly reduced to levels observed in ob/+ mice.
Formal Description Interaction-ID: 1504	gene/protein HSPA5 affects_expression of gene/protein FASN in liver
Drugbank entries	Show/Hide entries for HSPA5 or FASN
Drugbank DB00025	Antihemophilic Factor chaperone HSPA5
Drugbank DB01034	Cerulenin inhibitor FASN
Drugbank DB01083	Orlistat inhibitor FASN

Comment	The overexpression of GRP78 considerably decreased the size and number of lipid droplets in ob/ob mouse livers, decreased the hepatic triglyceride content, liver weight and plasma triglyceride concentration.
Formal Description Interaction-ID: 1505	gene/protein HSPA5 affects_quantity of drug/chemical compound Triacylglycerol in liver, in blood
Drugbank entries	Show/Hide entries for HSPA5
Drugbank DB00025	Antihemophilic Factor chaperone HSPA5

Comment	The expression of genes involved in cholesterol and isoprenoid metabolism (hydroxymethylglutaryl-CoA reductase, hydroxymethylglutaryl-CoA synthase, farnesyl diphosphatase, and squalene synthase) and cholesterol uptake (LDL receptor) were increased in livers of ob/ob mice compared with ob/+ mice, which indicates that SREBP-2 is activated. SREBP-2 expression was higher in ob/ob mice compared with ob/+ mice. Liver overexpression of GRP78 strongly reduced the mRNA levels of SREBP-2 and its target genes to values found in ob/+ mice.
Formal Description Interaction-ID: 1506	organism model ob/ob mouse increases_expression of gene/protein HMGCR in liver
Drugbank entries	Show/Hide entries for HMGCR
Drugbank DB00157	NADH not specified HMGCR
Drugbank DB00175	Pravastatin inhibitor HMGCR
Drugbank DB00227	Lovastatin inhibitor HMGCR
Drugbank DB00439	Cerivastatin inhibitor HMGCR
Drugbank DB00641	Simvastatin inhibitor HMGCR
Drugbank DB01076	Atorvastatin inhibitor HMGCR
Drugbank DB01095	Fluvastatin inhibitor HMGCR
Drugbank DB01098	Rosuvastatin inhibitor HMGCR
Drugbank DB01992	Coenzyme A not specified HMGCR
Drugbank DB03169	(S)-Hmg-Coa not specified HMGCR
Drugbank DB03431	Adenosine-5'-Diphosphate not specified HMGCR
Drugbank DB03461	2'-Monophosphoadenosine 5'-Diphosphoribo ... not specified HMGCR
Drugbank DB04377	3-Hydroxy-3-Methyl-Glutaric Acid not specified HMGCR
Drugbank DB04447	1,4-Dithiothreitol not specified HMGCR
Drugbank DB06693	Mevastatin inhibitor HMGCR
Drugbank DB06846	7-[3-(4-FLUORO-PHENYL)-1-ISOPROPYL-1H-IN ... not specified HMGCR
Drugbank DB00157	NADH not specified HMGCR
Drugbank DB00175	Pravastatin inhibitor HMGCR
Drugbank DB00439	Cerivastatin inhibitor HMGCR
Drugbank DB00641	Simvastatin inhibitor HMGCR
Drugbank DB01095	Fluvastatin inhibitor HMGCR
Drugbank DB01992	Coenzyme A not specified HMGCR
Drugbank DB03169	(S)-Hmg-Coa not specified HMGCR
Drugbank DB03431	Adenosine-5'-Diphosphate not specified HMGCR
Drugbank DB03461	2'-Monophosphoadenosine 5'-Diphosphoribo ... not specified HMGCR
Drugbank DB04377	3-Hydroxy-3-Methyl-Glutaric Acid not specified HMGCR
Drugbank DB04447	1,4-Dithiothreitol not specified HMGCR
Drugbank DB06693	Mevastatin inhibitor HMGCR

Comment	Overexpression of GRP78 leads to a clear improvement of hepatic steatosis and dyslipidemia in ob/ob mice.
Formal Description Interaction-ID: 1507	gene/protein HSPA5 affects_activity of disease Fatty liver disease, nonalcoholic
Drugbank entries	Show/Hide entries for HSPA5
Drugbank DB00025	Antihemophilic Factor chaperone HSPA5

Comment	In ob/ob mice overexpression of GRP78 lead to a decrease of IRS-1 protein and mRNA content, whereas IRS-2 protein and mRNA content markedly increased to a level comparable to that observed in ob/+ mice. IRS-1 and IRS-2 tyrosine phosphorylation per unit of IRS protein was stimulated, and IRS-1 serine phosphorylation was reduced, concomitantly with decreased phosphorylation of JNK. This led to a reduction in the IRS-1-associated p85 subunit of PI3K, but a huge increase in the IRS-2-associated p85 subnit of PI3K.
Formal Description Interaction-ID: 1508	gene/protein HSPA5 affects_activity of gene/protein IRS1
Drugbank entries	Show/Hide entries for HSPA5 or IRS1
Drugbank DB00025	Antihemophilic Factor chaperone HSPA5
Drugbank DB08513	[4-({5-(AMINOCARBONYL)-4-[(3-METHYLPHENY ... not specified IRS1

Comment	In ob/+ mice, GRP78 overexpression had minor effects, except for a large increase in IRS-1 mRNA.
Formal Description Interaction-ID: 1509	gene/protein HSPA5 affects_expression of gene/protein IRS1
Drugbank entries	Show/Hide entries for HSPA5 or IRS1
Drugbank DB00025	Antihemophilic Factor chaperone HSPA5
Drugbank DB08513	[4-({5-(AMINOCARBONYL)-4-[(3-METHYLPHENY ... not specified IRS1

Comment	IRS-2-mediated insulin signaling was the main pathway improved by counteracting ER stress in obese animals.
Formal Description Interaction-ID: 1510	process response to endoplasmic reticulum stress decreases_activity of gene/protein IRS2

Comment	Akt/PKB phosphorylation on both Thr308 and Ser473, which was strongly reduced in ob/ob mice compared with ob/+ mice, was upregulated by ER stress inhibition in ob/ob mice, whereas there were no marked effects of GRP78 overexpression in ob/+ mice.
Formal Description Interaction-ID: 1511	organism model ob/ob mouse affects_activity of gene/protein AKT1
Drugbank entries	Show/Hide entries for AKT1
Drugbank DB00171	Adenosine triphosphate not specified AKT1
Drugbank DB01169	Arsenic trioxide inducer AKT1
Drugbank DB01863	Inositol 1,3,4,5-Tetrakisphosphate not specified AKT1
Drugbank DB07584	N-[2-(5-methyl-4H-1,2,4-triazol-3-yl)phe ... not specified AKT1
Drugbank DB07585	5-(5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4 ... not specified AKT1
Drugbank DB00171	Adenosine triphosphate not specified AKT1
Drugbank DB01863	Inositol 1,3,4,5-Tetrakisphosphate not specified AKT1

Comment	As a result of insulin resistance, FoxO1 phosphorylation decreased, and gene expression of PEPCK and G6Pase was upregulated in livers of ob/ob mice compared with ob/+ mice. In ob/ob mice overexpression of GRP78 lead to increased phosphorylation of FoxO1, and expression of PEPCK and G6Pase was strongly reduced, whereas the effects of GRP78 overexpression in ob/+ mice were minor.
Formal Description Interaction-ID: 1513	disease Insulin resistance decreases_phosphorylation of gene/protein FOXO1 in liver

Comment	Overexpression of GRP78 in fed ob/ob mice strongly diminished plasma glucose and insulin, suggesting that their insulin sensitivity was improved.
Formal Description Interaction-ID: 1515	gene/protein HSPA5 affects_quantity of drug/chemical compound Glucose in blood
Drugbank entries	Show/Hide entries for HSPA5
Drugbank DB00025	Antihemophilic Factor chaperone HSPA5

Comment	Inhibition of ER stress by overexpression of GRP78 caused a 6-fold increase in ob/ob mice of the glucose infusion rate necessary to maintain euglycemia. This was secondary to a 40 % decrease in hepatic glucose production and a 69 % increase in glucose utilization rate, which suggests that both liver and peripheral tissues have improved insulin sensitivity. There was no such effect of GRP78 overexpression in ob/+ mice.
Formal Description Interaction-ID: 1517	gene/protein HSPA5 decreases_activity of process response to endoplasmic reticulum stress
Drugbank entries	Show/Hide entries for HSPA5
Drugbank DB00025	Antihemophilic Factor chaperone HSPA5

Comment	The mature form of SREBP-1c and proteins of the unfolded protein response (UPR) pathway are coinduced in the livers of insulin-resistant obese rodents.
Formal Description Interaction-ID: 12595	disease Insulin resistance increases_activity of process endoplasmic reticulum unfolded protein response in liver; in obese mice

Comment	Insig-1 mRNA increased in the livers of ob/ob mice compared with ob/+ mice, in agreement with the accumulation of nuclear SREBP-1c. Despite this increase, Insig-1 proteins were undetectable in the livers of ob/ob mice, suggesting that Insig-1 is not translated or is degraded.
Formal Description Interaction-ID: 12599	organism model ob/ob mouse NOT affects_quantity of gene/protein INSIG1 in liver

Comment	GRP78, ATF4, TRB3, and EDEM mRNA, induced in response to the activation of ATF6 and PERK, were increased in the livers of ob/ob mice compared to ob/+ mice.
Formal Description Interaction-ID: 12600	organism model ob/ob mouse affects_expression of gene/protein ATF4 in liver

Comment	GRP78, ATF4, TRB3, and EDEM mRNA, induced in response to the activation of ATF6 and PERK, were increased in the livers of ob/ob mice compared to ob/+ mice.
Formal Description Interaction-ID: 12601	organism model ob/ob mouse affects_expression of gene/protein TRIB3 in liver

Comment	GRP78, ATF4, TRB3, and EDEM mRNA, induced in response to the activation of ATF6 and PERK, were increased in the livers of ob/ob mice compared to ob/+ mice.
Formal Description Interaction-ID: 12602	organism model ob/ob mouse affects_expression of gene/protein EDEM1 in liver

Comment	The mature nuclear forms of the UPR transcription factors ATF6 and XBP-1 accumulated in the livers of ob/ob mice compared with ob/+ mice. In contrast, the amount of ATF6 precursor was reduced in the livers of ob/ob mice compared to ob/+ mice, showing that ATF6 was processed in ob/ob mice. Adenovirally mediated overexpression of GRP78 caused a major increase in the protein content of GRP78 in ob/+ and ob/ob mice and a strong decrease in ATF6 and XBP nuclear forms in ob/ob mice, demonstrating that ER stress was reduced in the livers of these animals.
Formal Description Interaction-ID: 12603	organism model ob/ob mouse affects_expression of gene/protein XBP1 in liver

Comment	The mature nuclear forms of the UPR transcription factors ATF6 and XBP-1 accumulated in the livers of ob/ob mice compared with ob/+ mice. In contrast, the amount of ATF6 precursor was reduced in the livers of ob/ob mice compared to ob/+ mice, showing that ATF6 was processed in ob/ob mice. Adenovirally mediated overexpression of GRP78 caused a major increase in the protein content of GRP78 in ob/+ and ob/ob mice and a strong decrease in ATF6 and XBP nuclear forms in ob/ob mice, demonstrating that ER stress was reduced in the livers of these animals.
Formal Description Interaction-ID: 12604	gene/protein HSPA5 affects_quantity of gene/protein ATF6 in liver
Drugbank entries	Show/Hide entries for HSPA5
Drugbank DB00025	Antihemophilic Factor chaperone HSPA5

Comment	The mature nuclear forms of the UPR transcription factors ATF6 and XBP-1 accumulated in the livers of ob/ob mice compared with ob/+ mice. In contrast, the amount of ATF6 precursor was reduced in the livers of ob/ob mice compared to ob/+ mice, showing that ATF6 was processed in ob/ob mice. Adenovirally mediated overexpression of GRP78 caused a major increase in the protein content of GRP78 in ob/+ and ob/ob mice and a strong decrease in ATF6 and XBP nuclear forms in ob/ob mice, demonstrating that ER stress was reduced in the livers of these animals.
Formal Description Interaction-ID: 12605	gene/protein HSPA5 affects_quantity of gene/protein XBP1 in liver
Drugbank entries	Show/Hide entries for HSPA5
Drugbank DB00025	Antihemophilic Factor chaperone HSPA5

Comment	The mature nuclear forms of the UPR transcription factors ATF6 and XBP-1 accumulated in the livers of ob/ob mice compared with ob/+ mice. In contrast, the amount of ATF6 precursor was reduced in the livers of ob/ob mice compared to ob/+ mice, showing that ATF6 was processed in ob/ob mice. Adenovirally mediated overexpression of GRP78 caused a major increase in the protein content of GRP78 in ob/+ and ob/ob mice and a strong decrease in ATF6 and XBP nuclear forms in ob/ob mice, demonstrating that ER stress was reduced in the livers of these animals.
Formal Description Interaction-ID: 12606	organism model ob/ob mouse decreases_activity of process response to endoplasmic reticulum stress in liver

Comment	As a consequence of the fall in hepatic SREBP-1c and ChREBP nuclear forms in ob/ob mice overexpressing GRP78 in the liver, the levels of FAS, SCD1, and malic enzyme mRNA, which are target genes of SREBP-1c and ChREBP, were strongly reduced to levels observed in ob/+ mice.
Formal Description Interaction-ID: 12607	gene/protein HSPA5 affects_expression of gene/protein SCD in liver
Drugbank entries	Show/Hide entries for HSPA5
Drugbank DB00025	Antihemophilic Factor chaperone HSPA5

Comment	As a consequence of the fall in hepatic SREBP-1c and ChREBP nuclear forms in ob/ob mice overexpressing GRP78 in the liver, the levels of FAS, SCD1, and malic enzyme mRNA, which are target genes of SREBP-1c and ChREBP, were strongly reduced to levels observed in ob/+ mice.
Formal Description Interaction-ID: 12608	gene/protein HSPA5 affects_expression of gene/protein ME1 in liver
Drugbank entries	Show/Hide entries for HSPA5 or ME1
Drugbank DB00025	Antihemophilic Factor chaperone HSPA5
Drugbank DB00157	NADH not specified ME1
Drugbank DB03461	2'-Monophosphoadenosine 5'-Diphosphoribo ... not specified ME1
Drugbank DB00157	NADH not specified ME1
Drugbank DB03461	2'-Monophosphoadenosine 5'-Diphosphoribo ... not specified ME1

Comment	The overexpression of GRP78 considerably decreased the size and number of lipid droplets in ob/ob mouse livers, decreased the hepatic triglyceride content, liver weight and plasma triglyceride concentration.
Formal Description Interaction-ID: 12610	gene/protein HSPA5 affects_quantity of tissue/cell line liver
Drugbank entries	Show/Hide entries for HSPA5
Drugbank DB00025	Antihemophilic Factor chaperone HSPA5

Comment	The expression of genes involved in cholesterol and isoprenoid metabolism (hydroxymethylglutaryl-CoA reductase, hydroxymethylglutaryl-CoA synthase, farnesyl diphosphatase, and squalene synthase) and cholesterol uptake (LDL receptor) were increased in livers of ob/ob mice compared with ob/+ mice, which indicates that SREBP-2 is activated. SREBP-2 expression was higher in ob/ob mice compared with ob/+ mice. Liver overexpression of GRP78 strongly reduced the mRNA levels of SREBP-2 and its target genes to values found in ob/+ mice.
Formal Description Interaction-ID: 12611	organism model ob/ob mouse increases_expression of gene/protein HMGCS1 in liver
Drugbank entries	Show/Hide entries for HMGCS1
Drugbank DB07740	(3R,5S,7R,12S,13R)-13-FORMYL-12,14-DIHYD ... not specified HMGCS1

Comment	The expression of genes involved in cholesterol and isoprenoid metabolism (hydroxymethylglutaryl-CoA reductase, hydroxymethylglutaryl-CoA synthase, farnesyl diphosphatase, and squalene synthase) and cholesterol uptake (LDL receptor) were increased in livers of ob/ob mice compared with ob/+ mice, which indicates that SREBP-2 is activated. SREBP-2 expression was higher in ob/ob mice compared with ob/+ mice. Liver overexpression of GRP78 strongly reduced the mRNA levels of SREBP-2 and its target genes to values found in ob/+ mice.
Formal Description Interaction-ID: 12612	organism model ob/ob mouse increases_expression of gene/protein FDPS in liver
Drugbank entries	Show/Hide entries for FDPS
Drugbank DB00282	Pamidronate inhibitor FDPS
Drugbank DB00399	Zoledronate inhibitor FDPS
Drugbank DB00630	Alendronate inhibitor FDPS
Drugbank DB00710	Ibandronate inhibitor FDPS
Drugbank DB00884	Risedronate inhibitor FDPS
Drugbank DB01785	Dimethylallyl Diphosphate not specified FDPS
Drugbank DB02508	Isopentyl Pyrophosphate not specified FDPS
Drugbank DB02552	Geranyl Diphosphate not specified FDPS
Drugbank DB04714	ISOPENTENYL PYROPHOSPHATE not specified FDPS
Drugbank DB07780	FARNESYL DIPHOSPHATE not specified FDPS
Drugbank DB07841	GERANYLGERANYL DIPHOSPHATE not specified FDPS
Drugbank DB00399	Zoledronate inhibitor FDPS
Drugbank DB00710	Ibandronate inhibitor FDPS
Drugbank DB00884	Risedronate inhibitor FDPS
Drugbank DB04714	ISOPENTENYL PYROPHOSPHATE not specified FDPS

Comment	The expression of genes involved in cholesterol and isoprenoid metabolism (hydroxymethylglutaryl-CoA reductase, hydroxymethylglutaryl-CoA synthase, farnesyl diphosphatase, and squalene synthase) and cholesterol uptake (LDL receptor) were increased in livers of ob/ob mice compared with ob/+ mice, which indicates that SREBP-2 is activated. SREBP-2 expression was higher in ob/ob mice compared with ob/+ mice. Liver overexpression of GRP78 strongly reduced the mRNA levels of SREBP-2 and its target genes to values found in ob/+ mice.
Formal Description Interaction-ID: 12613	organism model ob/ob mouse affects_activity of process cholesterol metabolic process in liver

Comment	The expression of genes involved in cholesterol and isoprenoid metabolism (hydroxymethylglutaryl-CoA reductase, hydroxymethylglutaryl-CoA synthase, farnesyl diphosphatase, and squalene synthase) and cholesterol uptake (LDL receptor) were increased in livers of ob/ob mice compared with ob/+ mice, which indicates that SREBP-2 is activated. SREBP-2 expression was higher in ob/ob mice compared with ob/+ mice. Liver overexpression of GRP78 strongly reduced the mRNA levels of SREBP-2 and its target genes to values found in ob/+ mice.
Formal Description Interaction-ID: 12614	organism model ob/ob mouse affects_activity of process isoprenoid metabolic process in liver

Comment	The expression of genes involved in cholesterol and isoprenoid metabolism (hydroxymethylglutaryl-CoA reductase, hydroxymethylglutaryl-CoA synthase, farnesyl diphosphatase, and squalene synthase) and cholesterol uptake (LDL receptor) were increased in livers of ob/ob mice compared with ob/+ mice, which indicates that SREBP-2 is activated. SREBP-2 expression was higher in ob/ob mice compared with ob/+ mice. Liver overexpression of GRP78 strongly reduced the mRNA levels of SREBP-2 and its target genes to values found in ob/+ mice.
Formal Description Interaction-ID: 12615	organism model ob/ob mouse affects_activity of process cholesterol import in liver

Comment	The expression of genes involved in cholesterol and isoprenoid metabolism (hydroxymethylglutaryl-CoA reductase, hydroxymethylglutaryl-CoA synthase, farnesyl diphosphatase, and squalene synthase) and cholesterol uptake (LDL receptor) were increased in livers of ob/ob mice compared with ob/+ mice, which indicates that SREBP-2 is activated. SREBP-2 expression was higher in ob/ob mice compared with ob/+ mice. Liver overexpression of GRP78 strongly reduced the mRNA levels of SREBP-2 and its target genes to values found in ob/+ mice.
Formal Description Interaction-ID: 12616	organism model ob/ob mouse increases_expression of gene/protein LDLR in liver
Drugbank entries	Show/Hide entries for LDLR
Drugbank DB00707	Porfimer other/unknown LDLR
Drugbank DB02944	Alpha-D-Mannose not specified LDLR
Drugbank DB00707	Porfimer other/unknown LDLR
Drugbank DB02944	Alpha-D-Mannose not specified LDLR

Comment	The expression of genes involved in cholesterol and isoprenoid metabolism (hydroxymethylglutaryl-CoA reductase, hydroxymethylglutaryl-CoA synthase, farnesyl diphosphatase, and squalene synthase) and cholesterol uptake (LDL receptor) were increased in livers of ob/ob mice compared with ob/+ mice, which indicates that SREBP-2 is activated. SREBP-2 expression was higher in ob/ob mice compared with ob/+ mice. Liver overexpression of GRP78 strongly reduced the mRNA levels of SREBP-2 and its target genes to values found in ob/+ mice.
Formal Description Interaction-ID: 12618	organism model ob/ob mouse increases_activity of gene/protein SREBF2 in liver

Comment	The expression of genes involved in cholesterol and isoprenoid metabolism (hydroxymethylglutaryl-CoA reductase, hydroxymethylglutaryl-CoA synthase, farnesyl diphosphatase, and squalene synthase) and cholesterol uptake (LDL receptor) were increased in livers of ob/ob mice compared with ob/+ mice, which indicates that SREBP-2 is activated. SREBP-2 expression was higher in ob/ob mice compared with ob/+ mice. Liver overexpression of GRP78 strongly reduced the mRNA levels of SREBP-2 and its target genes to values found in ob/+ mice.
Formal Description Interaction-ID: 12619	gene/protein HSPA5 affects_expression of gene/protein SREBF2 in liver
Drugbank entries	Show/Hide entries for HSPA5
Drugbank DB00025	Antihemophilic Factor chaperone HSPA5

Comment	In ob/ob mice overexpression of GRP78 lead to a decrease of IRS-1 protein and mRNA content, whereas IRS-2 protein and mRNA content markedly increased to a level comparable to that observed in ob/+ mice. IRS-1 and IRS-2 tyrosine phosphorylation per unit of IRS protein was stimulated, and IRS-1 serine phosphorylation was reduced, concomitantly with decreased phosphorylation of JNK. This led to a reduction in the IRS-1-associated p85 subunit of PI3K, but a huge increase in the IRS-2-associated p85 subnit of PI3K.
Formal Description Interaction-ID: 12622	gene/protein HSPA5 affects_activity of gene/protein IRS2
Drugbank entries	Show/Hide entries for HSPA5
Drugbank DB00025	Antihemophilic Factor chaperone HSPA5

Comment	In ob/ob mice overexpression of GRP78 lead to a decrease of IRS-1 protein and mRNA content, whereas IRS-2 protein and mRNA content markedly increased to a level comparable to that observed in ob/+ mice. IRS-1 and IRS-2 tyrosine phosphorylation per unit of IRS protein was stimulated, and IRS-1 serine phosphorylation was reduced, concomitantly with decreased phosphorylation of JNK. This led to a reduction in the IRS-1-associated p85 subunit of PI3K, but a huge increase in the IRS-2-associated p85 subnit of PI3K.
Formal Description Interaction-ID: 12623	gene/protein HSPA5 affects_activity of gene/protein MAPK8
Drugbank entries	Show/Hide entries for HSPA5 or MAPK8
Drugbank DB00025	Antihemophilic Factor chaperone HSPA5
Drugbank DB01782	2,6-Dihydroanthra/1,9-Cd/Pyrazol-6-One not specified MAPK8
Drugbank DB07218	6-CHLORO-9-HYDROXY-1,3-DIMETHYL-1,9-DIHY ... not specified MAPK8
Drugbank DB07268	2-({2-[(3-HYDROXYPHENYL)AMINO]PYRIMIDIN- ... not specified MAPK8
Drugbank DB07272	N-(4-AMINO-5-CYANO-6-ETHOXYPYRIDIN-2-YL) ... not specified MAPK8
Drugbank DB07276	5-CYANO-N-(2,5-DIMETHOXYBENZYL)-6-ETHOXY ... not specified MAPK8
Drugbank DB07845	2-fluoro-6-{[2-({2-methoxy-4-[(methylsul ... not specified MAPK8

Comment	IRS-2-mediated insulin signaling was the main pathway improved by counteracting ER stress in obese animals.
Formal Description Interaction-ID: 12624	gene/protein IRS2 increases_activity of process insulin receptor signaling pathway

Comment	IRS-2-mediated insulin signaling was the main pathway improved by counteracting ER stress in obese animals.
Formal Description Interaction-ID: 12625	disease Obesity increases_activity of process response to endoplasmic reticulum stress

Comment	As a result of insulin resistance, FoxO1 phosphorylation decreased, and gene expression of PEPCK and G6Pase was upregulated in livers of ob/ob mice compared with ob/+ mice. In ob/ob mice overexpression of GRP78 lead to increased phosphorylation of FoxO1, and expression of PEPCK and G6Pase was strongly reduced, whereas the effects of GRP78 overexpression in ob/+ mice were minor.
Formal Description Interaction-ID: 12626	disease Insulin resistance increases_expression of gene/protein PCK1 in liver
Drugbank entries	Show/Hide entries for PCK1
Drugbank DB01819	Phosphoenolpyruvate not specified PCK1
Drugbank DB02008	1-(2-Fluorobenzyl)-3-Butyl-8-(N-Acetyl-4 ... not specified PCK1
Drugbank DB03267	1-Allyl-3-Butyl-8-(N-Acetyl-4-Aminobenzy ... not specified PCK1
Drugbank DB03725	Phosphomethylphosphonic Acid-Guanylate E ... not specified PCK1
Drugbank DB01819	Phosphoenolpyruvate not specified PCK1
Drugbank DB02008	1-(2-Fluorobenzyl)-3-Butyl-8-(N-Acetyl-4 ... not specified PCK1
Drugbank DB03267	1-Allyl-3-Butyl-8-(N-Acetyl-4-Aminobenzy ... not specified PCK1
Drugbank DB03725	Phosphomethylphosphonic Acid-Guanylate E ... not specified PCK1

Comment	As a result of insulin resistance, FoxO1 phosphorylation decreased, and gene expression of PEPCK and G6Pase was upregulated in livers of ob/ob mice compared with ob/+ mice. In ob/ob mice overexpression of GRP78 lead to increased phosphorylation of FoxO1, and expression of PEPCK and G6Pase was strongly reduced, whereas the effects of GRP78 overexpression in ob/+ mice were minor.
Formal Description Interaction-ID: 12627	disease Insulin resistance increases_expression of gene/protein G6PC in liver

Comment	As a result of insulin resistance, FoxO1 phosphorylation decreased, and gene expression of PEPCK and G6Pase was upregulated in livers of ob/ob mice compared with ob/+ mice. In ob/ob mice overexpression of GRP78 lead to increased phosphorylation of FoxO1, and expression of PEPCK and G6Pase was strongly reduced, whereas the effects of GRP78 overexpression in ob/+ mice were minor.
Formal Description Interaction-ID: 12628	gene/protein HSPA5 affects_phosphorylation of gene/protein FOXO1 in liver
Drugbank entries	Show/Hide entries for HSPA5
Drugbank DB00025	Antihemophilic Factor chaperone HSPA5

Comment	Inhibition of ER stress by overexpression of GRP78 caused a 6-fold increase in ob/ob mice of the glucose infusion rate necessary to maintain euglycemia. This was secondary to a 40 % decrease in hepatic glucose production and a 69 % increase in glucose utilization rate, which suggests that both liver and peripheral tissues have improved insulin sensitivity. There was no such effect of GRP78 overexpression in ob/+ mice.
Formal Description Interaction-ID: 12636	gene/protein HSPA5 affects_activity of process glucose homeostasis
Drugbank entries	Show/Hide entries for HSPA5
Drugbank DB00025	Antihemophilic Factor chaperone HSPA5