General Information:

Id: 2,266
Diseases: Diabetes mellitus, type II - [OMIM]
Fatty liver disease, nonalcoholic
Insulin resistance
Obesity - [OMIM]
Mus musculus
male
SPP1 -/- mouse (OPN-/-)
article
Reference: Kiefer FW et al.(2011) Osteopontin deficiency protects against obesity-induced hepatic steatosis and attenuates glucose production in mice. Diabetologia 54: 2132-2142 [PMID: 21562757]

Interaction Information:

Comment Genetic osteopontin (OPN, SPP1) deficiency protected from obesity-induced hepatic steatosis, at least in part, by downregulating hepatic triacylglycerol synthesis.
Formal Description
Interaction-ID: 19333

gene/protein

SPP1

affects_activity of

disease

Fatty liver disease, nonalcoholic

in liver
Comment Genetic osteopontin (OPN, SPP1) deficiency protected from obesity-induced hepatic steatosis, at least in part, by downregulating hepatic triacylglycerol synthesis.
Formal Description
Interaction-ID: 19334

gene/protein

SPP1

affects_activity of

in liver
Comment Conversely, absence of OPN promoted fat storage in adipose tissue thereby preventing the obesity-induced shift to ectopic fat accumulation in the liver.
Formal Description
Interaction-ID: 19335

gene/protein

SPP1

affects_activity of

process

lipid storage

in adipose tissue
Comment Conversely, absence of OPN promoted fat storage in adipose tissue thereby preventing the obesity-induced shift to ectopic fat accumulation in the liver.
Formal Description
Interaction-ID: 19336

gene/protein

SPP1

affects_activity of

process

ectopic lipid storage

in liver
Comment Euglycaemic-hyperinsulinaemic clamp studies revealed that insulin resistance and excess hepatic glucose production in obesity were significantly attenuated in Opn (-/-) mice.
Formal Description
Interaction-ID: 19337

gene/protein

SPP1

affects_activity of

disease

Insulin resistance

in obese mice
Comment Euglycaemic-hyperinsulinaemic clamp studies revealed that insulin resistance and excess hepatic glucose production in obesity were significantly attenuated in Opn (-/-) mice.
Formal Description
Interaction-ID: 19338

gene/protein

SPP1

affects_activity of

process

hepatic glucose production

in liver; in obese mice
Comment OPN deficiency markedly improved hepatic insulin signalling as shown by enhanced insulin receptor substrate-2 phosphorylation and prevented upregulation of the major hepatic transcription factor Forkhead box O1 and its gluconeogenic target genes G6pc and Mttp.
Formal Description
Interaction-ID: 19339

gene/protein

SPP1

affects_activity of

in liver
Comment OPN deficiency markedly improved hepatic insulin signalling as shown by enhanced insulin receptor substrate-2 phosphorylation and prevented upregulation of the major hepatic transcription factor Forkhead box O1 and its gluconeogenic target genes G6pc and Mttp.
Formal Description
Interaction-ID: 19340

gene/protein

SPP1

affects_phosphorylation of

gene/protein

IRS2

in liver
Comment OPN deficiency markedly improved hepatic insulin signalling as shown by enhanced insulin receptor substrate-2 phosphorylation and prevented upregulation of the major hepatic transcription factor Forkhead box O1 and its gluconeogenic target genes G6pc and Mttp.
Formal Description
Interaction-ID: 19341

gene/protein

SPP1

affects_expression of

gene/protein

FOXO1

in liver
Comment OPN deficiency markedly improved hepatic insulin signalling as shown by enhanced insulin receptor substrate-2 phosphorylation and prevented upregulation of the major hepatic transcription factor Forkhead box O1 and its gluconeogenic target genes G6pc and Mttp.
Formal Description
Interaction-ID: 19342

gene/protein

SPP1

affects_activity of

process

gluconeogenesis

in liver
Comment OPN deficiency markedly improved hepatic insulin signalling as shown by enhanced insulin receptor substrate-2 phosphorylation and prevented upregulation of the major hepatic transcription factor Forkhead box O1 and its gluconeogenic target genes G6pc and Mttp.
Formal Description
Interaction-ID: 19343

gene/protein

SPP1

affects_expression of

gene/protein

G6PC

in liver; via FOXO1
Comment OPN deficiency markedly improved hepatic insulin signalling as shown by enhanced insulin receptor substrate-2 phosphorylation and prevented upregulation of the major hepatic transcription factor Forkhead box O1 and its gluconeogenic target genes G6pc and Mttp.
Formal Description
Interaction-ID: 19344

gene/protein

SPP1

affects_expression of

gene/protein

MTTP

in liver; via FOXO1
Drugbank entries Show/Hide entries for MTTP
Comment Obesity-driven hepatic inflammation and macrophage accumulation was blocked by OPN deficiency.
Formal Description
Interaction-ID: 19345

gene/protein

SPP1

affects_activity of

in liver; in obese mice
Comment Obesity-driven hepatic inflammation and macrophage accumulation was blocked by OPN deficiency.
Formal Description
Interaction-ID: 19346

gene/protein

SPP1

affects_activity of

into the liver; in obese mice
Comment Markers of fatty acid synthesis such as Fasn and Acaca did not differ between obese WT and Opn-/- mice.
Formal Description
Interaction-ID: 19347

gene/protein

SPP1

NOT affects_expression of

gene/protein

FASN

in liver
Drugbank entries Show/Hide entries for FASN
Comment Markers of fatty acid synthesis such as Fasn and Acaca did not differ between obese WT and Opn-/- mice.
Formal Description
Interaction-ID: 19348

gene/protein

SPP1

NOT affects_expression of

gene/protein

ACACA

in liver
Drugbank entries Show/Hide entries for ACACA
Comment Neither was enhanced fatty acid oxidation likely to contribute to reduced hepatic steatosis since important transcription factors driving beta-oxidation were unchanged or even downregulated as shown for Ppara and Ppargc1a, respectively.
Formal Description
Interaction-ID: 19349

gene/protein

SPP1

NOT affects_expression of

gene/protein

PPARA

in liver
Drugbank entries Show/Hide entries for PPARA
Comment Neither was enhanced fatty acid oxidation likely to contribute to reduced hepatic steatosis since important transcription factors driving beta-oxidation were unchanged or even downregulated as shown for Ppara and Ppargc1a, respectively.
Formal Description
Interaction-ID: 19350

gene/protein

SPP1

affects_expression of

gene/protein

PPARGC1A

in liver
Comment However, gene expression of the major transcriptional regulator of hepatic lipogenesis Srebf1 was markedly decreased in Opn-/- compared with WT animals. This was similarly found to be the case for Pparg, a hepatic sterol regulatory element-binding protein 1 (SREBP-1c) target gene.
Formal Description
Interaction-ID: 19351

gene/protein

SPP1

affects_expression of

gene/protein

SREBF1

in liver
Comment However, gene expression of the major transcriptional regulator of hepatic lipogenesis Srebf1 was markedly decreased in Opn-/- compared with WT animals. This was similarly found to be the case for Pparg, a hepatic sterol regulatory element-binding protein 1 (SREBP-1c) target gene.
Formal Description
Interaction-ID: 19352

gene/protein

SPP1

affects_activity of

in liver
Comment However, gene expression of the major transcriptional regulator of hepatic lipogenesis Srebf1 was markedly decreased in Opn-/- compared with WT animals. This was similarly found to be the case for Pparg, a hepatic sterol regulatory element-binding protein 1 (SREBP-1c) target gene.
Formal Description
Interaction-ID: 19353

gene/protein

SPP1

affects_expression of

gene/protein

PPARG

in liver
Drugbank entries Show/Hide entries for PPARG
Comment Given the downregulation of hepatic Pparg mRNA expression, the transcriptional targets Dgat1 and Dgat2 were examined, which catalyse the formation of triacylglycerols from diacylglycerol and acylcoenzyme A. Notably, Dgat1 expression was significantly downregulated in obese Opn-/- livers while Dgat2 followed the same trend, although the change was not significant.
Formal Description
Interaction-ID: 19354

gene/protein

SPP1

affects_expression of

gene/protein

DGAT1

in liver
Comment Given the downregulation of hepatic Pparg mRNA expression, the transcriptional targets Dgat1 and Dgat2 were examined, which catalyse the formation of triacylglycerols from diacylglycerol and acylcoenzyme A. Notably, Dgat1 expression was significantly downregulated in obese Opn-/- livers while Dgat2 followed the same trend, although the change was not significant.
Formal Description
Interaction-ID: 19355

gene/protein

SPP1

NOT affects_expression of

gene/protein

DGAT2

in liver
Comment Insulin-stimulated serine phosphorylation of AKT, which mediates signal transduction downstream of IRS, was markedly more enhanced in Opn-/- vs WT mice.
Formal Description
Interaction-ID: 19356

gene/protein

SPP1

affects_phosphorylation of

gene/protein

AKT1

in liver; at Ser residues of AKT1
Drugbank entries Show/Hide entries for AKT1
Comment Foxo1 mRNA and protein levels were significantly enhanced in obese WT livers, whereas absence of OPN protected from HF-induced hepatic FOXO1 upregulation.
Formal Description
Interaction-ID: 19357

disease

Obesity

increases_expression of

gene/protein

FOXO1

in liver
Comment HF feeding raised gene expression of the macrophage marker Emr1 significantly less in OPN-deficient than in WT livers.
Formal Description
Interaction-ID: 19358

gene/protein

SPP1

affects_expression of

gene/protein

EMR1

in liver
Comment HF feeding raised gene expression of the macrophage marker Emr1 significantly less in OPN-deficient than in WT livers.
Formal Description
Interaction-ID: 19359

environment

high-fat diet

increases_expression of

gene/protein

EMR1

in liver
Comment Hepatic gene expression of Ccl2 was markedly increased in obesity in WT but not in Opn-/- animals.
Formal Description
Interaction-ID: 19360

disease

Obesity

increases_expression of

gene/protein

CCL2

in liver
Drugbank entries Show/Hide entries for CCL2
Comment Hepatic gene expression of Ccl2 was markedly increased in obesity in WT but not in Opn-/- animals.
Formal Description
Interaction-ID: 19361

gene/protein

SPP1

affects_expression of

gene/protein

CCL2

in liver
Drugbank entries Show/Hide entries for CCL2
Comment Hepatic mRNA expression of inflammatory Tnf and Tgfb1, known to be crucially involved in pathogenesis and progression of NAFLD was increased with HF in WT mice but significantly less in Opn-/- mice.
Formal Description
Interaction-ID: 19362

environment

high-fat diet

increases_expression of

gene/protein

TNF

in liver
Drugbank entries Show/Hide entries for TNF
Comment Hepatic mRNA expression of inflammatory Tnf and Tgfb1, known to be crucially involved in pathogenesis and progression of NAFLD was increased with HF in WT mice but significantly less in Opn-/- mice.
Formal Description
Interaction-ID: 19363

environment

high-fat diet

increases_expression of

gene/protein

TGFB1

in liver
Drugbank entries Show/Hide entries for TGFB1
Comment Hepatic mRNA expression of inflammatory Tnf and Tgfb1, known to be crucially involved in pathogenesis and progression of NAFLD was increased with HF in WT mice but significantly less in Opn-/- mice.
Formal Description
Interaction-ID: 19364

gene/protein

SPP1

affects_expression of

gene/protein

TNF

in liver
Drugbank entries Show/Hide entries for TNF
Comment Hepatic mRNA expression of inflammatory Tnf and Tgfb1, known to be crucially involved in pathogenesis and progression of NAFLD was increased with HF in WT mice but significantly less in Opn-/- mice.
Formal Description
Interaction-ID: 19365

gene/protein

SPP1

affects_expression of

gene/protein

TGFB1

in liver
Drugbank entries Show/Hide entries for TGFB1