Essential Role of Protein-tyrosine Phosphatase 1B in the Modulation of Insulin Signaling by Acetaminophen in Hepatocytes

Mobasher, Maysa A.; Toro‐Martín, Juan de; González-Rodrı́guez, Águeda; Ramos, Sonia; Letzig, Lynda; James, Laura P.; Muntané, Jordi; Álvarez, Carmen; Valverde, Ángela M.

doi:10.1074/jbc.m113.539189

Cited by 16 publications

(14 citation statements)

References 46 publications

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“…NFκB induces expression of PTP1B, a negative regulator of insulin sensitivity [53] , and SIRT1 represses PTP1B in insulin resistant obese mice improving insulin sensitivity [54] . Since PTP1B deficiency increases glucose uptake [55,56] , the decreased inflammation in chronic-HFD ATKO mice compared to WT mice could lead to decreased PTP1B expression with a resulting increase in insulin sensitivity. Moreover, SIRT1 deacetylates IRS2, enhancing its tyrosine phosphorylation [57,58] .…”

Section: Discussionmentioning

confidence: 99%

Adipocyte SIRT1 knockout promotes PPARγ activity, adipogenesis and insulin sensitivity in chronic-HFD and obesity

Mayoral

Osborn

McNelis

et al. 2015

Molecular Metabolism

140

107

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ObjectiveAdipose tissue is the primary site for lipid deposition that protects the organisms in cases of nutrient excess during obesogenic diets. The histone deacetylase Sirtuin 1 (SIRT1) inhibits adipocyte differentiation by targeting the transcription factor peroxisome proliferator activated-receptor gamma (PPARγ).MethodsTo assess the specific role of SIRT1 in adipocytes, we generated Sirt1 adipocyte-specific knockout mice (ATKO) driven by aP2 promoter onto C57BL/6 background. Sirt1flx/flxaP2Cre+ (ATKO) and Sirt1flx/flxaP2Cre- (WT) mice were fed high-fat diet for 5 weeks (short-term) or 15 weeks (chronic-term). Metabolic studies were combined with gene expression analysis and phosphorylation/acetylation patterns in adipose tissue.ResultsOn standard chow, ATKO mice exhibit low-grade chronic inflammation in adipose tissue, along with glucose intolerance and insulin resistance compared with control fed mice. On short-term HFD, ATKO mice become more glucose intolerant, hyperinsulinemic, insulin resistant and display increased inflammation. During chronic HFD, WT mice developed a metabolic dysfunction, higher than ATKO mice, and thereby, knockout mice are more glucose tolerant, insulin sensitive and less inflamed relative to control mice. SIRT1 attenuates adipogenesis through PPARγ repressive acetylation and, in the ATKO mice adipocyte PPARγ was hyperacetylated. This high acetylation was associated with a decrease in Ser273-PPARγ phosphorylation. Dephosphorylated PPARγ is constitutively active and results in higher expression of genes associated with increased insulin sensitivity.ConclusionTogether, these data establish that SIRT1 downregulation in adipose tissue plays a previously unknown role in long-term inflammation resolution mediated by PPARγ activation. Therefore, in the context of obesity, the development of new therapeutics that activate PPARγ by targeting SIRT1 may provide novel approaches to the treatment of T2DM.

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Section: Discussionmentioning

confidence: 99%

Adipocyte SIRT1 knockout promotes PPARγ activity, adipogenesis and insulin sensitivity in chronic-HFD and obesity

Mayoral

Osborn

McNelis

et al. 2015

Molecular Metabolism

140

107

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“…Therefore, PTP1B deficiency may lead to prolonged Nrf2 accumulation in the nucleus and enhanced antioxidant response [69]. Further studies demonstrated that JNK and PTP1B converge on insulin signaling, based on the fact that JNK and PTP1B both negatively regulate insulin signaling at least in part through insulin receptor substrate (IRS-1) after APAP [65,70,71]. Consistent with that, an insulin sensitizer rosiglitazone reduces PTP1B protein expression and inhibits JNK activation and IRS phosphorylation after APAP [70].…”

Section: Evidence For Jnk As a Therapeutic Targetmentioning

confidence: 99%

“…Further studies demonstrated that JNK and PTP1B converge on insulin signaling, based on the fact that JNK and PTP1B both negatively regulate insulin signaling at least in part through insulin receptor substrate (IRS-1) after APAP [65,70,71]. Consistent with that, an insulin sensitizer rosiglitazone reduces PTP1B protein expression and inhibits JNK activation and IRS phosphorylation after APAP [70]. With that, it is possible that PTP1B modulates APAP-induced liver injury through GSK3β, IRS and JNK, suggesting an association between APAP and insulin resistance.…”

Section: Evidence For Jnk As a Therapeutic Targetmentioning

confidence: 99%

“…The effect of JNK activation and translocation to the mitochondria appears to be dependent on the presence of Sab in the mitochondria, which is the binding target of JNK but not RIP1 [77,78]. Because sustained JNK activation was suggested to be necessary for the development of toxicity [28,70], while transient JNK activation is normally beneficial for cells [96,97], we also need to explore how the balance between transient activation and sustained activation is regulated in APAP toxicity. Another critical issue for JNK would be its pathophysiological relevance in APAP overdose patients.…”

Section: Expert Opinion On the Role Of Jnk In Apap Hepatotoxicitymentioning

confidence: 99%

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Pathophysiological significance of c-junN-terminal kinase in acetaminophen hepatotoxicity

Xie

McGill

et al. 2015

Expert Opinion on Drug Metabolism & Toxicology

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Background Acetaminophen (APAP) overdose is the leading cause of acute liver failure in the US. Although substantial progress regarding the mechanisms of APAP hepatotoxicity has been made in the past several decades, therapeutic options are still limited and novel treatments are clearly needed. c-jun N-terminal Kinase (JNK) has emerged as a promising therapeutic target in recent years. Areas covered Early studies established the critical role of JNK activation and mitochondrial translocation in APAP hepatotoxicity. However, this concept has also been challenged. Initial studies failed to reproduce the protection of JNK deficiency in APAP toxicity and concerns over off-target effects of JNK inhibitors and even in knock-out mice are increasing. Interestingly, recent studies have even shown that liver injury can be altered with or without effects on JNK activation. The current review addresses these discrepancies and tries to explain or reconcile some of the conflicting results. Expert opinion JNK is a potential therapeutic target for APAP poisoning. However, controversies still exist regarding its actual role in APAP hepatotoxicity. Future studies are warranted for more in-depth testing of specific inhibitors in well-defined preclinical models and human hepatocytes before JNK can be considered a relevant therapeutic target for APAP poisoning.

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“…We have demonstrated that PTP1B inhibition restored hepatic insulin sensitivity in several in vivo models of insulin resistance. 28,40,41 On that basis, we investigated the effect of cytokines on IGF-IR-mediated signaling in retinal cells with reduced PTP1B expression using siRNA. Protein tyrosine phosphatase 1B protein content was decreased by almost 90% in 661W cells transfected with PTP1B siRNA (Fig.…”

Section: Reduction Of Ptp1b In Retinal Cells Protected Against Inflammentioning

confidence: 99%

Inhibition of Protein Tyrosine Phosphatase 1B Improves IGF-I Receptor Signaling and Protects Against Inflammation-Induced Gliosis in the Retina

Arroba

Valverde

2015

Invest. Ophthalmol. Vis. Sci.

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Essential Role of Protein-tyrosine Phosphatase 1B in the Modulation of Insulin Signaling by Acetaminophen in Hepatocytes

Cited by 16 publications

References 46 publications

Adipocyte SIRT1 knockout promotes PPARγ activity, adipogenesis and insulin sensitivity in chronic-HFD and obesity

Adipocyte SIRT1 knockout promotes PPARγ activity, adipogenesis and insulin sensitivity in chronic-HFD and obesity

Pathophysiological significance of c-junN-terminal kinase in acetaminophen hepatotoxicity

Inhibition of Protein Tyrosine Phosphatase 1B Improves IGF-I Receptor Signaling and Protects Against Inflammation-Induced Gliosis in the Retina

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