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Ortega-Molina A.,Tumor Suppression Group | Efeyan A.,Tumor Suppression Group | Lopez-Guadamillas E.,Tumor Suppression Group | Munoz-Martin M.,Tumor Suppression Group | And 12 more authors.
Cell Metabolism | Year: 2012

Aging in worms and flies is regulated by the PI3K/Akt/Foxo pathway. Here we extend this paradigm to mammals. Pten tg mice carrying additional genomic copies of Pten are protected from cancer and present a significant extension of life span that is independent of their lower cancer incidence. Interestingly, Pten tg mice have an increased energy expenditure and protection from metabolic pathologies. The brown adipose tissue (BAT) of Pten tg mice is hyperactive and presents high levels of the uncoupling protein Ucp1, which we show is a target of Foxo1. Importantly, a synthetic PI3K inhibitor also increases energy expenditure and hyperactivates the BAT in mice. These effects can be recapitulated in isolated brown adipocytes and, moreover, implants of Pten tg fibroblasts programmed with Prdm16 and Cebpβ form subcutaneous brown adipose pads more efficiently than wild-type fibroblasts. These observations uncover a role of Pten in promoting energy expenditure, thus decreasing nutrient storage and its associated damage. © 2012 Elsevier Inc.

Uzi D.,Hebrew University of Jerusalem | Barda L.,Hebrew University of Jerusalem | Scaiewicz V.,Hebrew University of Jerusalem | Mills M.,Hebrew University of Jerusalem | And 12 more authors.
Journal of Hepatology | Year: 2013

Background & Aims The liver is a major site of drug metabolism and elimination and as such is susceptible to drug toxicity. Drug induced liver injury is a leading cause of acute liver injury, of which acetaminophen (APAP) is the most frequent causative agent. APAP toxicity is initiated by its toxic metabolite NAPQI. However, downstream mechanisms underlying APAP induced cell death are still unclear. Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have recently emerged as major regulators of metabolic homeostasis. UPR regulation of the transcription repressor CHOP promotes cell death. We analyzed the role of UPR and CHOP in mediating APAP hepatotoxicity. Methods A toxic dose of APAP was orally administered to wild type (wt) and CHOP knockout (KO) mice and damage mechanisms were assessed. Results CHOP KO mice were protected from APAP induced damage and exhibited decreased liver necrosis and increased survival. APAP metabolism in CHOP KO mice was undisturbed and glutathione was depleted at similar kinetics to wt. ER stress and UPR activation were overtly seen 12 h following APAP administration, a time that coincided with strong upregulation of CHOP. Remarkably, CHOP KO but not wt mice exhibited hepatocyte proliferation at sites of necrosis. In vitro, large T immortalized CHOP KO hepatocytes were protected from APAP toxicity in comparison to wt control cells. Conclusions CHOP upregulation during APAP induced liver injury compromises hepatocyte survival in various mechanisms, in part by curtailing the regeneration phase following liver damage. Thus, CHOP plays a pro-damage role in response to APAP intoxication. © 2013 European Association for the Study of the Liver.

Manieri E.,CSIC - National Center for Biotechnology | Verdugo A.,CSIC - National Center for Biotechnology | Gonzalez-Rodriguez A.,Institute of Biomedicine Alberto Sols CSIC UAM | Gonzalez-Rodriguez A.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas | And 3 more authors.
Journal of Clinical Investigation | Year: 2013

Bacterial LPS (endotoxin) has been implicated in the pathogenesis of acute liver disease through its induction of the proinflammatory cytokine TNF-α. TNF-α is a key determinant of the outcome in a well-established mouse model of acute liver failure during septic shock. One possible mechanism for regulating TNF-α expression is through the control of protein elongation during translation, which would allow rapid cell adaptation to physiological changes. However, the regulation of translational elongation is poorly understood. We found that expression of p38γ/δMAPK proteins is required for the elongation of nascent TNF-α protein in macrophages. The MKK3/6-p38γ/δpathway mediated an inhibitory phosphorylation of eukaryotic elongation factor 2 (eEF2) kinase, which in turn promoted eEF2 activation (dephosphorylation) and subsequent TNF-α elongation. These results identify a new signaling pathway that regulates TNF-α production in LPS-induced liver damage and suggest potential cell-specific therapeutic targets for liver diseases in which TNF-α production is involved.

Fernandez-Marcos P.J.,Tumor Suppression Group | Pantoja C.,Tumor Suppression Group | Gonzalez-Rodriguez A.,Institute of Biomedicine Alberto Sols CSIC UAM | Gonzalez-Rodriguez A.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas Ciberdem | And 6 more authors.
PLoS ONE | Year: 2010

Sei1 is a positive regulator of proliferation that promotes the assembly of Cdk4-cyclin D complexes and enhances the transcriptional activity of E2f1. The potential oncogenic role of Sei1 is further suggested by its overexpression in various types of human cancers. To study the role of Sei1, we have generated a mouse line deficient for this gene. Sei1-null fibroblasts did not show abnormalities regarding proliferation or susceptibility to neoplastic transformation, nor did we observe defects on Cdk4 complexes or E2f activity. Sei1-null mice were viable, did not present overt pathologies, had a normal lifespan, and had a normal susceptibility to spontaneous and chemically-induced cancer. Pancreatic insulinproducing cells are known to be particularly sensitive to Cdk4-cyclin D and E2f activities, and we have observed that Sei1 is highly expressed in pancreatic islets compared to other tissues. Interestingly, Sei1-null mice present lower number of islets, decreased β-cell area, impaired insulin secretion, and glucose intolerance. These defects were associated to nuclear accumulation of the cell-cycle inhibitors p21 Cip1 and p27Kip1 in islet cells. We conclude that Sei1 plays an important role in pancreatic β-cells, which supports a functional link between Sei1 and the core cell cycle regulators specifically in the context of the pancreas. © 2010 Fernandez-Marcos et al.

Gonzalez-Rodriguez A.,Institute of Biomedicine Alberto Sols CSIC UAM | Gonzalez-Rodriguez A.,Research Center Biomedica en Red Diabetes y Enfermedades Metabolicas Asociadas | Mas-Gutierrez J.A.,Rey Juan Carlos University | Mirasierra M.,Institute of Biomedicine Alberto Sols CSIC UAM | And 14 more authors.
Aging Cell | Year: 2012

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin signaling and a therapeutic target for type 2 diabetes (T2DM). In this study, we have evaluated the role of PTP1B in the development of aging-associated obesity, inflammation, and peripheral insulin resistance by assessing metabolic parameters at 3 and 16months in PTP1B -/- mice maintained on mixed genetic background (C57Bl/6J×129Sv/J). Whereas fat mass and adipocyte size were increased in wild-type control mice at 16months, these parameters did not change with aging in PTP1B -/- mice. Increased levels of pro-inflammatory cytokines, crown-like structures, and hypoxia-inducible factor (HIF)-1α were observed only in adipose tissue from 16-month-old wild-type mice. Similarly, islet hyperplasia and hyperinsulinemia were observed in wild-type mice with aging-associated obesity, but not in PTP1B -/- animals. Leanness in 16-month-old PTP1B -/- mice was associated with increased energy expenditure. Whole-body insulin sensitivity decreased in 16-month-old control mice; however, studies with the hyperinsulinemic-euglycemic clamp revealed that PTP1B deficiency prevented this obesity-related decreased peripheral insulin sensitivity. At a molecular level, PTP1B expression and enzymatic activity were up-regulated in liver and muscle of 16-month-old wild-type mice as were the activation of stress kinases and the expression of p53. Conversely, insulin receptor-mediated Akt/Foxo1 signaling was attenuated in these aged control mice. Collectively, these data implicate PTP1B in the development of inflammation and insulin resistance associated with obesity during aging and suggest that inhibition of this phosphatase by therapeutic strategies might protect against age-dependent T2DM. © 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

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