Ptpn1 deletion protects oval vells against lipoapotosis by favoring lipid droplet formation and dynamics

Trabajo presentado en el The international liver congress, celebrado en Londres (Inglaterra) del 22 al 26 de junio de 2022.[Background and aims]: Activation of oval cells has been related to hepatocyte injury during chronic liver diseases including nonalcoholic fatty liver disease (NAFLD). However, oval cells plasticity can be affected by the pathological environment. We previously found a protection against hepatocyte cell death by inhibiting protein tyrosine phosphatase 1B (PTP1B). Herein, we investigated the molecular and cellular processes involved in the lipotoxic susceptibility in oval cells expressing or not PTP1B. [Method]: Palmitic acid (PA) induced apoptotic cell death in wild-type (Ptpn1+/+) oval cells in parallel to oxidative stress and impaired autophagy. This lipotoxic effect was attenuated in oval cells lacking Ptpn1 that showed up-regulated antioxidant defences, increased unfolded protein response (UPR) signaling, higher endoplasmic reticulum (ER) content and elevated stearoyl CoA desaturase (Scd1) expression and activity. [Results]: These effects in Ptpn1−/− oval cells concurred with an active autophagy, higher mitochondrial efficiency and a molecular signature of starvation, favoring lipid droplet (LD) formation and dynamics. Autophagy blockade in Ptpn1−/− oval cells reduced Scd1 expression, mitochondrial fitness, LD formation and restored lipoapoptosis, an effect also recapitulated by Scd1 silencing. Importantly, oval cells with LDs were found in livers from Ptpn1−/− mice with NAFLD. [Conclusion]: Ptpn1 deficiency restrained lipoapoptosis in oval cells through a metabolic rewiring towards a “starvation-like” fate, favoring autophagy, mitochondrial fitness and LD formation. Dynamic LD-lysosomal interations likely ensured lipid recycling and, overall, these adaptations protect against lipotoxicity. The identification of LDs in oval cells from Ptpn1−/− mice with NAFLD opens new therapeutic perspectives to ensure oval cells viability and plasticity under lipotoxic liver damage

El catálogo colectivo de REBIUN: situación actual y ejes de desarrollo

Se trata de un póster presentado en las XIV Jornadas Españolas de Documentación, Fesabid'15, celebradas en Gijón los días 28, 29 y 30 de mayo de 2015, bajo el lema Cultura abierta: conocimiento compartido.[ES] Se presenta la evolución desde su nacimiento del catálogo colectivo de REBIUN, Red de Bibliotecas Universitarias y Científicas de España, y se plantean los nuevos retos y desarrollo futuro para que siga siendo una herramienta útil para las instituciones que lo forman y también para los usuarios finales.N

La filosofía entre el bachillerato y la universidad: Perspectivas docentes para la educación en el siglo XXI

Depto. de Lógica y Filosofía TeóricaGrupo de Investigación "Metafísica, Crítica y Política"Fac. de FilosofíaFALSEsubmitte

Estudios bioquímicos, biofísicos y celulares de la estructura del tallo ribosómico de Saccharomyces cerevisiae

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 22-03-200

Convenio Marco con la Fundación Fraunhofer Chile Research, Chile.

El presente convenio tiene por objeto establecer y desarrollar relaciones de cooperación internacional con el fin de efectuar programas de investigación y desarrollo en apoyo de proyectos conjuntos en la medida de las posibilidades de cada Parte y para beneficio mutuo

Efectos del AL sobre la función mitocondrial y el estrés oxidativo en la NAFLD asociada a obesidad

Non-alcoholic steatosis is an important hepatic complication of obesity linked to mitochondrial dysfunction and oxidative stress. In this context, the sirtuin family has been demonstrated to play an important role in the regulation of mitochondrial function and in the activation of antioxidant dfenses. Lipoic acid (LA) has been reported to have beneficial effects on mitochondrial function and to attenuate oxidative stress. In this thesis, the potential protective effect of LA supplementation against the development of non-alcoholic steatosis associated with a long-term high-fat diet feeding and the potential mechanisms involved in these effects were analyzed. Particularly, I researched the effects of LA on the modulation of mitochondrial defenses through the situin pathway. To achieved these objectives, male Wistar rats were fed a standard diet (C, n=10) and a high-fat diet supplemented with LA (OLIP, n=10). A group pair-fed to the latter group (PFO, n=6) was also included. LA prevents hepatic triglyceride accumulation and liver damage in rats fed on a high-fat diet, through the modulation of genes involved in lipogenesis and mitochondrial β-oxidation, and by improving insulin sensitivity. Moreover, this molecule showed an inhibitory action on electron transport chain complexes activities and ATP synthesis, and reduced significantly energy efficiency. By contrast, LA induces an increase in mitochondrial copy number and in Ucp2 gene expression. Moreover, LA prevents liver oxidative damage through the inhibition of hydroperoxide production and the simulation of mitochondrial antioxidant defenses. LA treatment up-regulated manganese superoxide dismutase and glutathione peroxidase activities, and increased the GSH: GSSG ratio and UCP2 mRNA levels. Moreover, this molecule reduced oxidative damage in mitochondrial DNA and increased mitochondrial copy number. LA treatment decreased the acetylation levels of Foxo3a and PGC1β through the stimulation of SIRT3 and SIRT1. In summary, our results demonstrate that the beneficial effects of LA supplementation on hepatic steatosis coud be mediated by its ability to restore the oxidative balance by increasing antioxidant defenses through the deacetylation of Foxo3a and PGC1β by SIRT1 and SIRT3. Finally, the novelty and importance of this study is the finding of how lipoic acid modulates some of the mitochondrial processes involved in energy homeostasis. The reduction in mitochondrial energy efficiency could also explain, at least in part, the beneficial effects of lipoic acid not only in fatty liver but also in preventing excessive body weight gain

Efectos del AL sobre la función mitocondrial y el estrés oxidativo en la NAFLD asociada a obesidad

Non-alcoholic steatosis is an important hepatic complication of obesity linked to mitochondrial dysfunction and oxidative stress. In this context, the sirtuin family has been demonstrated to play an important role in the regulation of mitochondrial function and in the activation of antioxidant dfenses. Lipoic acid (LA) has been reported to have beneficial effects on mitochondrial function and to attenuate oxidative stress. In this thesis, the potential protective effect of LA supplementation against the development of non-alcoholic steatosis associated with a long-term high-fat diet feeding and the potential mechanisms involved in these effects were analyzed. Particularly, I researched the effects of LA on the modulation of mitochondrial defenses through the situin pathway. To achieved these objectives, male Wistar rats were fed a standard diet (C, n=10) and a high-fat diet supplemented with LA (OLIP, n=10). A group pair-fed to the latter group (PFO, n=6) was also included. LA prevents hepatic triglyceride accumulation and liver damage in rats fed on a high-fat diet, through the modulation of genes involved in lipogenesis and mitochondrial β-oxidation, and by improving insulin sensitivity. Moreover, this molecule showed an inhibitory action on electron transport chain complexes activities and ATP synthesis, and reduced significantly energy efficiency. By contrast, LA induces an increase in mitochondrial copy number and in Ucp2 gene expression. Moreover, LA prevents liver oxidative damage through the inhibition of hydroperoxide production and the simulation of mitochondrial antioxidant defenses. LA treatment up-regulated manganese superoxide dismutase and glutathione peroxidase activities, and increased the GSH: GSSG ratio and UCP2 mRNA levels. Moreover, this molecule reduced oxidative damage in mitochondrial DNA and increased mitochondrial copy number. LA treatment decreased the acetylation levels of Foxo3a and PGC1β through the stimulation of SIRT3 and SIRT1. In summary, our results demonstrate that the beneficial effects of LA supplementation on hepatic steatosis coud be mediated by its ability to restore the oxidative balance by increasing antioxidant defenses through the deacetylation of Foxo3a and PGC1β by SIRT1 and SIRT3. Finally, the novelty and importance of this study is the finding of how lipoic acid modulates some of the mitochondrial processes involved in energy homeostasis. The reduction in mitochondrial energy efficiency could also explain, at least in part, the beneficial effects of lipoic acid not only in fatty liver but also in preventing excessive body weight gain

Lipoic acid improves mitochondrial function in nonalcoholic steatosis through the stimulation of sirtuin 1 and sirtuin 3

Nonalcoholic steatosis is an important hepatic complication of obesity linked to mitochondrial dysfunction and oxidative stress. Lipoic acid (LA) has been reported to have beneficial effects on mitochondrial function and to attenuate oxidative stress. The sirtuin (SIRT) family has been demonstrated to play an important role in the regulation of mitochondrial function and in the activation of antioxidant defenses. In this study, we analyzed the potential protective effect of LA supplementation, via the modulation of mitochondrial defenses through the SIRT pathway, against oxidative stress associated with high-fat feeding. Wistar rats were fed a standard diet (control group (C), n = 10), a high-fat diet (obese group (OB), n = 10) and a high-fat diet supplemented with LA (OLIP, n = 10). A group pair-fed to the latter group (pair-fed OLIP group (PFO), n = 6) was also included. LA prevented hepatic triglyceride (TG) accumulation (68.2%) and liver oxidative damage (P < 0.01) through the inhibition of hydroperoxide (H 2 O 2 ) production (P < 0.001) and the stimulation of mitochondrial antioxidant defenses. LA treatment upregulated manganese superoxide dismutase (SOD2) (60.6%) and glutathione peroxidase (GPx) (100.2%) activities, and increased the reduced glutathione (GSH): oxidized glutathione (GSSG) ratio and UCP2 mRNA levels (P < 0.001-P < 0.01). Moreover, this molecule reduced oxidative damage in mitochondrial DNA (mtDNA) and increased mitochondrial copy number (P < 0.001- P < 0.01). LA treatment decreased the acetylation levels of Forkhead transcription factor 3a (Foxo3a) and PGC1 (P < 0.001- P < 0.01) through the stimulation of SIRT3 and SIRT1 (P < 0.001). In summary, our results demonstrate that the beneficial effects of LA supplementation on hepatic steatosis could be mediated by its ability to restore the oxidative balance by increasing antioxidant defenses through the deacetylation of Foxo3a and PGC1 by SIRT1 and SIRT3