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

Dual role of protein tyrosine phosphatase 1B in the progression and reversion of non-alcoholic steatohepatitis

Objectives: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. Protein tyrosine phosphatase 1B (PTP1B), a negative modulator of insulin and cytokine signaling, is a therapeutic target for type 2 diabetes and obesity. We investigated the impact of PTP1B deficiency during NAFLD, particularly in non-alcoholic steatohepatitis (NASH). Methods: NASH features were evaluated in livers from wild-type (PTP1BWT) and PTP1B-deficient (PTP1BKO) mice fed methionine/cholinedeficient diet (MCD) for 8 weeks. A recovery model was established by replacing MCD to chow diet (CHD) for 2e7 days. Non-parenchymal liver cells (NPCs) were analyzed by flow cytometry. Oval cells markers were measured in human and mouse livers with NASH, and in oval cells from PTP1BWT and PTP1BKO mice. Results: PTP1BWT mice fed MCD for 8 weeks exhibited NASH, NPCs infiltration, and elevated Fgf21, Il6 and Il1b mRNAs. These parameters decreased after switching to CHD. PTP1B deficiency accelerated MCD-induced NASH. Conversely, after switching to CHD, PTP1BKO mice rapidly reverted NASH compared to PTP1BWT mice in parallel to the normalization of serum triglycerides (TG) levels. Among NPCs, a drop in cytotoxic natural killer T (NKT) subpopulation was detected in PTP1BKO livers during recovery, and in these conditions M2 macrophage markers were upregulated. Oval cells markers (EpCAM and cytokeratin 19) significantly increased during NASH only in PTP1B-deficient livers. HGF-mediated signaling and proliferative capacity were enhanced in PTP1BKO oval cells. In NASH patients, oval cells markers were also elevated. Conclusions: PTP1B elicits a dual role in NASH progression and reversion. Additionally, our results support a new role for PTP1B in oval cell proliferation during NAFLD