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The main aim was to evaluate changes in urea cycle enzymes in NAFLD patients and in two preclinical animal models mimicking this entity. Seventeen liver specimens from NAFLD patients were included for immunohistochemistry and gene expression analyses. Three-hundred-and-eighty-two biopsy-proven NAFLD patients were genotyped for rs1047891, a functional variant located in carbamoyl phosphate synthetase-1 (CPS1) gene. Two preclinical models were employed to analyse CPS1 by immunohistochemistry, a choline deficient high-fat diet model (CDA-HFD) and a high fat diet LDLr knockout model (LDLr −/−). A significant downregulation in mRNA was observed in CPS1 and ornithine transcarbamylase (OTC1) in simple steatosis and NASH-fibrosis patients versus controls. Further, age, obesity (BMI > 30 kg/m), diabetes mellitus and ALT werefound to be risk factors whereas A-allele from CPS1 was a protective factor from liver fibrosis. CPS1 hepatic expression was diminished in parallel with the increase of fibrosis, and its levels reverted up to normality after changing diet in CDA-HFD mice. In conclusion, liver fibrosis and steatosis were associated with a reduction in both gene and protein expression patterns of mitochondrial urea cycle enzymes. A-allele from a variant on CPS1 may protect from fibrosis development. CPS1 expression is restored in a preclinical model when the main trigger of the liver damage disappears.

Dietary fatty acids play a role in the pathogenesis of obesity-associated non-alcoholic fatty liver disease (NAFLD), which is associated with insulin resistance (IR). Fatty acid composition is critical for IR and subsequent NAFLD development. Extra-virgin olive oil (EVOO) is the main source of monounsaturated fatty acids (MUFA) in Mediterranean diets. This study examined whether EVOO containing high fat diets may prevent diet-induced NAFLD using Ldlr−/−. Leiden mice. In female Ldlr−/−.Leiden mice, the efects of the following high fat diets (HFDs) were examined: a lard-based HFD (HFD-L); an EVOO-based HFD (HFD-EVOO); a phenolic compounds-rich EVOO HFD (HFD-OL). We studied changes in body weight (BW), lipid profle, transaminases, glucose homeostasis, liver pathology and transcriptome. Both EVOO diets reduced body weight (BW) and improved insulin sensitivity. The EVOOs did not improve transaminase values and increased LDL-cholesterol and liver collagen content. EVOOs and HFD-L groups had comparable liver steatosis. The profbrotic efects were substantiated by an up-regulation of gene transcripts related to glutathione metabolism, chemokine signaling and NF-kappa-B activation and down-regulation of genes relevant for fatty acid metabolism. Collectivelly, EVOO intake improved weight gain and insulin sensitivity but not liver infammation and fbrosis, which was supported by changes in hepatic genes expression.

Liver fibrosis can be caused by non-alcoholic steatohepatitis (NASH), among other conditions. We performed a study to analyze the effects of a nontoxic, water-soluble extract of the edible mushroom Agaricus bisporus (AB) as a potential inhibitor of fibrosis progression in vitro using human hepatic stellate cell (LX2) cultures and in vivo in LDLR-/- mice. Treatment of LX2 cells with the AB extract reduced the levels of fibrotic and oxidative-related markers and increased the levels of GATA4 expression. In LDLR-/- mice with high-fat diet (HFD)-induced liver fibrosis and inflammation, the progression of fibrosis, oxidative stress, inflammation, and apoptosis were prevented by AB extract treatment. Moreover, in the mouse model, AB extract could exert an antiatherogenic effect. These data suggest that AB mushroom extract seems to exert protective effects by alleviating inflammation and oxidative stress during the progression of liver fibrosis, possibly due to a decrease in Toll-like receptor 4 (TLR4) expression and a reduction in Nod-like receptor protein 3 (NLRP3) inflammasome activation. In addition, we observed a potential atheroprotective effect in our mouse model.

Dietary fatty acids intake and their composition play a role in nonalcoholic fatty liver disease (NAFLD) pathogenesis, being the main hepatic manifestation of metabolic syndrome. Maternal obesogenic diet exposure contributes to offspring's NAFLD susceptibility. We examined if a maternal high fat diet (HFD) based on extra virgin olive oil (EVOO), rich in monounsaturated fatty acids and poliphenols, reduces the risk of offspring NAFLD through epigenetic microRNA (miR) changes.

Liver fibrosis can be caused by non-alcoholic steatohepatitis (NASH), among other condi-tions. We performed a study to analyze the effects of a nontoxic, water-soluble extract of the edible mushroom Agaricus bisporus (AB) as a potential inhibitor of fibrosis progression in vitro using human hepatic stellate cell (LX2) cultures and in vivo in LDLR-/-mice. Treatment of LX2 cells with the AB extract reduced the levels of fibrotic and oxidative-related markers and increased the levels of GATA4 expression. In LDLR-/-mice with high-fat diet (HFD)-induced liver fibrosis and inflammation, the progression of fibrosis, oxidative stress, inflammation, and apoptosis were prevented by AB extract treatment. Moreover, in the mouse model, AB extract could exert an antiatherogenic effect. These data suggest that AB mushroom extract seems to exert protective effects by alleviating inflammation and oxidative stress during the progression of liver fibrosis, possibly due to a decrease in Toll-like receptor 4 (TLR4) expression and a reduction in Nod-like receptor protein 3 (NLRP3) inflammasome activation. In addition, we observed a potential atheroprotective effect in our mouse model.

Dietary fatty acids play a role in the pathogenesis of obesity-associated non-alcoholic fatty liver disease (NAFLD), which is associated with insulin resistance (IR). Fatty acid composition is critical for IR and subsequent NAFLD development. Extra-virgin olive oil (EVOO) is the main source of monounsaturated fatty acids (MUFA) in Mediterranean diets. This study examined whether EVOO-containing high fat diets may prevent diet-induced NAFLD using Ldlr−/−. Leiden mice. In female Ldlr−/−.Leiden mice, the effects of the following high fat diets (HFDs) were examined: a lard-based HFD (HFD-L); an EVOO-based HFD (HFD-EVOO); a phenolic compounds-rich EVOO HFD (HFD-OL). We studied changes in body weight (BW), lipid profile, transaminases, glucose homeostasis, liver pathology and transcriptome. Both EVOO diets reduced body weight (BW) and improved insulin sensitivity. The EVOOs did not improve transaminase values and increased LDL-cholesterol and liver collagen content. EVOOs and HFD-L groups had comparable liver steatosis. The profibrotic effects were substantiated by an up-regulation of gene transcripts related to glutathione metabolism, chemokine signaling and NF-kappa-B activation and down-regulation of genes relevant for fatty acid metabolism. Collectivelly, EVOO intake improved weight gain and insulin sensitivity but not liver inflammation and fibrosis, which was supported by changes in hepatic genes expression.

[Scope] The present study investigates the effect of olive oils with different phenolic content in high‐fat diets (HFDs) on hypertrophy and inflammation in adipose tissue and associated atherosclerosis, in the context of obesity., [Methods and results] Ldlr−/−.Leiden mice were fed three different HFDs for 32 weeks and were compared with mice fed the standard low‐fat diet (LFD). The different fats provided in the HFDs were lard (HFD‐L), extra‐virgin olive oil (EVOO; 79 mg kg–1 of phenolic compounds, HFD‐EVOO), or EVOO rich in phenolic compounds (OL, 444 mg kg–1 of phenolic compounds, HFD‐OL). All HFD‐fed mice became obese, but only HFD‐L–induced adipocyte hypertrophy. HFD‐EVOO mice exhibited the greatest levels of Adiponectin in adipose tissue and presented atherosclerotic lesions similar to the LFD group, with a very low count of monocyte/macrophage compared with HFD‐L and HFD‐OL mice. Enrichment of the phenolic content of olive oil reduced the secretion of nitrites/nitrates in the aorta, but atherosclerosis was not attenuated in HFD‐OL mice compared to other HFD mice., [Conclusion] Consumption of olive oil with a natural content of phenolic compounds attenuates adipose tissue hypertrophy and inflammation and exerts antiatherosclerotic effects in mice. A higher phenolic content of olive oil did not provide further benefits in the prevention of atherosclerosis.

Desde su concepción las IPC tuvieron como objetivo principal, la atención de las demandas sociales en la provisión de la infraestructura pública y la prestación de servicios públicos mediante una colaboración o asociación público – privado. El Estado soportaría al privado en la financiación de aquellos proyectos de alta rentabilidad social pero escasa o nula rentabilidad económica. No obstante, los altos costos de transacción y demoras que involucra la tramitación de las IPC, ha generado grandes cuestionamientos sobre la idoneidad de la herramienta, más aún si habiendo transcurrido más de 5 años desde su creación formal, hasta el momento no hay ejemplos de proyectos adjudicados mediante IPC. El presente trabajo de investigación analiza las posibles causas de los problemas e inconvenientes que enfrenta las IPC, así como las fortalezas y oportunidades que dispone para lograr su objetivo de reducción de brechas de infraestructura y servicios públicos, Tesis

Desde su concepción las IPC tuvieron como objetivo principal, la atención de las demandas sociales en la provisión de la infraestructura pública y la prestación de servicios públicos mediante una colaboración o asociación público – privado. El Estado soportaría al privado en la financiación de aquellos proyectos de alta rentabilidad social pero escasa o nula rentabilidad económica. No obstante, los altos costos de transacción y demoras que involucra la tramitación de las IPC, ha generado grandes cuestionamientos sobre la idoneidad de la herramienta, más aún si habiendo transcurrido más de 5 años desde su creación formal, hasta el momento no hay ejemplos de proyectos adjudicados mediante IPC. El presente trabajo de investigación analiza las posibles causas de los problemas e inconvenientes que enfrenta las IPC, así como las fortalezas y oportunidades que dispone para lograr su objetivo de reducción de brechas de infraestructura y servicios públicos, Tesis

Desde su concepción las IPC tuvieron como objetivo principal, la atención de las demandas sociales en la provisión de la infraestructura pública y la prestación de servicios públicos mediante una colaboración o asociación público – privado. El Estado soportaría al privado en la financiación de aquellos proyectos de alta rentabilidad social pero escasa o nula rentabilidad económica. No obstante, los altos costos de transacción y demoras que involucra la tramitación de las IPC, ha generado grandes cuestionamientos sobre la idoneidad de la herramienta, más aún si habiendo transcurrido más de 5 años desde su creación formal, hasta el momento no hay ejemplos de proyectos adjudicados mediante IPC. El presente trabajo de investigación analiza las posibles causas de los problemas e inconvenientes que enfrenta las IPC, así como las fortalezas y oportunidades que dispone para lograr su objetivo de reducción de brechas de infraestructura y servicios públicos, Tesis