Liver injury in non-alcoholic fatty liver disease is associated with urea cycle enzyme dysregulation

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.The research leading to these results has received funding from the Consejería de Salud de la Junta de Andalucía under grant agreement PC-0148-2016-0148 and PE-0451-2018 and Instituto de Salud Carlos III under grant agreements CD21/00095, PI16/01842, PI19/01404, PI19/00589, IFI18/00041, FI20/00201, CD18/00126 and EHD18PI04/2021. Rocío Gallego-Durán has received the Andrew K Burroughs Fellowship from European Association for the Study of the Liver (EASL), Aprendizaje de Nuevas Tecnologías fellowship from Asociación Española para el Estudio del Hígado (AEEH) and CIBERehd Grant to support researcher’s mobility

Role of age and comorbidities in mortality of patients with infective endocarditis

[Purpose]: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. [Methods]: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015.Patients were stratified into three age groups:<65 years,65 to 80 years,and ≥ 80 years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk. [Results]: A total of 3120 patients with IE (1327 < 65 years;1291 65-80 years;502 ≥ 80 years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients ≥80 years who underwent surgery were significantly lower compared with other age groups (14.3%,65 years; 20.5%,65-79 years; 31.3%,≥80 years). In-hospital mortality was lower in the <65-year group (20.3%,<65 years;30.1%,65-79 years;34.7%,≥80 years;p < 0.001) as well as 1-year mortality (3.2%, <65 years; 5.5%, 65-80 years;7.6%,≥80 years; p = 0.003).Independent predictors of mortality were age ≥ 80 years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32–3.34), CCI ≥ 3 (HR:1.62; 95% CI:1.39–1.88),and non-performed surgery (HR:1.64;95% CI:11.16–1.58).When the three age groups were compared,the AUROC curve for CCI was significantly larger for patients aged <65 years(p < 0.001) for both in-hospital and 1-year mortality. [Conclusion]: There were no differences in the clinical presentation of IE between the groups. Age ≥ 80 years, high comorbidity (measured by CCI),and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group

Estudio del efecto de dietas hiperlipídicas basadas en aceite de oliva virgen extra sobre el tejido adiposo, y su implicación en la aterosclerosis en el modelo LDLR-/-.Leiden

Programa de Doctorado en Biotecnología, Ingeniería y Tecnología QuímicaLínea de Investigación: Patología NutricionalClave Programa: DBICódigo Línea: 25La obesidad se considera uno de los principales problemas de salud a nivel mundial, cuya prevalencia se ha triplicado en los últimos 40 años según la Organización Mundial de la Salud (2017). Entre las consecuencias comunes del sobrepeso y la obesidad, se encuentra la aterosclerosis, una enfermedad cardiovascular que afecta al corazón y las arterias, y que representa la principal causa de morbimortalidad en los países desarrollados. Empleando el modelo murino de hipercolesterolemia familiar, Ldlr-/-.Leiden, analizamos los procesos inflamatorios relacionados con el aumento del tejido adiposo en la obesidad, que parecen subyacer a los mecanismos responsables de las complicaciones cardiovasculares que se producen en la aterosclerosis. A su vez, quisimos evaluar el efecto de las dietas hiperlipídicas basadas en aceite de oliva virgen extra (AOVE), con diferentes concentraciones de compuestos fenólicos (concentración estándar, EVOO, y rico en estos compuestos, OL), sobre la hipertrofia e inflamación del tejido adiposo visceral, así como sobre la disfunción endotelial, inflamación y estrés oxidativo en el tejido aórtico. Nuestros resultados mostraron que el consumo de AOVE EVOO, con una concentración menor de compuestos fenólicos, mejoró el estado inflamatorio y de estrés oxidativo en el tejido adiposo, y correlativamente, previno el avance de la aterosclerosis por la mayor inducción de la expresión de adiponectina anti-inflamatoria, y reducción de la disfunción endotelial. En cambio, el AOVE OL, aunque atenuó la hipertrofia del tejido adiposo, no mostró los mismos efectos ateroprotectores.Universidad Pablo de Olavide de Sevilla. Departamento de Biología Molecular e Ingeniería BioquímicaPostprin

Extra‐virgin olive oil with Natural phenolic content exerts an anti‐inflammatory effect in adipose tissue and attenuates the severity of atherosclerotic lesions in Ldlr−/−.Leiden Mice

[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.This work was supported by the Ministerio de Economía ́ıa y Competitividad (grant number AGL2014-5458-R) and Junta de Andalucía ́ıa (PAI-BIO311)Peer reviewe

Contribution of Liver and Pancreatic Islet Crosstalk to β-Cell Function/Dysfunction in the Presence of Fatty Liver

Tissue-to-tissue crosstalk regulates organ function, according to growing data. This phenomenon is relevant for pancreatic b-cells and the liver, as both tissues are involved in glucose homeostasis and lipid metabolism. The ability to fine-tune regulation and adaptive responses is enabled through communication between pancreatic b-cells and the liver. However, the crosstalk between both tissues changes when metabolic dysregulation is present. Factors and cargo from extracellular vesicles (EVs) released by liver and pancreatic b-cells that reach the circulation form the words of this interaction. The molecules released by the liver are called hepatokines and are usually secreted in response to the metabolic state. When hepatokines reach the pancreatic islets several mechanisms are initiated for their protection or damage. In the case of the crosstalk between pancreatic b-cells and the liver, only one factor has been found to date. This protein, pancreatic derived factor (PANDER) has been proposed as a novel linker between insulin resistance (IR) and type 2 diabetes mellitus (T2D) and could be considered a biomarker for non-alcoholic fatty liver disease (NAFLD) and T2D. Furthermore, the cargo released by EVs, mainly miRNAs, plays a significant role in this crosstalk. A better knowledge of the crosstalk between liver and pancreatic b-cells is essential to understand both diseases and it could lead to better prevention and new therapeutic options.Ministerio de Ciencia e InnovaciónJunta de Andalucí

White button mushroom extracts modulate hepatic fibrosis progression, inflammation, and oxidative stress in vitro and in ldlr-/-mice

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.This research was funded by the Junta de Andalucía (PAI-BIO311) and Ministerio de Economía y Competitividad (AGL2017-86927-R) to F.M. A.L.-S. was supported by Junta de Andalucía (PAI-BIO311); Instituto de Salud Carlos III (PI14/01349) integrated in the national I+D+i 2013-2016 and co-funded by European Union (ERDF/ESF, “Investing in your future”). J.A.D.C. is supported by Nicolás Monardes Program from Servicio Andaluz de Salud (SAS)

Maternal high fat diets based on olive oil protect offspring against nafld features through epigenetic alterations

Trabajo presentado en el ESPEN 2021 Virtual Congress on Clinical nutrition & Metabolism, celebrado online, del 9 al 14 de septiembre de 2021Dietary 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

Contribution of Liver and Pancreatic Islet Crosstalk to β-Cell Function/Dysfunction in the Presence of Fatty Liver

Tissue-to-tissue crosstalk regulates organ function, according to growing data. This phenomenon is relevant for pancreatic β-cells and the liver, as both tissues are involved in glucose homeostasis and lipid metabolism. The ability to fine-tune regulation and adaptive responses is enabled through communication between pancreatic β-cells and the liver. However, the crosstalk between both tissues changes when metabolic dysregulation is present. Factors and cargo from extracellular vesicles (EVs) released by liver and pancreatic β-cells that reach the circulation form the words of this interaction. The molecules released by the liver are called hepatokines and are usually secreted in response to the metabolic state. When hepatokines reach the pancreatic islets several mechanisms are initiated for their protection or damage. In the case of the crosstalk between pancreatic β-cells and the liver, only one factor has been found to date. This protein, pancreatic derived factor (PANDER) has been proposed as a novel linker between insulin resistance (IR) and type 2 diabetes mellitus (T2D) and could be considered a biomarker for non-alcoholic fatty liver disease (NAFLD) and T2D. Furthermore, the cargo released by EVs, mainly miRNAs, plays a significant role in this crosstalk. A better knowledge of the crosstalk between liver and pancreatic β-cells is essential to understand both diseases and it could lead to better prevention and new therapeutic options.Funding from the following sources was used for this manuscript: AGL2017-86927-R and PID2020-116731RB-C21 from Ministerio de Ciencia e Innovación to FM and PC-0148- 2016-0148 from Junta de Andalucı́a to FM and RG-D

White Button Mushroom Extracts Modulate Hepatic Fibrosis Progression, Inflammation, and Oxidative Stress In Vitro and in LDLR-/- Mice

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.España Junta de Andalucía (PAI-BIO311)España, Ministerio de Economía y Competitividad (AGL2017-86927-R)España, Instituto de Salud Carlos III (PI14/01349

Extra virgin olive oil improved body weight and insulin sensitivity in high fat diet-induced obese LDLr−/−.Leiden mice without attenuation of steatohepatitis

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