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INTRODUCTION: non-alcoholic fatty liver disease is one of the most prevalent liver disorders in the developed world. Currently, there is no approved pharmacological therapy except for lifestyle intervention. Therefore, there is a need to increase the knowledge of preclinical models in order to boost novel discoveries that could lead to a better therapeutic management. MATERIAL AND METHODS: this study characterized the effects of two different diets, a long-term high-fat high-fructose diet (HF-HFD) and a choline-deficient, methionine supplemented high-fat diet (CDA-HFD) in C57BL/6J mice for 52 weeks or 16 weeks, respectively. Body weight, lipid and hepatic profile were analyzed and liver histology was subsequently evaluated. RESULTS: HF-HFD animals had an increased body weight and total cholesterol levels, whereas the opposite occurred in CDA-HFD. Both HF-HFD and CDA-HFD animals had higher ALT and AST levels. With regard to histology findings, HF-HFD and CDA-HFD diets induced an increased collagen deposit and intrahepatic steatosis accumulation. CONCLUSION: in conclusion, the comparison of these models aided in the selection of a long-term, more physiological model for physiopathology studies or a more rapid NASH model for novel molecule testing.
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Colina , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Fructosa/administración & dosificación , Metionina/administración & dosificación , Enfermedad del Hígado Graso no Alcohólico/etiología , Edulcorantes/administración & dosificación , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Peso Corporal , Colesterol/sangre , Hígado/enzimología , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/patología , Distribución AleatoriaRESUMEN
AIM: We aimed to assess the role of FGF21 in metabolic dysfunction-associated steatotic liver disease (MASLD) at a multi-scale level. METHODS: We used human MASLD pathology samples for FGF21 gene expression analyses (qPCR and RNAseq), serum to measure circulating FGF21 levels and DNA for genotyping the FGF21 rs838133 variant in both estimation and validation cohorts. A hepatocyte-derived cell line was exposed to free fatty acids at different timepoints. Finally, C57BL/6J mice were fed a high-fat and choline-deficient diet (CDA-HFD) for 16 weeks to assess hepatic FGF21 protein expression and FGF21 levels by ELISA. RESULTS: A significant upregulation in FGF21 mRNA expression was observed in the liver analysed by both qPCR (fold change 5.32 ± 5.25 vs. 0.59 ± 0.66; p = 0.017) and RNA-Seq (3.5 fold; FDR: 0.006; p < 0.0001) in MASLD patients vs. controls. Circulating levels of FGF21 were increased in patients with steatohepatitis vs. bland steatosis (386.6 ± 328.9 vs. 297.9 ± 231.5 pg/mL; p = 0.009). Besides, sex, age, A-allele from FGF21, GG genotype from PNPLA3, ALT, type 2 diabetes mellitus and BMI were independently associated with MASH and significant fibrosis in both estimation and validation cohorts. In vitro exposure of Huh7.5 cells to high concentrations of free fatty acids (FFAs) resulted in overexpression of FGF21 (p < 0.001). Finally, Circulating FGF21 levels and hepatic FGF21 expression were found to be significantly increased (p < 0.001) in animals under CDA-HFD. CONCLUSIONS: Hepatic and circulating FGF21 expression was increased in MASH patients, in Huh7.5 cells under FFAs and in CDA-HFD animals. The A-allele from the rs838133 variant was also associated with an increased risk of steatohepatitis and significant and advanced fibrosis in MASLD patients.
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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/m2), diabetes mellitus and ALT were found 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.
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Enfermedad del Hígado Graso no Alcohólico , Animales , Carbamoil-Fosfato Sintasa (Amoniaco)/genética , Carbamoil-Fosfato Sintasa (Amoniaco)/metabolismo , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Humanos , Hígado/metabolismo , Cirrosis Hepática/patología , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Urea/metabolismoRESUMEN
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.
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Peso Corporal/efectos de los fármacos , Resistencia a la Insulina , Obesidad/dietoterapia , Aceite de Oliva/farmacología , Receptores de LDL/genética , Animales , Dieta Alta en Grasa , Dieta Mediterránea , Femenino , Resistencia a la Insulina/fisiología , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratones , Ratones Noqueados , Ratones Obesos , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/genética , Obesidad/complicaciones , Obesidad/genética , Obesidad/metabolismoRESUMEN
Dietary composition plays an important role in the pathophysiology of type 2 diabetes. Monounsaturated fatty acid consumption has been positively associated with improved insulin sensitivity and ß-cell function. We examined whether an extra virgin olive oil (EVOO) high fat diet (HFD) can improve glucose homeostasis. C57BL/6J mice were fed a standard diet or a lard-based HFD to induce type 2 diabetes. Then, HFD mice were fed with three different based HFD (lard, EVOO and EVOO rich in phenolic compounds) for 24 weeks. HFD-EVOO diets significantly improved glycemia, insulinemia, glucose tolerance, insulin sensitivity and insulin degradation. Moreover, EVOO diets reduced ß-cell apoptosis, increased ß-cell number and normalized islet glucose metabolism and glucose induced insulin secretion. No additional effects were observed by higher levels of phenolic compounds. Thus, EVOO intake regulated glucose homeostasis by improving insulin sensitivity and pancreatic ß-cell function, in a type 2 diabetes HFD animal model.
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Diabetes Mellitus Tipo 2/dietoterapia , Dieta Alta en Grasa/métodos , Resistencia a la Insulina , Células Secretoras de Insulina/metabolismo , Aceite de Oliva/uso terapéutico , Animales , Glucemia/metabolismo , Células Cultivadas , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animales de Enfermedad , Glucosa/metabolismo , Insulina/metabolismo , Secreción de Insulina , Masculino , Ratones Endogámicos C57BLRESUMEN
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.
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Tejido Adiposo Blanco/efectos de los fármacos , Antiinflamatorios/farmacología , Aterosclerosis/prevención & control , Aceite de Oliva/farmacología , Fenoles/análisis , Receptores de LDL/fisiología , Adipocitos/fisiología , Tejido Adiposo Blanco/patología , Animales , Antioxidantes/farmacología , Dieta Alta en Grasa , Femenino , Mediadores de Inflamación/análisis , Ratones , Óxido Nítrico Sintasa de Tipo II/fisiología , Aceite de Oliva/análisisRESUMEN
INTRODUCTION: It has been found that the olfactorygustatory function is altered in patients with eating disorders, with an impairment affecting the perception of olfactory and gustatory stimuli. OBJECTIVE: The aim was to explore the subjective reactivity after the exposure and tasting of foods with different gradient of sweetness and different fats textures. In addition, changes in the thought-shape fusion (TSF) cognitive distortion were assessed after tasting those different presentations as well as the correlations between the initial scores on TSF-Questionnaire (TSF-Q) and the different responses after that tasting. METHOD: A total of 15 healthy controls and 23 outpatients with anorexia nervosa underwent two sessions of tasting (sweets with different gradient of sweetness and fats with different textures) and they filled several questionnaires (pre- and post-tasting) to measure their responses after tasting. RESULTS: Participants showed less "self-control" after tasting sweets. The score on TSF-Q increased significantly after the sweets tasting in the patients group. Patients had the worst response after tasting presentations with more quantity of glucose (less gradient of sweetness) than after tasting those with more amount of sucrose (much more sweetness). With respect to the fats, patients showed the worst reaction after tasting the most unfamiliar texture. Pre fats tasting TSF-Q scores correlated significantly with all responses in the patients group. DISCUSSION: Both psychological and biological (e.g. genetic) factors could be involved in the reactions of patients with anorexia nervosa after tasting sweets and fats.
Introduction: It has been found that the olfactorygustatory function is altered in patients with eating disorders, with an impairment affecting the perception of olfactory and gustatory stimuli. Objective: The aim was to explore the subjective reactivity after the exposure and tasting of foods with different gradient of sweetness and different fats textures. In addition, changes in the thought-shape fusion (TSF) cognitive distortion were assessed after tasting those different presentations as well as the correlations between the initial scores on TSF-Questionnaire (TSF-Q) and the different responses after that tasting. Method: A total of 15 healthy controls and 23 outpatients with anorexia nervosa underwent two sessions of tasting (sweets with different gradient of sweetness and fats with different textures) and they filled several questionnaires (pre- and post-tasting) to measure their responses after tasting. Results: Participants showed less "self-control" after tasting sweets. The score on TSF-Q increased significantly after the sweets tasting in the patients group. Patients had the worst response after tasting presentations with more quantity of glucose (less gradient of sweetness) than after tasting those with more amount of sucrose (much more sweetness). With respect to the fats, patients showed the worst reaction after tasting the most unfamiliar texture. Pre fats tasting TSF-Q scores correlated significantly with all responses in the patients group. Discussion: Both psychological and biological (e.g. genetic) factors could be involved in the reactions of patients with anorexia nervosa after tasting sweets and fats.
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Anorexia Nerviosa/psicología , Cognición , Grasas de la Dieta , Gusto , Adolescente , Adulto , Femenino , Humanos , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Introduction: non-alcoholic fatty liver disease is one of the most prevalent liver disorders in the developed world. Currently, there is no approved pharmacological therapy except for lifestyle intervention. Therefore, there is a need to increase the knowledge of preclinical models in order to boost novel discoveries that could lead to a better therapeutic management. Material and methods: this study characterized the effects of two different diets, a long-term high-fat high-fructose diet (HF-HFD) and a choline-deficient, methionine supplemented high-fat diet (CDA-HFD) in C57BL/6J mice for 52 weeks or 16 weeks, respectively. Body weight, lipid and hepatic profile were analyzed and liver histology was subsequently evaluated. Results: HF-HFD animals had an increased body weight and total cholesterol levels, whereas the opposite occurred in CDA-HFD. Both HF-HFD and CDA-HFD animals had higher ALT and AST levels. With regard to histology findings, HF-HFD and CDA-HFD diets induced an increased collagen deposit and intrahepatic steatosis accumulation. Conclusion: in conclusion, the comparison of these models aided in the selection of a long-term, more physiological model for physiopathology studies or a more rapid NASH model for novel molecule testing
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Animales , Ratones , Hígado Graso/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Cirrosis Hepática/metabolismo , Modelos Animales de Enfermedad , Alanina Transaminasa/metabolismo , Aspartato Aminotransferasas/metabolismo , Dieta Alta en Grasa/efectos adversos , Colina/metabolismo , Edulcorantes/metabolismo , Metionina/metabolismoRESUMEN
Introduction: It has been found that the olfactorygustatory function is altered in patients with eating disorders, with an impairment affecting the perception of olfactory and gustatory stimuli. Objective: The aim was to explore the subjective reactivity after the exposure and tasting of foods with different gradient of sweetness and different fats textures. In addition, changes in the thought-shape fusion (TSF) cognitive distortion were assessed after tasting those different presentations as well as the correlations between the initial scores on TSF-Questionnaire (TSF-Q) and the different responses after that tasting. Method: A total of 15 healthy controls and 23 outpatients with anorexia nervosa underwent two sessions of tasting (sweets with different gradient of sweetness and fats with different textures) and they filled several questionnaires (pre- and post-tasting) to measure their responses after tasting. Results: Participants showed less "self-control" after tasting sweets. The score on TSF-Q increased significantly after the sweets tasting in the patients group. Patients had the worst response after tasting presentations with more quantity of glucose (less gradient of sweetness) than after tasting those with more amount of sucrose (much more sweetness). With respect to the fats, patients showed the worst reaction after tasting the most unfamiliar texture. Pre fats tasting TSF-Q scores correlated significantly with all responses in the patients group. Discussion: Both psychological and biological (e.g. genetic) factors could be involved in the reactions of patients with anorexia nervosa after tasting sweets and fats (AU)
Introducción: Se ha encontrado que la función olfativagustativa está alterada en pacientes con trastornos de la alimentación, con una alteración que afecta la percepción de los estímulos olfativos y gustativos. Objetivo: El propósito fue explorar la reactividad subjetiva tras la exposición y prueba de alimentos con distintos gradientes de dulzor y diferentes texturas grasas. Además, se evaluaron los cambios en la distorsión cognitiva de la fusión idea-forma (FIF) tras probar diferentes presentaciones así como las correlaciones entre las puntuaciones iniciales del Cuestionario FIF (C-FIF) y las distintas respuestas tras esa prueba. Método: Un total de 15 controles sanos y 23 pacientes ambulatorios con anorexia nerviosa se sometieron a dos sesiones de pruebas (dulces con distintos grados de dulzor y grasas con distintas texturas) y rellenaron varios cuestionarios (pre y post-prueba) para medir sus respuestas tras la prueba. Resultados: Los participantes mostraron menos "autocontrol" tras las pruebas con dulces. La puntuación del CFIF-Q aumentó de forma significativa tras las pruebas con dulces en el grupo de pacientes. Los pacientes tuvieron una peor respuesta tras las pruebas con aquellos alimentos con mayor contenido en glucosa (menor gradiente de dulzor) que tras probar aquellos alimentos con una mayor cantidad de sucrosa (mucho más dulzor). Con respecto a las grasas, los pacientes mostraron una peor reacción tras probar la textura menos familiar. Las puntuaciones del C-FIF preprueba se correlacionaron significativamente con todas las respuestas en el grupo de pacientes. Discusión: Tanto factores psicológicos como biológicos (p. ej., genéticos) podrían estar implicados en las reacciones de los pacientes con anorexia nerviosa tras las pruebas con dulces y grasas (AU)