Stevia-derived compounds attenuate the toxic effects of ectopic lipid accumulation in the liver of obese mice: a transcriptomic and metabolomic study.

There is a close interaction between Type 2 Diabetes, obesity and liver disease. We have studied the effects of the two most abundant Stevia-derived steviol glycosides, stevioside and rebaudioside A, and their aglycol derivative steviol on liver steatosis and the hepatic effects of lipotoxicity using a mouse model of obesity and insulin resistance. We treated ob/ob and LDLR-double deficient mice with stevioside (10 mg⋅kg(-1)⋅day-1 p.o., n = 8), rebaudioside A (12 mg⋅kg(-1)⋅day-1 p.o., n = 8), or steviol (5 mg⋅kg(-1)⋅day(-1) p.o., n = 8). We determined their effects on liver steatosis and on the metabolic effects of lipotoxicity by histological analysis, and by combined gene-expression and metabolomic analyses. All compounds attenuated hepatic steatosis. This could be explained by improved glucose metabolism, fat catabolism, bile acid metabolism, and lipid storage and transport. We identified PPARs as important regulators and observed differences in effects on insulin resistance, inflammation and oxidative stress between Stevia-derived compounds. We conclude that Stevia-derived compounds reduce hepatic steatosis to a similar extent, despite differences in effects on glucose and lipid metabolism, and inflammation and oxidative stress. Thus our data show that liver toxicity can be reduced through several pathophysiological changes. Further identification of active metabolites and underlying mechanisms are warranted.

Xenohormetic and anti-aging activity of secoiridoid polyphenols present in extra virgin olive oil: a new family of gerosuppressant agents.

Aging can be viewed as a quasi-programmed phenomenon driven by the overactivation of the nutrient-sensing mTOR gerogene. mTOR-driven aging can be triggered or accelerated by a decline or loss of responsiveness to activation of the energy-sensing protein AMPK, a critical gerosuppressor of mTOR. The occurrence of age-related diseases, therefore, reflects the synergistic interaction between our evolutionary path to sedentarism, which chronically increases a number of mTOR activating gero-promoters (e.g., food, growth factors, cytokines and insulin) and the "defective design" of central metabolic integrators such as mTOR and AMPK. Our laboratories at the Bioactive Food Component Platform in Spain have initiated a systematic approach to molecularly elucidate and clinically explore whether the "xenohormesis hypothesis," which states that stress-induced synthesis of plant polyphenols and many other phytochemicals provides an environmental chemical signature that upregulates stress-resistance pathways in plant consumers, can be explained in terms of the reactivity of the AMPK/mTOR-axis to so-called xenohormetins. Here, we explore the AMPK/mTOR-xenohormetic nature of complex polyphenols naturally present in extra virgin olive oil (EVOO), a pivotal component of the Mediterranean style diet that has been repeatedly associated with a reduction in age-related morbid conditions and longer life expectancy. Using crude EVOO phenolic extracts highly enriched in the secoiridoids oleuropein aglycon and decarboxymethyl oleuropein aglycon, we show for the first time that (1) the anticancer activity of EVOO secoiridoids is related to the activation of anti-aging/cellular stress-like gene signatures, including endoplasmic reticulum (ER) stress and the unfolded protein response, spermidine and polyamine metabolism, sirtuin-1 (SIRT1) and NRF2 signaling; (2) EVOO secoiridoids activate AMPK and suppress crucial genes involved in the Warburg effect and the self-renewal capacity of "immortal" cancer stem cells; (3) EVOO secoiridoids prevent age-related changes in the cell size, morphological heterogeneity, arrayed cell arrangement and senescence-associated ß-galactosidase staining of normal diploid human fibroblasts at the end of their proliferative lifespans. EVOO secoiridoids, which provide an effective defense against plant attack by herbivores and pathogens, are bona fide xenohormetins that are able to activate the gerosuppressor AMPK and trigger numerous resveratrol-like anti-aging transcriptomic signatures. As such, EVOO secoiridoids constitute a new family of plant-produced gerosuppressant agents that molecularly "repair" the aimless (and harmful) AMPK/mTOR-driven quasi-program that leads to aging and aging-related diseases, including cancer.

Moderately high folic acid supplementation exacerbates experimentally induced liver fibrosis in rats.

Under certain clinical circumstances, folic acid can have undesirable effects. We investigated the following: (i) the effects of moderately high folic acid supplementation on the course of liver impairment in CCl(4)-treated rats and (ii) the influence of folic acid supplements on the hepatic recovery following the interruption of the CCl(4)-induced toxic injury. Four experimental groups of rats were used: CCl(4)-treated rats (0.5 ml of CCl(4) twice a week i.p.) fed standard chow for up to 12 weeks (Group A); treated rats fed chow supplemented with 25 mg/kg folic acid from weeks 6 to 12 (Group B); treated rats fed a standard diet but with CCl(4) discontinued after 6 weeks to allow for tissue recovery over 4 weeks (Group C); rats as Group C but fed a diet supplemented with 25 mg/kg folic acid from weeks 6 to 10 (Group D). Liver and blood samples were obtained for biochemical, histological, and gene expression analyses. Animals that received the supplement had a higher content of collagen, activated stellate cells, and apoptotic parenchymal cells in biopsy tissue at weeks 8 and 10 of treatment and more extensive alterations in serum albumin and bilirubin concentrations (Group B vs. Group A). In some of the time periods analyzed, alterations were observed in the expression of genes related to apoptosis (B-cell leukemia/lymphoma 2, inhibitor of apoptosis 2) and to fibrosis (procollagen I, matrix metalloproteinase 7). In the recovery period (Groups C and D), folic acid administration was associated with increased hepatic inflammation and apoptosis and with a decrease in the tissue inhibitor of metalloproteinase-3 expression following 1 week of recovery. We conclude that folic acid administration aggravates the development of fibrosis in CCl(4)-treated rats. Follow-up studies are needed to determine whether folic acid treatment would be contraindicated in patients with chronic liver diseases.

La grasa saturada en la dieta disminuye la expresión hepática de APOA5 en ratones deficientes en apo E / Saturated fat from diet downregulates APOA5 hepatic expression in apo E-deficient mice

Introducción. En el desarrollo de la arteriosclerosis intervienen numerosos factores; en especial la edad, la dieta y la hiperlipidemia. La apolipoproteína (apo) A-V desempeña un papel destacado en el control del metabolismo lipídico. Nuestro objetivo es estudiar en ratones hiperlipémicos el efecto que la grasa de la dieta tiene en la expresión hepática del gen de la apo A-V (APOA5) y su relación con el desarrollo de la arteriosclerosis y sus factores de riesgo. Material y métodos. Utilizamos 72 ratones knock-out para el gen de la apo E (KO-APOE) separados en 3 grupos (n = 24): los que recibían dieta convencional de ratón o dieta rica en grasa saturada (20% aceite de palma) sola o suplementada con 0,25% de colesterol. Las muestras se tomaron a las 16, 24 y 32 semanas de edad. Las determinaciones analíticas incluyeron parámetros lipídicos e inflamatorios, la superficie de lesión arteriosclerótica en la aorta y la expresión de APOA5 en hígado. Resultados. La ingesta de dieta rica en grasa saturada disminuye un 48% (p = 0,001) de media la expresión hepática de APOA5 y la suplementación con colesterol revierte este efecto. Estos efectos se observaron a las diferentes edades de los ratones. La expresión hepática de APOA5 aumenta significativamente (p < 0,0001) en función de la edad, el número de lesiones arterioscleróticas en la aorta y el grado de inflamación en los ratones. Conclusiones. La grasa saturada de la dieta disminuye significativamente la expresión hepática de APOA5, que a su vez aumenta con la edad a todas las dietas suministradas y se correlaciona con el área ateromatosa y el estado inflamatorio (AU)

Introduction. Many factors are involved in atherosclerosis development, especially age, diet and hyperlipidemia. Apolipoprotein (apo) A-V plays a key role in the control of lipid metabolism. The aim of this study was to determine the effect of dietary fat intake on hepatic expression of the apo A-V gene (APOA5) in hyperlipidemic mice and its association with risk factors for atherosclerosis and atherosclerosis development. Material and methods. We used 72 knock-out mice for the apo E gene (KO-APOE) divided in three groups (n=24) that received a chow diet, a diet rich in saturated fat (20% palm oil) alone, or a diet supplemented with 0.25% of cholesterol. Samples were obtained at 16, 24, and 32 weeks. Laboratory determinations included lipid and inflammatory parameters, area of atherosclerotic lesions in the aorta, and APOA5 expression in the liver. Results. Intake of a saturated fat-rich diet reduced mean hepatic expression of APOA5 by 48% (P=0.001), while cholesterol supplementation reversed this effect. These effects were found at the different ages of mice. Hepatic APOA5 expression significantly increased (P=0.001), depending on age, the number of atherosclerotic lesions in the aorta, and the degree of inflammation in these mice. Conclusions. Saturated dietary fat significantly downregulates hepatic APOA5 expression, which also increases with age, in all the diets administered and correlates with atheromatous area and inflammatory status (AU)