Fructose during pregnancy provokes fetal oxidative stress: The key role of the placental heme oxygenase-1.

SCOPE: One of the features of metabolic syndrome caused by liquid fructose intake is an impairment of redox status. We have investigated whether maternal fructose ingestion modifies the redox status in pregnant rats and their fetuses. METHODS AND RESULTS: Fructose (10% wt/vol) in the drinking water of rats throughout gestation, leads to maternal hepatic oxidative stress. However, this change was also observed in glucose-fed rats and, in fact, both carbohydrates produced a decrease in antioxidant enzyme activity. Surprisingly, mothers fed carbohydrates displayed low plasma lipid oxidation. In contrast, fetuses from fructose-fed mothers showed elevated levels of plasma lipoperoxides versus fetuses from control or glucose-fed mothers. Interestingly, a clearly augmented oxidative stress was observed in placenta of fructose-fed mothers, accompanied by a lower expression of the transcription factor Nuclear factor-erythroid 2-related factor-2 (Nrf2) and its target gene, heme oxygenase-1 (HO-1), a potent antioxidant molecule. Moreover, histone deacetylase 3 (HDAC3) that has been proposed to upregulate HO-1 expression by stabilizing Nrf2, exhibited a diminished expression in placenta of fructose-supplemented mothers. CONCLUSIONS: Maternal fructose intake provoked an imbalanced redox status in placenta and a clear diminution of HO-1 expression, which could be responsible for the augmented oxidative stress found in their fetuses.

Fructose supplementation impairs rat liver autophagy through mTORC activation without inducing endoplasmic reticulum stress.

Supplementation with 10% liquid fructose to female rats for 2weeks caused hepatic steatosis through increased lipogenesis and reduced peroxisome proliferator activated receptor (PPAR) α activity and fatty acid catabolism, together with increased expression of the spliced form of X-binding protein-1 (Rebollo et al., 2014). In the present study, we show that some of these effects are preserved after sub-chronic (8weeks) fructose supplementation, specifically increased hepatic expression of lipid synthesis-related genes (stearoyl-CoA desaturase, ×6.7-fold; acetyl-CoA carboxylase, ×1.6-fold; glycerol-3-phosphate acyltransferase, ×1.65-fold), and reduced fatty acid ß-oxidation (×0.77-fold), resulting in increased liver triglyceride content (×1.69-fold) and hepatic steatosis. However, hepatic expression of PPARα and its target genes was not modified and, further, livers of 8-week fructose-supplemented rats showed no sign of unfolded protein response activation, except for an increase in p-IRE1 levels. Hepatic mTOR phosphorylation was enhanced (×1.74-fold), causing an increase in the phosphorylation of UNC-51-like kinase 1 (ULK-1) (×2.8-fold), leading to a decrease in the ratio of LC3B-II/LC3B-I protein expression (×0.39-fold) and an increase in the amount of the autophagic substrate p62, indicative of decreased autophagy activity. A harmful cycle may be established in the liver of 8-week fructose-supplemented rats where lipid accumulation may cause defective autophagy, and reduced autophagy may result in decreased free fatty acid formation from triglyceride depots, thus reducing the substrates for ß-oxidation and further increasing hepatic steatosis. In summary, the length of supplementation is a key factor in the metabolic disturbances induced by fructose: in short-term studies, PPARα inhibition and ER stress induction are critical events, whereas after sub-chronic supplementation, mTOR activation and autophagy inhibition are crucial.

Liquid fructose downregulates Sirt1 expression and activity and impairs the oxidation of fatty acids in rat and human liver cells.

Fructose ingestion is associated with the production of hepatic steatosis and hypertriglyceridemia. For fructose to attain these effects in rats, simultaneous induction of fatty acid synthesis and inhibition of fatty acid oxidation is required. We aimed to determine the mechanism involved in the inhibition of fatty acid oxidation by fructose and whether this effect occurs also in human liver cells. Female rats were supplemented or not with liquid fructose (10% w/v) for 7 or 14 days; rat (FaO) and human (HepG2) hepatoma cells, and human hepatocytes were incubated with fructose 25mM for 24h. The expression and activity of the enzymes and transcription factors relating to fatty acid ß-oxidation were evaluated. Fructose inhibited the activity of fatty acid ß-oxidation only in livers of 14-day fructose-supplemented rats, as well as the expression and activity of peroxisome proliferator activated receptor α (PPARα). Similar results were observed in FaO and HepG2 cells and human hepatocytes. PPARα downregulation was not due to an osmotic effect or to an increase in protein-phosphatase 2A activity caused by fructose. Rather, it was related to increased content in liver of inactive and acetylated peroxisome proliferator activated receptor gamma coactivator 1α, due to a reduction in sirtuin 1 expression and activity. In conclusion, fructose inhibits liver fatty acid oxidation by reducing PPARα expression and activity, both in rat and human liver cells, by a mechanism involving sirtuin 1 down-regulation.

Reduction of liver fructokinase expression and improved hepatic inflammation and metabolism in liquid fructose-fed rats after atorvastatin treatment.

Consumption of beverages that contain fructose favors the increasing prevalence of metabolic syndrome alterations in humans, including non-alcoholic fatty liver disease (NAFLD). Although the only effective treatment for NAFLD is caloric restriction and weight loss, existing data show that atorvastatin, a hydroxymethyl-glutaryl-CoA reductase inhibitor, can be used safely in patients with NAFLD and improves hepatic histology. To gain further insight into the molecular mechanisms of atorvastatin's therapeutic effect on NAFLD, we used an experimental model that mimics human consumption of fructose-sweetened beverages. Control, fructose (10% w/v solution) and fructose+atorvastatin (30 mg/kg/day) Sprague-Dawley rats were sacrificed after 14 days. Plasma and liver tissue samples were obtained to determine plasma analytes, liver histology, and the expression of liver proteins that are related to fatty acid synthesis and catabolism, and inflammatory processes. Fructose supplementation induced hypertriglyceridemia and hyperleptinemia, hepatic steatosis and necroinflammation, increased the expression of genes related to fatty acid synthesis and decreased fatty acid ß-oxidation activity. Atorvastatin treatment completely abolished histological signs of necroinflammation, reducing the hepatic expression of metallothionein-1 and nuclear factor kappa B binding. Furthermore, atorvastatin reduced plasma (x 0.74) and liver triglyceride (x 0.62) concentrations, decreased the liver expression of carbohydrate response element binding protein transcription factor (x 0.45) and its target genes, and increased the hepatic activity of the fatty acid ß-oxidation system (x 1.15). These effects may be related to the fact that atorvastatin decreased the expression of fructokinase (x 0.6) in livers of fructose-supplemented rats, reducing the metabolic burden on the liver that is imposed by continuous fructose ingestion.

Tratamiento de la hipertrigliceridemia: fibratos frente a ácidos grasos omega-3 / Treatment of hypertriglyceridemia: fibrates versus omega-3 fatty acids

Por ser un componente del síndrome metabólico y de la diabetes, entidades que en la actualidad son epidémicas, la hipertrigliceridemia (HTG) asociada con valores bajos de colesterol unido a lipoproteínas de alta densidad (cHDL) es la dislipidemia de presentación clínica más frecuente. Además, es la alteración lipídica característica de pacientes con enfermedad cardiaca coronaria. La HTG se debe a un aumento de la síntesis hepática de las lipoproteínas de muy baja densidad (VLDL), en general por un exceso de grasa visceral, o a un defecto en el aclaramiento de VLDL por hipoactividad de la lipoproteinlipasa (LPL) de causa genética o adquirida, y con frecuencia hay un defecto doble. Además del cHDL bajo, la HTG se asocia con la formación de partículas LDL densas y pequeñas, que son muy aterogénicas. Esto justifica que la HTG sea un factor de riesgo cardiovascular independiente y deba tratarse con la misma intensidad que la hipercolesterolemia. Actualmente, se recomiendan como deseables unas cifras de triglicéridos (TG) <150 mg/dl. El tratamiento conservador de la HTG con dieta y normalización del peso es muy eficaz, pero difícil de realizar en la práctica. El tratamiento farmacológico convencional de la HTG son los fibratos, agentes que activan el factor de transcripción PPAR-α. Esto promueve la oxidación de ácidos grasos y estimula la actividad LPL, lo que reduce los TG, y aumenta la síntesis de apoproteínas de las HDL, lo que incrementa las cifras de cHDL. En promedio, los fibratos reducen los TG un 36% y aumentan el cHDL un 8%. En dosis de 2-4 g/día, los ácidos grasos n-3 (AGn-3) de origen marino son tan eficaces como los fibratos en la reducción de TG y carecen de efectos secundarios. Los AGn-3 también son ligandos de PPAR-α, pero reducen la síntesis de ácidos grasos por mecanismos independientes, lo cual justifica que su efecto de reducción de los TG sea complementario del de los fibratos. La eficacia de los AGn-3 en la reducción de TG se ha demostrado en monoterapia y en tratamiento combinado con estatinas. En la HTG grave del síndrome de quilomicronemia, los AGn-3 añaden su efecto al de los fibratos, con lo que se consiguen reducciones adicionales de los TG de hasta un 50% y se minimiza el riesgo de pancreatitis. Por tanto, los fibratos y los AGn-3 no están enfrentados, sino que son complementarios (AU)

Hypertriglyceridemia (HTG) combined with a low highdensity lipoprotein (HDL) cholesterol level is the characteristic lipid abnormality in two prevalent conditions: the metabolic syndrome and diabetes. Moreover, it is also the commonest dyslipidemia in patients with coronary heart disease. HTG is caused by increased hepatic synthesis of very-low-density lipoprotein (VLDL), usually due to excess visceral fat, or to defective VLDL clearance secondary to genetic or acquired impairment of lipoprotein lipase activity (LPL). Frequently, there is both excess VLDL input to the circulation and reduced clearance. In addition to a low HDL cholesterol level, HTG is also associated with the formation of small dense low-density lipoprotein (LDL) particles that are particularly atherogenic. This explains why HTG is an independent cardiovascular risk factor that must be treated as intensively as hypercholesterolemia. At present, a triglyceride concentration < 150 mg/dL is regarded as desirable. Conservative treatment of HTG by lifestyle modification involving diet and weight loss is very effective but difficult to implement. Fibrates are the conventional pharmacological treatment for HTG. These agents are activators of transcription factor PPAR-α, and consequently promote fatty acid oxidation and enhance LPL. This, in turn, reduces the serum level and stimulates synthesis of HDL apolipoproteins, thereby increasing the HDL cholesterol level. On average, fibrates reduce the level by 36% and increase HDL cholesterol by 8%. Given at a dose of 2-4 g/day, marine omega-3 fatty acids are as effective as fibrates in lowering the triglyceride level. Moreover, they are devoid of side effects. In addition, omega-3 fatty acids also interact with PPAR-α, although they decrease fatty acid synthesis by alternative mechanisms. This explains why the lowering effect of omega-3 fatty acids is complementary to that of fibrates. Omega-3 fatty acids have been found to be effective in lowering the, triglyceride level when given either as monotherapy or in combination with statins. In the severe HTG found with chylomicronemia syndromes, the effect of omega-3 fatty acids is additive to that of fibrates, resulting in an additional reduction in levels of up to 50% beyond that induced by fibrates alone, thereby minimizing the risk of acute pancreatitis. Consequently, fibrates and omega-3 fatty acids do not have opposing actions. Instead, they complement each other when used for the treatment of hypertriglyceridemia (AU)