1. Investigación

A tight relationship between gut-liver diseases and brain functions has recently emerged. Bile acid (BA) receptors, bacterial-derived molecules and the blood-brain barrier (BBB) play key roles in this association. This study was aimed to evaluate how non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) impact the BA receptors Farnesoid X receptor (FXR) and Takeda G-protein coupled receptor 5 (TGR5) expression in the brain and to correlate these effects with circulating BAs composition, BBB integrity and neuroinflammation. A mouse model of NAFLD was set up by a high-fat and sugar diet, and NASH was induced with the supplementation of dextran-sulfate-sodium (DSS) in drinking water. FXR, TGR5 and ionized calcium-binding adaptor molecule 1 (Iba-1) expression in the brain was detected by immunohistochemistry, while Zonula occludens (ZO)-1, Occludin and Plasmalemmal Vesicle Associated Protein-1 (PV-1) were analyzed by immunofluorescence. Biochemical analyses investigated serum BA composition, lipopolysaccharidebinding protein (LBP) and S100 protein (S100 ) levels. Results showed a down-regulation of FXR in NASH and an up-regulation of TGR5 and Iba-1 in the cortex and hippocampus in both treated groups as compared to the control group. The BA composition was altered in the serum of both treated groups, and LBP and S100 were significantly augmented in NASH. ZO-1 and Occludin were attenuated in the brain capillary endothelial cells of both treated groups versus the control group. We demonstrated that NAFLD and NASH provoke different grades of brain dysfunction, which are characterized by the altered expression of BA receptors, FXR and TGR5, and activation of microglia. These effects are somewhat promoted by a modification of circulating BAs composition and by an increase in LBP that concur to damage BBB, thus favoring neuroinflammation.

El envejecimiento y la gestación son dos situaciones fisiológicas que cursan con metainflamación y resistencia a la insulina. La pleiotrofina regula el recambio lipídico, la homeostasis energética, la sensibilidad a la insulina y la plasticidad del tejido adiposo. Nuestra hipótesis es que la pleiotrofina podría modular las adaptaciones metabólicas del hígado durante el último tercio de la gestación y durante el envejecimiento. Para corroborar nuestra hipótesis empleamos ratones hembra Knock out para pleiotrofina y sus respectivos controles (Wild type) a los 3, 6, 12 y 15 meses de edad (modelo de envejecimiento) o a los 18 días de gestación. La deleción de pleiotrofina se asocia a un menor peso corporal y del hígado, una menor acumulación de lípidos hepáticos e intolerancia a la glucosa. Asimismo, observamos un papel regulatorio de la pleiotrofina en la biogénesis y función mitocondriales en el hígado y un papel de la glicerol quinasa en la regulación de la homeostasis glucídica durante la gestación. La pleiotrofina es esencial en el mantenimiento de la metabolismo lipídico y glucídico hepático y la deleción de pleiotrofina evita la acumulación ectópica de grasa en el hígado y protege frente al desarrollo de esteatosis.

Scope : Fructose intake from added sugars correlates with the epidemic rise in metabolic syndrome and cardiovascular diseases. However, consumption of beverages containing fructose is allowed during gestation. Homocysteine (Hcy) is a well-known risk factor for cardiovascular diseases while hydrogen sulfide (H2S), a product of its metabolism, has been proved to exert opposite effects to Hcy. Methods and results : First, we investigated whether maternal fructose intake produces subsequent changes in Hcy metabolism and H2S synthesis of the progeny. Carbohydrates were supplied to pregnant rats in drinking water (10% wt/vol) throughout gestation. Adult female descendants from fructosefed, control or glucose-fed mothers were studied. Females from fructose-fed mothers had elevated homocysteinemia, hepatic H2S production, cystathionine -lyase (CSE) (the key enzyme in H2S synthesis) expression and plasma H2S, versus the other two groups. Second, we studied how adult female progeny from control (C/F), fructose- (F/F) and glucose-fed (G/F) mothers responded to liquid fructose and compared them to the control group (C/C). Interestingly, both hepatic CSE expression and H2S synthesis were diminished by fructose intake, this effect being more pronounced in F/F females. Conclusions : Maternal fructose intake produces a fetal programming that increases hepatic H2S production and, in contrast, exacerbates its fructose-induced drop in female progeny.

Three days after a single injection of streptozotocin rats showed hyperglycemia, hyperketonemia and hypoinsulinemia. Body and liver weights were reduced and the concentration of DNA-P, phospholipid-P, proteins and acetyl-CoA in the liver was augmented, while the concentration of glycogen and citric acid in these animals compared with the controls which did not receive the drug was decreased. After 48 h starvation, blood glucose remained higher in the streptozotocin-treated animals, while circulating ketones and insulin were not different from those in the controls. With the exception of body and liver weights, which were lower, and of liver DNA-P, which was higher than when fed, neither of the other parameters studied in the s:reptozotocin treated animals changed with fasting, while the response in the c0ntrols was normal; The incapacity of increasing the postprandial insulin secretion in these animals may contribute to the metabolic alterations found in the fed state.

Background: Routine total parenteral nutrition (TPN) in neonatal care can result in hepatic dysfunction in 40–60% of patients, most commonly as fatty liver, but little work has been conducted on the underlying mechanisms causing hepatic dysfunction. Objective: To use a piglet model for the premature human neonate on TPN, supplemented with lipid emulsions, to investigate hepatic responses. Method: Piglets were delivered 2 days prematurely. Six control piglets were fed enterally (E), whilst twelve animals were maintained on TPN. TPN piglets received the standard TPN solution plus the lipid emulsion as either ClinOleic (C, n = 6) or Intralipid (I, n = 6). Hepatic lipid content and the fatty acid composition of liver triacylglyercol (TAG) as well as hepatic lipase (HL) activity were determined. Lipoprotein lipase (LPL) activity was measured in the liver, muscle and adipose tissue. The plasma concentrations of choline, bilirubin, TAG and non-esterified fatty acids (NEFA) were also measured. Results: Liver lipid was significantly increased in piglets on TPN and the tissue fatty acid profiles reflected the lipid emulsion. HL and LPL activities were reduced in liver but LPL increased in adipose tissue during TPN. Plasma concentrations of choline, bilirubin, TAG and NEFA were similar across the treatments. Conclusions: The results suggest fatty liver occurs in neonates receiving TPN and the source of the accumulated lipid appears to be the lipid emulsion used. The factors regulating lipase activity during TPN require further study. The piglet can be used as a model for neonatal TPN.

To study the effect of diabetes on hepatic protein synthesis and polysomal aggregation in pregnant rats, female rats were treated with streptozotocin prior to conception. Some animals were mated. and studied at day 20 of pregnancy, whereas. others were studied in parallel under non pregnant conditions. The protein synthesis rate measured with an "in l'ITTO .. cell-free system was higher in pregnant than in virgin control rats. It decreased with diahetes in both groups. although values remained higher in diabetic pregnant rats than in the virgin animals. The fetuses of diabetic rats had a lower protein synthesis rate than those from controls, although they showed a higher protein synthesis rate than either their respective mothers or virgin rats. Liver R~A concentration was higher in control and diabetic. pregnant rats than in virgin rats, and the effect of diabetes decreasing this parameter was only significant for pregnant rats. Liver RNA concentration in fetuses was lower than in their mothers, and did not differ between control and diabetic animals. The decreased protein synthesis found in d1ahe11c animals was accompanied by disaggregation of hea,·y polysomes into lighter species, indicating an impairment in peptide-chain initiation.

1) Thyoridectomized rats were fed with a low iodine diet, injected daily with 0, 0.1, 1.8 or 25 µg of L-thyroxine/100 g body wt., and compared with intact controls. 2) Plasma protein-bound iodine was decreased in the rats given the 0 and 0.1 µg doses, unchanged in those given the 1.8 µg doses, unchanged in those given the 1.8 µg dose increased in those given the 25 µg one. 3) The liver content of DNA-P, phospholipid-P, proteins and fatty acids was decreased in the rats that did not receive thyr.oxine, practically recuperated in those receiving 0.1 µg and normal in those given 1.8 or 25 µg of thyroxine. 4) 3 h of starvation produced a reduction in the liver content of total fatty acids that disappeared after 24 h. 5) When fod, liver glycogen concentration was low in the rats given 25 µg of thyroxine. 6) With starvation, the fall in liver glycogen and blood glucose, and the rise in liver acetylCoA and citrate and blood glycerol concentrations were faster in the thyroidectomized rats that did not receive thyroxine than in the other groups. 7) The rise in plasma free fatty acid and blood ketone bodies concentrations were similar in all the groups, the greater level of the first parameter being observed after 6 h of starvation in the rats given 25 µg of thyroxine and in the second one after 24 h in the rats given either 0.1, 1.8 or 25 µg of thyroxine. 8) The rapid decrease in the availability of carbohydrate stores with starvation in the thyroidcctomized rats could be responsible for their fast call for lipid utilization. The slower response to fasting in the hyperthyroid animals is probably a consequence of their reduced amount of endogenous substrates to be mobilized.