Hepatic steatosis is commonly present during the development of insulin resistance, and it is a clear sign of lipotoxicity attributable in part to an accelerated lipogenesis. There is evidence that a soy protein diet prevents the overexpression of hepatic sterol-regulatory element binding protein-1 (SREBP-1), decreasing lipid accumulation. Therefore, the aim of the present work was to study whether a soy protein diet may prevent the development of fatty liver through the regulation of transcription factors involved in lipid metabolism in hyperinsulinemic and hyperleptinemic Zucker obese fa/fa rats. Serum and hepatic cholesterol and triglyceride levels, as well as VLDL-triglyceride and LDL-cholesterol, were significantly lower in rats fed soy protein than in rats fed a casein diet for 160 days. The reduction in hepatic cholesterol was associated with a low expression of liver X receptor-␣ and its target genes, 7-␣ hydroxylase and ABCA1. Obesity and associated diabetes are epidemic throughout the world. Obesity is the leading cause of insulin resistance and hyperinsulinemia, which predispose to glucose intolerance, diabetes, and cardiovascular diseases. As many as 40% of type 2 diabetics develop evidence of hepatic steatosis or fatty liver (1, 2).Several lines of evidence indicate that fatty liver in insulin-resistant states is caused by the activation of the sterolregulatory element binding protein-1c (SREBP-1c), which is increased in response to high insulin levels even in resistant states (3). SREBP-1c is a member of the family of SREBP membrane-bound transcription factors that activates mainly the transcription of genes involved in fatty acid synthesis (4). Thus, an increase in SREBP-1c expression increases the rate of lipogenesis in the liver (5). Analysis of the SREBP1c promoter has revealed an insulin-responsive region that maps to a binding site for liver X receptors (LXRs), suggesting a common pathway of action (6, 7).LXRs are nuclear hormone receptors that form active heterodimers with retinoid X receptors. They are activated by oxysterols and serve as key sensors of intracellular sterol levels by regulating the expression of genes that control cholesterol absorption, storage, transport, and elimination (8). Studies have demonstrated that the addition of the synthetic LXR ligand T0901317 increased the expression of SREBP-1c (9), indicating that these nuclear receptors provide interregulatory control of the cholesterol and fatty acid metabolism.Several studies in humans and experimental animals have demonstrated that the ingestion of soy protein reduces serum cholesterol and triglycerides (10-12). Furthermore, it has been shown that soy protein consumption also reduces the accumulation of cholesterol and triglycerides in the liver, preventing the development of fatty liver (13). There is evidence that soy protein regulates the concentration of serum and hepatic lipids by different mechanisms. We have demonstrated that rats fed a soy protein diet can control serum and hepatic lipid concentration b...

Acetaldehyde (Ac), the main metabolite of ethanol oxidation, is a very reactive compound involved in alcohol-induced liver damage. In the present work, we studied the effect of Ac in mitochondria functionality. Mitochondria from Wistar rats were isolated and treated with Ac. Ac decreased respiratory control by 50% which was associated with a decrease in adenosine triphosphate content (28.5%). These results suggested that Ac could be inducing changes in cell redox status. We determined protein oxidation, superoxide dismutase (SOD) activity, and glutathione ratio, indicating that Ac induced an enhanced oxidation of proteins and a decrease in SOD activity (90%) and glutathione/oxidized GSH ratio (36%). The data suggested that Ac-induced oxidative stress mediated by mitochondria dysfunction can lead to cell sensitization and to a second oxidative challenge. We pretreated hepatocytes with Ac followed by treatment with antimycin A, and this experiment revealed a noticeable decrease in cell viability, determined by neutral red assay, in comparison with cells treated with Ac alone. Our data demonstrate that Ac impairs mitochondria functionality generating oxidative stress that sensitizes cells to a second damaging signal contributing to the development of alcoholic liver disease.

Protein restriction during pregnancy affects maternal liver lipid metabolism and fetal brain lipid composition in the rat. Am J Physiol Endocrinol Metab 298: E270 -E277, 2010. First published November 17, 2009 doi:10.1152/ajpendo.00437.2009.-Suboptimal developmental environments program offspring to lifelong metabolic problems. The aim of this study was to determine the impact of protein restriction in pregnancy on maternal liver lipid metabolism at 19 days of gestation (dG) and its effect on fetal brain development. Control (C) and restricted (R) mothers were fed with isocaloric diets containing 20 and 10% of casein. At 19 dG, maternal blood and livers and fetal livers and brains were collected. Serum insulin and leptin levels were determinate in mothers. Maternal and fetal liver lipid and fetal brain lipid quantification were performed. Maternal liver and fetal brain fatty acids were quantified by gas chromatography. In mothers, liver desaturase and elongase mRNAs were measured by RT-PCR. Maternal body and liver weights were similar in both groups. However, fat body composition, including liver lipids, was lower in R mothers. A higher fasting insulin at 19 dG in the R group was observed (C ϭ 0.2 Ϯ 0.04 vs. R ϭ 0.9 Ϯ 0.16 ng/ml, P Ͻ 0.01) and was inversely related to early growth retardation. Serum leptin in R mothers was significantly higher than that observed in C rats (C ϭ 5 Ϯ 0.1 vs. R ϭ 7 Ϯ 0.7 ng/ml, P Ͻ 0.05). In addition, protein restriction significantly reduced gene expression in maternal liver of desaturases and elongases and the concentration of arachidonic (AA) and docosahexanoic (DHA) acids. In fetus from R mothers, a low body weight (C ϭ 3 Ϯ 0.3 vs. R ϭ 2 Ϯ 0.1 g, P Ͻ 0.05), as well as liver and brain lipids, including the content of DHA in the brain, was reduced. This study showed that protein restriction during pregnancy may negatively impact normal fetal brain development by changes in maternal lipid metabolism.programming; development; docosahexaenoic acid; arachidonic acid HUMAN EPIDEMIOLOGICAL (28, 31) and experimental animal studies (16,23,25) have shown that a suboptimal environment either in the womb or early in the neonatal life alters growth and predisposes individuals to lifelong health problems. Maternal dietary deficiencies in pregnancy result in multiple adverse outcomes in the offspring (3, 12). Fetal growth depends mostly on the amount and type of nutrients obtained from the mother. Therefore, the mother must adapt her metabolism to support this continuous draining of substrates. The effects of an altered intrauterine environment can be passed transgenerationally by epigenetic mechanisms involving changes in gene expression (41). During late gestation, maternal liver plays a central role in whole body lipid metabolism. Maternal triglycerides (TG) are not transported intact across the placenta, whereas free fatty acids (FAs), including longchain polyunsaturated fatty acids (LC-PUFAs), can be transported (32). Therefore, a deficient maternal FA intake, particularly essential FAs (...

Our results suggest that SP isoflavones stimulate the phosphorylation of LXRα or LXRβ, resulting in different biological effects for each LXR isoform.

Amino acid transport via system A plays an important role during lactation, promoting the uptake of small neutral amino acids, mainly alanine and glutamine. However, the regulation of gene expression of system A [sodium-coupled neutral amino acid transporter (SNAT)2] in mammary gland has not been studied. The aim of the present work was to understand the possible mechanisms of regulation of SNAT2 in the rat mammary gland. Incubation of gland explants in amino acid-free medium induced the expression of SNAT2, and this response was repressed by the presence of small neutral amino acids or by actinomycin D but not by large neutral or cationic amino acids. The half-life of SNAT2 mRNA was 67 min, indicating a rapid turnover. In addition, SNAT2 expression in the mammary gland was induced by forskolin and PMA, inducers of PKA and PKC signaling pathways, respectively. Inhibitors of PKA and PKC pathways partially prevented the upregulation of SNAT2 mRNA during adaptive regulation. Interestingly, SNAT2 mRNA was induced during pregnancy and to a lesser extent at peak lactation. beta-Estradiol stimulated the expression of SNAT2 in mammary gland explants; this stimulation was prevented by the estrogen receptor inhibitor ICI-182780. Our findings clearly demonstrated that the SNAT2 gene is regulated by multiple pathways, indicating that the expression of this amino acid transport system is tightly controlled due to its importance for the mammary gland during pregnancy and lactation to prepare the gland for the transport of amino acids during lactation.