ABSTRACT
Androgens play a central role in homeostatic and pathological processes of the prostate gland. At the cellular level, testosterone activates both the genomic signaling pathway, through the intracellular androgen receptor (AR), and membrane-initiated androgen signaling (MIAS), by plasma membrane receptors. We have previously shown that the activation of MIAS induces uncontrolled proliferation and fails to stimulate the beneficial immunomodulatory effects of testosterone in prostatic cells, becoming necessary to investigate if genomic signaling mediates homeostatic effects of testosterone. However, the lack of specific modulators for genomic androgen signaling has delayed the understanding of this mechanism. In this article, we demonstrate that monosialoganglioside (GM1) micelles are capable of delivering testosterone into the cytoplasm to specifically activate genomic signaling. Stimulation with testosterone-loaded GM1 micelles led to the activation of androgen response element (ARE)-regulated genes in vitro as well as to the recovery of normal prostate size and histology after castration in mice. In addition, these micelles avoided MIAS, as demonstrated by the absence of rapid signaling pathway activation and the inability to induce uncontrolled cell proliferation. In conclusion, our results validate a novel tool for the specific activation of genomic androgen signaling and demonstrate the importance of selective pathway activation in androgen-mediated proliferation.
Subject(s)
Prostatic Neoplasms , Receptors, Androgen , Androgens , Animals , G(M1) Ganglioside , Genomics , Humans , Male , Mice , Micelles , Receptors, Androgen/genetics , Signal Transduction , TestosteroneABSTRACT
Androgen signaling in prostate smooth muscle cells (pSMCs) is critical for the maintenance of prostate homeostasis, the alterations of which are a central aspect in the development of pathological conditions. Testosterone can act through the classic androgen receptor (AR) in the cytoplasm, eliciting genomic signaling, or through different types of receptors located at the plasma membrane for nongenomic signaling. We aimed to find evidence of nongenomic testosterone-signaling mechanisms in pSMCs and their participation in cell proliferation, differentiation, and the modulation of the response to lipopolysaccharide. We demonstrated that pSMCs can respond to testosterone by a rapid activation of ERK1/2 and Akt. Furthermore, a pool of ARs localized at the cell surface of pSMCs is responsible for a nongenomic testosterone-induced increase in cell proliferation. Through membrane receptor stimulation, testosterone favors a muscle phenotype, indicated by an increase in smooth muscle markers. We also showed that the anti-inflammatory effects of testosterone, capable of attenuating lipopolysaccharide-induced proinflammatory actions, are promoted only by receptors located inside the cell. We postulate that testosterone might perform prohomeostatic effects through intracellular-initiated mechanisms by modulating cell proliferation and inflammation, whereas some pathological, hyperproliferative actions would be induced by membrane-initiated nongenomic signaling in pSMCs.
Subject(s)
Muscle, Smooth/drug effects , Myocytes, Smooth Muscle/drug effects , Prostate/drug effects , Receptors, Androgen/metabolism , Testosterone/pharmacology , Animals , Cells, Cultured , Male , Muscle, Smooth/metabolism , Myocytes, Smooth Muscle/metabolism , Prostate/cytology , Prostate/metabolism , Rats, Wistar , Signal Transduction/drug effects , Tissue DistributionABSTRACT
The aim of this study was to investigate the effects of trans-fatty acids (TFA) on liver and serum TAG regulation in mice fed diets containing different proportions of n-3, n-6 and n-9 unsaturated fatty acids (UFA) from olive (O), maize (C) or rapeseed (R) oils partially substituted or not with TFA (Ot, Ct and Rt, respectively). Male CF1 mice were fed (30 d) one of these diets. The effects of the partial substitution (1 %, w/w) of different UFA with TFA on the activity and expression of hepatic enzymes involved in lipogenesis and fatty acids oxidation were evaluated, as well as their transcription factor expressions. Some of the mechanisms involved in the serum TAG regulation, hepatic VLDL rich in TAG (VLDL-TAG) secretion rate and lipoprotein lipase (LPL) activity were assessed. In liver, TFA induced an increase in TAG content in the Ot and Rt groups, and this effect was associated with an imbalance between lipogenesis and ß-oxidation. In the Ot group, exacerbated lipogenesis may be one of the mechanisms responsible for the liver steatosis induced by TFA, whereas in Rt it has been related to a decreased ß-oxidation, compared with their respective controls. The enhanced hepatic VLDL-TAG secretion in the Ot and Rt groups was compensated with a differential removal of TAG by LPL enzyme in extrahepatic tissues, leading to unchanged serum TAG levels. In brief, the effects of low levels of TFA on liver and serum TAG regulation in mice depend on the dietary proportions of n-3, n-6 and n-9 UFA.
Subject(s)
Diet, High-Fat/adverse effects , Dietary Fats, Unsaturated/metabolism , Plant Oils/metabolism , Trans Fatty Acids/pharmacology , Triglycerides/metabolism , Animals , Corn Oil/chemistry , Corn Oil/metabolism , Fatty Acids, Omega-3/administration & dosage , Fatty Acids, Omega-3/metabolism , Fatty Acids, Omega-6/administration & dosage , Fatty Acids, Omega-6/metabolism , Fatty Liver/metabolism , Leukotrienes/metabolism , Lipogenesis , Lipoprotein Lipase/metabolism , Lipoproteins, VLDL/metabolism , Liver/metabolism , Male , Mice , Olive Oil/chemistry , Olive Oil/metabolism , Oxidation-Reduction , Plant Oils/chemistry , Rapeseed Oil , Triglycerides/biosynthesisABSTRACT
INTRODUCTION: Evidences suggest that commercial and natural conjugated linoleic acids (CLA) differentially affect nutritional status and lipid metabolism. OBJECTIVE: To investigate the differential effect of two types of CLA preparations supplemented to dietary fats containing different proportions of n-9, n-6 and n-3 fatty acids (FA) on body composition, triacylglycerol (TG) levels and lipid metabolism in mice. METHODS: Growing mice were fed diets containing olive, maize and rapeseed oils supplemented with an equimolecular mixture of CLA (mix-CLA) or a rumenic acid (RA)-rich oil for 30 days. Body weight gain, carcass composition, tissue weights, plasma and tissue TG levels, and lipid regulation parameters were evaluated. RESULTS: Independently of the dietary fats, mix-CLA decreased body weight gain and fat depots related to lower energy efficiency, hepatomegaly, increase of serum TG and decrease of muscle TG. Rapeseed oil prevented the hepatic steatosis observed with mix-CLA supplementation to olive and maize oils by increasing TG secretion. RA-rich oil supplementation decreased fat depots without hepatomegaly, hepatic steatosis and hypertriglyceridemia. Olive oil, by an equilibrium between FA uptake/oxidation, prevented the increase of muscle TG induced by the RA-rich oil supplementation to maize and rapeseed oils. DISCUSSION AND CONCLUSION: The proportions of dietary unsaturated FA modulated the different mix-CLA and RA-rich oil response to lipid metabolism in mice. Finally, rapeseed oil prevented the hepatic steatosis induced by mix-CLA, and the most beneficial effects of RA-rich oil were observed when supplemented to olive oil, due to the reduced lipid accretion without changes in TG levels.
Introducción: Las evidencias sugieren que las mezclas de Ácido Linoleico Conjugado (ALC) de origen comercial o natural diferencialmente afectan diferencialment al estado nutricional y al metabolismo lipídico. Objetivo: Investigar el efecto de dos preparaciones de ALC como complemento de grasas dietarias con diferentes proporciones de ácidos grasos (AG) n-9, n-6 y n-3 sobre composición corporal, niveles de triacilglicéridos (TG) y metabolismo lipídico en ratones. Métodos: Se alimentó a ratones en crecimiento con dietas con aceite de oliva, maíz y canola, o colza suplementadas con una mezcla equimolecular de ALC (mezcla-ALC) o aceites ricos en ácido ruménico (AR) por 30 días. Se evaluó: ganancia de peso, composición corporal, peso de tejidos, niveles de TG plasmáticos y séricos, y parámetros de regulación lipídica. Resultados: Independientemente de las grasas dietarias, la mezcla-ALC redujo el peso corporal y depósitos grasos relacionados con hepatomegalia, incremento de TG séricos y descenso de TG musculares. El aceite de canola previno la esteatosis hepática producida por la mezcla-ALC a aceites de oliva y maíz por incremento de la secreción de TG. AR decreció los depósitos grasos sin hepatomegalia, esteatosis hepática e hipertrigliceridemia. Aceite de oliva previno el incremento de TG musculares inducidos por suplementación con AR al aceite de maíz y canola. Discusión y conclusión: Las proporciones de AG insaturados dietarios modularon la respuesta de mezcla-ALC y AR al metabolismo lipídico en ratones. Finalmente, aceite de canola previno la esteatosis hepática inducida por mezcla-ALC, y los efectos benéficos más notorios fueron observados cuando aceite de oliva fue suplementado con AR, debido a la reducida acreción de lípidos sin cambios en los niveles de TG.
Subject(s)
Body Composition/drug effects , Dietary Fats, Unsaturated/pharmacology , Linoleic Acid/pharmacology , Lipid Metabolism/drug effects , Animals , Fatty Acids/blood , Male , Mice , Triglycerides/bloodABSTRACT
Introduction: Evidences suggest that commercial and natural conjugated linoleic acids (CLA) differentially affect nutritional status and lipid metabolism. Objective: To investigate the differential effect of two types of CLA preparations supplemented to dietary fats containing different proportions of n-9, n-6 and n-3 fatty acids (FA) on body composition, triacylglycerol (TG)levels and lipid metabolism in mice. Methods: Growing mice were fed diets containing olive, maize and rapeseed oils supplemented with an equimolecular mixture of CLA (mix-CLA) or a rumenic acid (RA)-rich oil for 30 days. Body weight gain, carcass composition, tissue weights, plasma and tissue TG levels, and lipid regulation parameters were evaluated. Results: Independently of the dietary fats, mix-CLA decreased body weight gain and fat depots related to lower energy efficiency, hepatomegaly, increase of serum TG and decrease of muscle TG. Rapeseed oil prevented the hepaticsteatosis observed with mix-CLA supplementation to olive and maize oils by increasing TG secretion. RA-rich oil supplementation decreased fat depots without hepatomegaly, hepatic steatosis and hypertriglyceridemia. Olive oil, by an equilibrium between FA uptake/oxidation, prevented the increase of muscle TG induced by the RA-rich oil supplementation to maize and rapeseed oils. Discussion and conclusion: The proportions of dietary unsaturated FA modulated the different mix-CLA and RA-rich oil response to lipid metabolism in mice. Finally, rapeseed oil prevented the hepatic steatosis induced bymix-CLA, and the most beneficial effects of RA-rich oil were observed when supplemented to olive oil, due to the reduced lipid accretion without changes in TG levels (AU)
Introducción: Las evidencias sugieren que las mezclas de Ácido Linoleico Conjugado (ALC) de origen comercial o natural diferencialmente afectan deferencialmente al estado nutricional y al metabolismo lipídico. Objetivo: Investigar el efecto de dos preparaciones de ALC como complemento de grasas dietarias con diferentes proporciones de ácidos grasos (AG) n-9, n-6 y n-3sobre composición corporal, niveles de triacilglicéridos (TG) y metabolismo lipídico en ratones. Métodos: Se alimentó a ratones en crecimiento con dietas con aceite de oliva, maíz y canola, o colza suplementadas con una mezcla equimolecular de ALC (mezcla-ALC)o aceites ricos en ácido ruménico (AR) por 30 días. Se evaluó: ganancia de peso, composición corporal, peso de tejidos, niveles de TG plasmáticos y séricos, y parámetros de regulación lipídica. Resultados: Independientemente de las grasas dietarias,la mezcla-ALC redujo el peso corporal y depósitos grasos relacionados con hepatomegalia, incremento de TG séricos y descenso de TG musculares. El aceite de canola previnola esteatosis hepática producida por la mezcla-ALC a aceites de oliva y maíz por incremento de la secreción de TG.AR decreció los depósitos grasos sin hepatomegalia, esteatosis hepática e hipertrigliceridemia. Aceite de oliva previno el incremento de TG musculares inducidos por suplementación on AR al aceite de maíz y canola. Discusión y conclusión: Las proporciones de AG insaturados dietarios modularon la respuesta de mezcla-ALC y AR al metabolismo lipídico en ratones. Finalmente, aceite de canola previno la esteatosis hepática inducida por mezcla-ALC, y los efectos benéficos más notorios fueron observados cuando aceite de oliva fue suplementado con AR, debido a la reducida acreción de lípidos sin cambios en los niveles de TG (AU)
Subject(s)
Animals , Mice , Linoleic Acids, Conjugated/therapeutic use , Oils/therapeutic use , Nutrition Assessment , Nutritional Status , Models, Animal , Body Composition , Lipid Metabolism , Energy IntakeABSTRACT
AIM: Our aim was to investigate the effects of trans-fatty acids (TFA) on liver lipid metabolism in mice fed on experimental diets rich in either oleic or linoleic acid. METHODS: Twenty-two male CF1 mice (22.0 ± 0.1 g) were fed with diets rich in corn oil or olive oil, supplemented or not with TFA (0.75 g TFA/100 g diet), for 4 weeks. Changes in triacylglycerol content, the activity and expression of enzymes involved in lipogenesis and fatty acid oxidation were measured. RESULTS: Supplementation of an olive oil-rich diet with TFA increased liver triacylglycerols, the activity and expression of lipogenic enzymes and sterol regulatory element-binding protein SREBP-1a expression. By contrast, when TFA were added to a corn oil-rich diet, they did not modify these parameters. No significant differences were observed among the experimental groups in the activity and expression of carnitine palmitoyltransferase-Ia, body and liver weights or serum triacylglycerol concentrations. CONCLUSIONS: The effect of TFA on liver fat accumulation depends on the dietary fatty acid composition. Steatosis induced by TFA when included in an olive oil diet (but not in a corn oil diet) was associated with an increased lipogenesis but not with a decreased fatty acid oxidation in animals fed on the olive oil diet. This metabolic change is mediated by SREBP-1a but not by SREBP-1c, and seems to be independent of insulin.
Subject(s)
Dietary Fats/metabolism , Fatty Liver/etiology , Gene Expression Regulation , Lipid Metabolism , Liver/metabolism , Trans Fatty Acids/adverse effects , Animals , Corn Oil/adverse effects , Corn Oil/metabolism , Dietary Fats/adverse effects , Fatty Liver/enzymology , Fatty Liver/metabolism , Hydrogenation , Linoleic Acid/adverse effects , Linoleic Acid/metabolism , Lipogenesis , Liver/enzymology , Male , Mice , Mice, Inbred Strains , Oleic Acid/adverse effects , Oleic Acid/metabolism , Olive Oil , Oxidation-Reduction , Plant Oils/adverse effects , Plant Oils/metabolism , Random Allocation , Sterol Regulatory Element Binding Protein 1/metabolism , Triglycerides/adverse effects , Triglycerides/metabolismABSTRACT
PROBLEM: The aim of this study was to determine if dietary fatty acids (FA) level or isomeric FA type may affect reproductive parameters in mice. METHOD: of study Mice were fed for 1 month diets differing in cisFA (cFA) content or type of isomeric FA. Resorption, number of fetuses and placental cytokine expression were determined and sperm acrosome reaction was evaluated after induction by calcium ionophore. RESULTS: Mice fed high fat diets showed increased fetal resorptions, a decrease in interleukin (IL)-4 placental expression in the first generation and an increase of tumor necrosis factor-alpha (TNF-alpha) in the second generation. In this generation, conjugated linoleic acid (CLA) returned TNF-alpha to normal levels and diminished IL-4 and transforming growth factor-beta (TGF-beta) expressions; males fed transFA (tFA) and CLA showed a lower rate of induced acrosome reaction. CONCLUSION: The amount and type of dietary FA may affect reproductive performance in mice by affecting sperm membrane functionality and placental cytokine production.
Subject(s)
Dietary Fats/administration & dosage , Fatty Acids/administration & dosage , Reproduction/drug effects , Animals , Body Weight/drug effects , Dietary Fats/metabolism , Fatty Acids/metabolism , Female , Fetal Resorption/etiology , Fetal Resorption/metabolism , Interleukin-4/biosynthesis , Interleukin-4/immunology , Isomerism , Male , Mice , Organ Size/drug effects , Placenta/immunology , Reproduction/immunology , Reproduction/physiology , Spermatozoa/drug effects , Transforming Growth Factor beta2/biosynthesis , Transforming Growth Factor beta2/immunology , Tumor Necrosis Factor-alpha/immunologyABSTRACT
OBJECTIVE: Protein depletion is associated with decreased body weight gain, low nitrogen balance, intrahepatic lipid accumulation, and hypoalbuminemia. Because conjugated linoleic acid (CLA) can increase lean body mass, enhance feed efficiency, and modulate lipid metabolism, this study investigated the effects of CLA at two levels of dietary fat on energy efficiency, nitrogen retention, and plasmatic and hepatic lipid levels in rats during dietary protein repletion. METHODS: The animals were subjected to a moderate protein restriction for 14 d. After that, they were fed a protein repletion diet for 30 d, supplemented or not with CLA at recommended and high-fat levels. Energy efficiency, nitrogen balance, and nutritional parameters in serum and tissues were evaluated. RESULTS: Protein repletion improved most of the nutritional parameters evaluated independently of CLA supplementation at both fat levels. At recommended fat levels, CLA did not have any effect. At high-fat levels, energy efficiency increased more than 20% by fat accumulation in carcasses and epididymal pads, serum cholesterol increased (two-fold), and liver triacylglycerol accumulation remained elevated. However, at high-fat levels, CLA prevented lipid accumulation in liver and adipose tissue. CONCLUSION: Protein repletion improved the nutritional status of protein-restricted rats with minor effects of CLA at both dietary fat levels. However, when high-fat diets were given, CLA-enriched oil showed preventive effects on liver and adipose tissue lipid accumulation and no deleterious effects were observed. Because there are no studies dealing with CLA effects on protein repletion, this experimental model could improve nutritional interventions to overcome the protein-deficit stage.
