RESUMO
ATP citrate lyase (ACLY) is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA, which is a key precursor of both fatty acid and mevalonate synthesis pathways. Genetic variation of the ACLY gene may influence multiple traits associated with animal production. Here, we identified three non-synonymous mutations in ACLY exons in five beef cattle populations using DNA pool sequencing and high-resolution melting analysis. Results from association analyses revealed that the single nucleotide polymorphism (SNP) g.17127C>T is significantly associated with chest girth (P < 0.01) and body height (P < 0.05) in the Fleckvieh x Zhangye local crossbred cattle, and with body slanting length (P < 0.05) in the Simmental x Guyuan local crossbred cattle. SNP g.40427T>C is significantly associated with an increase in chest girth (P < 0.05) in the Simmental x Huzhu cattle population. These results provide preliminary evidence that polymorphisms in the bovine ACLY gene are associated with growth traits in beef cattle in northwest China. However, a larger sample set is needed to validate these findings.
Assuntos
ATP Citrato (pro-S)-Liase/genética , ATP Citrato (pro-S)-Liase/metabolismo , Bovinos/crescimento & desenvolvimento , Bovinos/genética , Animais , Sequência de Bases , Tamanho Corporal/genética , Peso Corporal/genética , Cruzamento , China , Éxons , Frequência do Gene , Variação Genética , Haplótipos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNARESUMO
Despite major advances in pharmacologic therapy over the last few decades, dyslipidemia remains a prevalent, insufficiently recognized, and undercontrolled risk factor for cardiovascular disease. Statins are the mainstay of hypercholesterolemia treatment, but because of adherence and tolerability issues that limit dose titration, there is a need for additional therapies with good efficacy and better tolerability. Adenosine triphosphate (ATP) citrate lyase, a cytoplasmic enzyme responsible for the generation of acetyl coenzyme A for the de novo synthesis of fatty acids and cholesterol, is a very interesting molecular target for the reduction of plasma lipids. Furthermore, ATP citrate lyase inhibition may be accompanied by activation of 5'-adenosine monophosphate-activated protein kinase, a key signaling molecule that acts a central hub in cellular metabolic regulation. ETC-1002 is a small molecule inhibitor of ATP citrate lyase that also activates 5'-adenosine monophosphate-activated protein kinase, effectively reducing low-density lipoprotein cholesterol and inducing some other positive metabolic changes. Recent evidence from phase I and II clinical trials in humans has shown a positive efficacy and safety profile of ETC-1002, with low-density lipoprotein cholesterol reductions similar to those attainable by usual doses of many statins and with no major apparent side effects. These results potentially introduce a new family of medications that may expand our therapeutic arsenal against hypercholesterolemia.
Assuntos
ATP Citrato (pro-S)-Liase , Ácidos Dicarboxílicos/uso terapêutico , Dislipidemias , Ácidos Graxos/uso terapêutico , ATP Citrato (pro-S)-Liase/antagonistas & inibidores , ATP Citrato (pro-S)-Liase/metabolismo , Animais , Colesterol/biossíntese , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Coenzima A/biossíntese , Dislipidemias/tratamento farmacológico , Dislipidemias/enzimologia , Ácidos Graxos/biossíntese , HumanosRESUMO
Endurance exercise has been shown to reduce pancreatic islets glucose-stimulated insulin secretion (GSIS). Anaplerotic/cataplerotic pathways are directly related to GSIS signaling. However, the effect of endurance training upon pancreatic islets anaplerotic enzymes is still unknown. In this sense, we tested the hypothesis that endurance exercise decreases GSIS by reducing anaplerotic/cataplerotic enzymes content. Male Wistar rats were randomly assigned to one of the four experimental groups as follows: control sedentary group (CTL), trained 1 day per week (TRE1×), trained 3 days per week (TRE3×) and trained 5 days per week (TRE5x) and submitted to an 8 weeks endurance-training protocol. After the training protocol, pancreatic islets were isolated and incubated with basal (2.8 mM) and stimulating (16.7 mM) glucose concentrations for GSIS measurement by radioimmunoassay. In addition, pyruvate carboxylase (PYC), pyruvate dehydrogenase (PDH), pyruvate dehydrogenase kinase 4 (PDK4), ATP-citrate lyase (ACL) and glutamate dehydrogenase (GDH) content were quantified by western blotting. Our data showed that 8 weeks of chronic endurance exercise reduced GSIS by 50% in a dose-response manner according to weekly exercise frequency. PYC showed significant twofold increase in TRE3×. PYC enhancement was even higher in TRE5× (p < 0.0001). PDH and PDK4 reached significant 25 and 50% enhancement, respectively compared with CTL. ACL and GDH also reported significant 50 and 75% increase, respectively. The absence of exercise-induced correlations among GSIS and anaplerotic/cataplerotic enzymes suggests that exercise may control insulin release by activating other signaling pathways. The observed anaplerotic and cataplerotic enzymes enhancement might be related to ß-cell surviving rather than insulin secretion.
Assuntos
Enzimas/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/enzimologia , Condicionamento Físico Animal/fisiologia , ATP Citrato (pro-S)-Liase/metabolismo , Animais , Enzimas/análise , Glucose/farmacologia , Glutamato Desidrogenase/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Masculino , Condicionamento Físico Animal/efeitos adversos , Resistência Física/fisiologia , Proteínas Quinases/metabolismo , Piruvato Carboxilase/metabolismo , Ratos , Ratos Wistar , Via Secretória/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
In rats, a high degree of brain development and myelination occurs during the first 15 days after birth. Ethanol intake by lactating rats modified 12 day-old pups' brain development and metabolism. The aim of the present study was to evaluate the effect of maternal ethanol ingestion during lactation on prepubertal (24-day-old) pups' brain and liver metabolism. Lactating rats (4 male and 4 female litters) were divided into 2 groups: control--received control liquid diet, and ethanol--received liquid diet containing 4% of ethanol. On postnatal day 24, the pups were killed by decapitation. Liver and brain were utilized for measuring Adenosine Tri-phosphate-citrate lyase and malic enzymes activities. Brain slices were incubated in medium containing glucose to determine glucose consumption and oxidation, and lipid synthesis. The ethanol intake decreased male and female pups' body, brain and liver weight. Liver Adenosine Tri-phosphate-citrate lyase activity was decreased only in male pups of the ethanol group. The intake of ethanol solution by the dams increased glucose consumption and oxidation by the incubated female pups' brain slices and decreased glucose oxidation by the male pups' brain slices. It can be concluded that the effects of maternal ethanol intake on pups' development and metabolism are gender-related.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Etanol/administração & dosagem , Lactação , Fígado/efeitos dos fármacos , Fígado/metabolismo , ATP Citrato (pro-S)-Liase/metabolismo , Animais , Animais Lactentes , Peso Corporal/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Feminino , Glucose/metabolismo , Fígado/crescimento & desenvolvimento , Malato Desidrogenase/metabolismo , Masculino , Tamanho do Órgão/efeitos dos fármacos , Oxirredução , Ratos , Ratos Wistar , Caracteres Sexuais , DesmameRESUMO
OBJECTIVE: We investigated the effect of diets rich in omega-6 and omega-3 fatty acids on hepatic metabolism. METHODS: Male Wistar rats, just weaned, were fed ad libitum for 8 wk with one of the following diets: rat chow (C), rat chow containing 15% (w/w) soybean oil (S), rat chow containing 15% (w/w) fish oil (F), and rat chow containing 15% soy bean and fish oil (SF; 5:1, w/w). Casein was added to the fatty diets to achieve the same content of protein (20%) as the control chow. The rats were killed by decapitation, and the hepatic tissue was removed and weighed. Tissue lipid, glycogen, and protein content, in vivo lipogenesis rate, and adenosine triphosphate citrate lyase and malic enzyme activities were evaluated. Plasma total lipids, triacylglycerol, and cholesterol concentrations were assessed. RESULTS: Body weight gain was higher in F and SF than in C and S rats. Liver weight, lipid content, and lipogenesis rate increased in F and SF rats, although adenosine triphosphate citrate lyase activity decreased. Glycogen concentration decreased in S, F, and SF rats compared with C rats. Plasma total lipids and triacylglycerol concentrations were lower in F and SF than in C rats. Total and high-density lipoprotein cholesterol (HDL-C) plasma levels decreased in F rats, with maintenance of the total:HDL-C ratio. In SF rats, an increase in HDL-C led to a lower total:HDL-C ratio. CONCLUSIONS: These results indicated that an enrichment of the diet with omega-3 polyunsaturated fatty acids produces hypolipidemia but may cause changes in liver metabolism that favor lipid deposition. They also suggested that the addition of a small amount of eicosapentaenoic and docosahexaenoic polyunsaturated fatty acids to an omega-6-rich diet further improve the circulating lipid profile, in comparison with an omega-3-rich diet, but it does not prevent excess liver lipid accumulation.
Assuntos
Peso Corporal/efeitos dos fármacos , Dieta , Gorduras Insaturadas na Dieta/metabolismo , Ácidos Graxos Insaturados/metabolismo , Fígado/metabolismo , ATP Citrato (pro-S)-Liase/efeitos dos fármacos , ATP Citrato (pro-S)-Liase/metabolismo , Animais , Colesterol/sangue , Colesterol/metabolismo , Metabolismo dos Lipídeos , Glicogênio Hepático/metabolismo , Malato Desidrogenase/efeitos dos fármacos , Malato Desidrogenase/metabolismo , Masculino , Tamanho do Órgão/efeitos dos fármacos , Proteínas/efeitos dos fármacos , Proteínas/metabolismo , Ratos , Ratos Wistar , Triglicerídeos/sangue , Triglicerídeos/metabolismoRESUMO
Although trans fatty acids are known to influence essential fatty acid (EFA) metabolism and serum levels of lipids and lipoproteins, little is known about their effects on the metabolism of mammary glands (MGs) during lactation. In this study, 5 groups of lactating Wistar rats were fed semisynthetic diets containing 7% soy oil (control); 7% partially hydrogenated vegetable oil (7% PHVO); 13% PHVO +7% soy oil (13% PHVO); 5% PHVO +2% soy oil (5% PHVO), and 3.5% PHVO +3.5% soy oil (3.5% PHVO). Dams were killed on the 12th day of lactation. Weight, lipid content (LC), in vivo lipogenesis rate (LR) and activity of the lipogenic (ATP-citrate lyase and malic) enzymes were evaluated in the MGs. Maternal food intake, weight gain, and total MG weight were not found to be significantly different between the groups. The groups with 13, 7 and 5% PHVO presented a lower (p < 0.05) LR in MGs when compared to controls, whereas MG LC was higher in the 7 and 13% groups than in controls. The observed decrease in MG lipogenesis was accompanied by a diminution (p < 0.05) in the activities of ATP-citrate lyase and malic enzymes. These data indicate a potential impairment of lipid metabolism in the MG by trans isomers in lactating rats.
Assuntos
Ácidos Graxos/administração & dosagem , Lactação/metabolismo , Lipídeos/biossíntese , Glândulas Mamárias Animais/metabolismo , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , ATP Citrato (pro-S)-Liase/metabolismo , Análise de Variância , Animais , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Malato Desidrogenase/metabolismo , Ratos , Ratos Wistar , Fatores de TempoRESUMO
The effect of cold acclimation on brown adipose tissue (BAT) fatty acid synthesis was investigated in rats adapted to a high-protein, carbohydrate-free diet. At an ambient temperature (25 degrees C), rates of fatty acid synthesis in BAT from rats adapted to the high-protein diet were reduced to 27% of rats fed the balanced diet and increased markedly after cold acclimation (10 days at 4 degrees C), although the increase was smaller than in control rats. BAT weight increase induced by cold acclimation was smaller in rats fed the high-protein diet (30%) than in controls (100%). When expressed per whole tissue, maximal activities of BAT glucose-6-phosphate dehydrogenase, malic enzyme, adenosine triphosphate (ATP)-citrate lyase, and acetyl-coenzyme A carboxylase were markedly reduced in high-protein diet-adapted rats at 25 degrees C and increased after cold acclimation in BAT from the 2 groups. However, when expressed per milligram protein, only acetyl-coenzyme A carboxylase showed an increase in both controls and in rats fed the high-protein diet. G6P-dehydrogenase, malic enzyme, and ATP-citrate lyase increased (per milligram protein) only in rats adapted to the high-protein diet and actually decreased in BAT from cold-acclimated control rats. Initial (before activation) pyruvate dehydrogenase (PDH) complex activity was lower in BAT from rats fed the high-protein diet at 25 degrees C and increased in cold-acclimated rats from the 2 groups. Circulating levels of insulin decreased in the 2 groups after cold acclimation. The data suggest that the cold acclimation-induced increase in BAT lipogenesis in rats adapted to the high-protein diet was due to a restoration of sympathetic activity, which induced both BAT hyperplasia and activation of adipocyte free fatty acid (FFA) synthesis, with an important participation of acetyl-coenzyme A carboxylase and pyruvate dehydrogenase.
Assuntos
Aclimatação , Tecido Adiposo Marrom/metabolismo , Temperatura Baixa , Carboidratos da Dieta/administração & dosagem , Proteínas Alimentares/administração & dosagem , Ácidos Graxos/biossíntese , ATP Citrato (pro-S)-Liase/metabolismo , Acetil-CoA Carboxilase/metabolismo , Adaptação Fisiológica , Tecido Adiposo Marrom/anatomia & histologia , Animais , Temperatura Corporal , Glucosefosfato Desidrogenase/metabolismo , Malato Desidrogenase/metabolismo , Masculino , Tamanho do Órgão , Complexo Piruvato Desidrogenase/metabolismo , Ratos , Ratos WistarRESUMO
Although adrenal glucocorticoids were known to be important for adequate milk production, little is known about their effects on the metabolism of mammary glands during lactation. In this study, lactating Wistar rats on the 12th day of lactation were divided in the following groups: sham-operated (SO) and adrenalectomized (ADX) receiving no treatment; SO and ADX starved for 24 h and refed intragastrically with 2.5 ml of 50% glucose solution, 2 h before the experiment (SOR and ADXR) and ADX receiving substitute therapy with dexamethasone (ADX + DEX). Sacrifices were performed 2 days after surgery. Weight, lipid content and in vivo lipogenesis rate were evaluated in mammary gland (M.GLAND), liver, parametrial white adipose tissue (PARA) and interescapular brown adipose tissue (BAT). ATP citrate lyase activity was measured in M.GLAND, liver and PARA of SO, ADX and ADX + DEX. The rate of lipogenesis and 14CO2 production from 14C-glucose by isolated acini from M.GLAND and plasma glucose were also determined. In ADX rats, food intake, lipid content, in vivo lipogenesis rate and ATP citrate lyase activity in M.GLAND were significantly lower than those in SO rats. The M.GLAND lipogenesis rate of SOR group was similar to the value found in SO rats. In ADXR rats, the M.GLAND lipogenesis rate was not normalized. However, the therapy with DEX elevated lipid content, in vivo lipogenesis rate and ATP citrate lyase activity to levels similar to those in SO. These results suggest that the glucocorticoids are essential for the occurrence of normal lipid synthesis in M.GLAND during lactation.
Assuntos
Adrenalectomia , Dexametasona/uso terapêutico , Glucocorticoides/uso terapêutico , Lactação/fisiologia , Metabolismo dos Lipídeos , ATP Citrato (pro-S)-Liase/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Glicemia/metabolismo , Peso Corporal , Ingestão de Alimentos , Feminino , Lipídeos/biossíntese , Fígado/metabolismo , Glândulas Mamárias Animais/metabolismo , Ratos , Ratos WistarRESUMO
Follicle-stimulating hormone (FSH) and insulin regulate glycide metabolism in Sertoli cells, thus stimulating lactate production. These stimulatory effects of FSH and insulin do not require protein synthesis, suggesting a modulation of enzyme activity and/or regulation of glucose transport. The present investigation was performed to characterize the hormonal control of lipid metabolism in Sertoli cells. The data indicate that FSH and insulin have a regulatory effect on lipid metabolism in Sertoli cells. After 8 h of preincubation with insulin (5 micrograms/ml), the activity of the enzyme ATP-citrate lyase in cultured Sertoli cells was increased from 0.19 to 0.34 nmol NAD+ formed microgram protein-1 min-1. FSH (100 ng/ml) had no effect on this enzyme. Glycerol phosphate dehydrogenase activity was not affected by any of the hormones tested. When Sertoli cells from 19-day old rats were incubated with [1,2-14C]acetate for 90 or 360 min, the [14C] label was present predominantly in triglyceride and phospholipid fractions with minor amounts in other lipids. In Sertoli cells pretreated for 16 h with insulin and FSH, an increase in acetate incorporation into lipids was observed. Most of the label was in esterified lipids and this percentage increased with the time of treatment; this increase was remarkable in triglycerides of control cells (18.8% to 30.6%). Since Sertoli cell triglycerides participate in the control of spermatogenesis, the present data suggest that the hormonal control of lipid metabolism in Sertoli cells is important not only for maintaining the energy of the cell itself, but also for the control of the spermatogenesis process.
Assuntos
Hormônio Foliculoestimulante/metabolismo , Insulina/metabolismo , Ácido Láctico/biossíntese , Lipídeos/biossíntese , Células de Sertoli/metabolismo , ATP Citrato (pro-S)-Liase/metabolismo , Acetatos/metabolismo , Animais , Técnicas de Cultura de Células , Glucose/metabolismo , Glicerolfosfato Desidrogenase/metabolismo , Masculino , Ratos , Ratos WistarRESUMO
Follicle-stimulating hormone (FSH) and insulin regulate glycide metabolism in Sertoli cells, thus stimulating lactate production. These stimulatory effects of FSH and insulin do not require protein synthesis, suggesting a modulation of enzyme activity and/or regulation of glucose transport. The present investigation was performed to characterize the hormonal control of lipid metabolism in Sertoli cells. The data indicate that FSH and insulin have a regulatory effect on lipid metabolism in Sertoli cells. After 8 h of preincubation with insulin (5 mug/ml), the activity of the enzyme ATP-citrate lyase in sultured Sertoli cells was increased from 0.19 to 0.34 nmol NAD+ formed mug protein(-1) min(-1). FSH (100 ng/ml) had no effect on this enzyme. Glycerol phosphate dehydrogenase activity was not affected by any of the hormones tested. When Sertoli cells from 19-day old rats were incubated with [1,2-14C] acetate for 90 or 360 min, the [14C] label was present predominantly in triglyceride and phospholipid fractions with minor amounts in other lipids. In Sertoli cells pretreated for 16 h with insulin and FSH, an increase in acetate incorporation into lipids was observed. Most of the label was in esterified lipids and this percentage increased with the time of treatment; this increase was remarkable in triglycerides of control cells (18.8 percent to 30.6 percent). Since Sertoli cell triglycerides participate in the control of spermatogenesis, the present data suggest that the hormonal control of lipid metabolism in Sertoli cells is important not only for maintaining the energy of the cell itself, but also for the control of the spermatogenesis process.