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1.
Int J Mol Sci ; 25(13)2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-39000145

RESUMO

Alanine and glutamine are the principal glucogenic amino acids. Most originate from muscles, where branched-chain amino acids (valine, leucine, and isoleucine) are nitrogen donors and, under exceptional circumstances, a source of carbons for glutamate synthesis. Glutamate is a nitrogen source for alanine synthesis from pyruvate and a substrate for glutamine synthesis by glutamine synthetase. The following differences between alanine and glutamine, which can play a role in their use in gluconeogenesis, are shown: (i) glutamine appearance in circulation is higher than that of alanine; (ii) the conversion to oxaloacetate, the starting substance for glucose synthesis, is an ATP-consuming reaction for alanine, which is energetically beneficial for glutamine; (iii) most alanine carbons, but not glutamine carbons, originate from glucose; and (iv) glutamine acts a substrate for gluconeogenesis in the liver, kidneys, and intestine, whereas alanine does so only in the liver. Alanine plays a significant role during early starvation, exposure to high-fat and high-protein diets, and diabetes. Glutamine plays a dominant role in gluconeogenesis in prolonged starvation, acidosis, liver cirrhosis, and severe illnesses like sepsis and acts as a substrate for alanine synthesis in the small intestine. Interactions among muscles and the liver, kidneys, and intestine ensuring optimal alanine and glutamine supply for gluconeogenesis are suggested.


Assuntos
Alanina , Gluconeogênese , Glutamina , Intestino Delgado , Rim , Fígado , Glutamina/metabolismo , Alanina/metabolismo , Fígado/metabolismo , Animais , Rim/metabolismo , Humanos , Intestino Delgado/metabolismo , Glucose/metabolismo
2.
Nutrients ; 15(18)2023 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-37764806

RESUMO

Aspartic acid exists in L- and D-isoforms (L-Asp and D-Asp). Most L-Asp is synthesized by mitochondrial aspartate aminotransferase from oxaloacetate and glutamate acquired by glutamine deamidation, particularly in the liver and tumor cells, and transamination of branched-chain amino acids (BCAAs), particularly in muscles. The main source of D-Asp is the racemization of L-Asp. L-Asp transported via aspartate-glutamate carrier to the cytosol is used in protein and nucleotide synthesis, gluconeogenesis, urea, and purine-nucleotide cycles, and neurotransmission and via the malate-aspartate shuttle maintains NADH delivery to mitochondria and redox balance. L-Asp released from neurons connects with the glutamate-glutamine cycle and ensures glycolysis and ammonia detoxification in astrocytes. D-Asp has a role in brain development and hypothalamus regulation. The hereditary disorders in L-Asp metabolism include citrullinemia, asparagine synthetase deficiency, Canavan disease, and dicarboxylic aminoaciduria. L-Asp plays a role in the pathogenesis of psychiatric and neurologic disorders and alterations in BCAA levels in diabetes and hyperammonemia. Further research is needed to examine the targeting of L-Asp metabolism as a strategy to fight cancer, the use of L-Asp as a dietary supplement, and the risks of increased L-Asp consumption. The role of D-Asp in the brain warrants studies on its therapeutic potential in psychiatric and neurologic disorders.

3.
Metabolism ; 145: 155614, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37286128

RESUMO

Gluconeogenesis, a pathway for glucose synthesis from non-carbohydrate substances, begins with the synthesis of oxaloacetate (OA) from pyruvate and intermediates of citric acid cycle in hepatocyte mitochondria. The traditional view is that OA does not cross the mitochondrial membrane and must be shuttled to the cytosol, where most enzymes involved in gluconeogenesis are compartmentalized, in the form of malate. Thus, the possibility of transporting OA in the form of aspartate has been ignored. In the article is shown that malate supply to the cytosol increases only when fatty acid oxidation in the liver is activated, such as during starvation or untreated diabetes. Alternatively, aspartate synthesized from OA by mitochondrial aspartate aminotransferase (AST) is transported to the cytosol in exchange for glutamate via the aspartate-glutamate carrier 2 (AGC2). If the main substrate for gluconeogenesis is an amino acid, aspartate is converted to OA via urea cycle, therefore, ammonia detoxification and gluconeogenesis are simultaneously activated. If the main substrate is lactate, OA is synthesized by cytosolic AST, glutamate is transported to the mitochondria through AGC2, and nitrogen is not lost. It is concluded that, compared to malate, aspartate is a more suitable form of OA transport from the mitochondria for gluconeogenesis.


Assuntos
Ácido Aspártico , Gluconeogênese , Ácido Aspártico/metabolismo , Malatos , Glutamatos/metabolismo , Ácido Pirúvico , Ácido Láctico
4.
BMB Rep ; 56(7): 385-391, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37254569

RESUMO

Aspartate-glutamate carrier 2 (AGC2, citrin) is a mitochondrial carrier expressed in the liver that transports aspartate from mitochondria into the cytosol in exchange for glutamate. The AGC2 is the main component of the malate-aspartate shuttle (MAS) that ensures indirect transport of NADH produced in the cytosol during glycolysis, lactate oxidation to pyruvate, and ethanol oxidation to acetaldehyde into mitochondria. Through MAS, AGC2 is necessary to maintain intracellular redox balance, mitochondrial respiration, and ATP synthesis. Through elevated cytosolic Ca2+ level, the AGC2 is stimulated by catecholamines and glucagon during starvation, exercise, and muscle wasting disorders. In these conditions, AGC2 increases aspartate input to the urea cycle, where aspartate is a source of one of two nitrogen atoms in the urea molecule (the other is ammonia), and a substrate for the synthesis of fumarate that is gradually converted to oxaloacetate, the starting substrate for gluconeogenesis. Furthermore, aspartate is a substrate for the synthesis of asparagine, nucleotides, and proteins. It is concluded that AGC2 plays a fundamental role in the compartmentalization of aspartate and glutamate metabolism and linkage of the reactions of MAS, glycolysis, gluconeogenesis, amino acid catabolism, urea cycle, protein synthesis, and cell proliferation. Targeting of AGC genes may represent a new therapeutic strategy to fight cancer. [BMB Reports 2023; 56(7): 385-391].


Assuntos
Ácido Aspártico , Glucose , Glucose/metabolismo , Ácido Aspártico/metabolismo , Fígado/metabolismo , Ácido Glutâmico/metabolismo
5.
Int J Mol Sci ; 24(2)2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36675238

RESUMO

The most frequent alterations in plasma amino acid concentrations in type 1 and type 2 diabetes are decreased L-serine and increased branched-chain amino acid (BCAA; valine, leucine, and isoleucine) levels. The likely cause of L-serine deficiency is decreased synthesis of 3-phosphoglycerate, the main endogenous precursor of L-serine, due to impaired glycolysis. The BCAA levels increase due to decreased supply of pyruvate and oxaloacetate from glycolysis, enhanced supply of NADH + H+ from beta-oxidation, and subsequent decrease in the flux through the citric acid cycle in muscles. These alterations decrease the supply of α-ketoglutarate for BCAA transamination and the activity of branched-chain keto acid dehydrogenase, the rate-limiting enzyme in BCAA catabolism. L-serine deficiency contributes to decreased synthesis of phospholipids and increased synthesis of deoxysphinganines, which play a role in diabetic neuropathy, impaired homocysteine disposal, and glycine deficiency. Enhanced BCAA levels contribute to increased levels of aromatic amino acids (phenylalanine, tyrosine, and tryptophan), insulin resistance, and accumulation of various metabolites, whose influence on diabetes progression is not clear. It is concluded that amino acid concentrations should be monitored in patients with diabetes, and systematic investigation is needed to examine the effects of L-serine and glycine supplementation on diabetes progression when these amino acids are decreased.


Assuntos
Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Aminoácidos de Cadeia Ramificada/metabolismo , Aminoácidos/metabolismo , Ácido Pirúvico , Glicólise , Glicina/metabolismo , Serina/metabolismo
6.
Metabolites ; 12(10)2022 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-36295872

RESUMO

Studies from the last decades indicate that increased levels of ammonia contribute to muscle wasting in critically ill patients. The aim of the article is to examine the effects of two different causes of hyperammonemia-increased ATP degradation in muscles during strenuous exercise and impaired ammonia detoxification to urea due to liver cirrhosis. During exercise, glycolysis, citric acid cycle (CAC) activity, and ATP synthesis in muscles increase. In cirrhosis, due to insulin resistance and mitochondrial dysfunction, glycolysis, CAC activity, and ATP synthesis in muscles are impaired. Both during exercise and in liver cirrhosis, there is increased ammonia detoxification to glutamine (Glu + NH3 + ATP → Gln + ADP + Pi), increased drain of ketoglutarate (α-KG) from CAC for glutamate synthesis by α-KG-linked aminotransferases, glutamate, aspartate, and α-KG deficiency, increased oxidation of branched-chain amino acids (BCAA; valine, leucine, and isoleucine), and protein-energy wasting in muscles. It is concluded that ammonia can contribute to muscle wasting regardless of the cause of its increased levels and that similar strategies can be designed to increase muscle performance in athletes and reduce muscle loss in patients with hyperammonemia. The pros and cons of glutamate, α-KG, aspartate, BCAA, and branched-chain keto acid supplementation are discussed.

7.
Nutrients ; 14(9)2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35565953

RESUMO

L-serine plays an essential role in a broad range of cellular functions including protein synthesis, neurotransmission, and folate and methionine cycles and synthesis of sphingolipids, phospholipids, and sulphur containing amino acids. A hydroxyl side-chain of L-serine contributes to polarity of proteins, and serves as a primary site for binding a phosphate group to regulate protein function. D-serine, its D-isoform, has a unique role. Recent studies indicate increased requirements for L-serine and its potential therapeutic use in some diseases. L-serine deficiency is associated with impaired function of the nervous system, primarily due to abnormal metabolism of phospholipids and sphingolipids, particularly increased synthesis of deoxysphingolipids. Therapeutic benefits of L-serine have been reported in primary disorders of serine metabolism, diabetic neuropathy, hyperhomocysteinemia, and amyotrophic lateral sclerosis. Use of L-serine and its metabolic products, specifically D-serine and phosphatidylserine, has been investigated for the therapy of renal diseases, central nervous system injury, and in a wide range of neurological and psychiatric disorders. It is concluded that there are disorders in which humans cannot synthesize L-serine in sufficient quantities, that L-serine is effective in therapy of disorders associated with its deficiency, and that L-serine should be classified as a "conditionally essential" amino acid.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Serina , Aminoácidos Essenciais , Humanos , Fosfolipídeos , Esfingolipídeos/metabolismo
8.
Biomolecules ; 10(11)2020 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-33114049

RESUMO

Beta-hydroxy-beta-methyl butyrate (HMB) is a unique product of leucine catabolism with positive effects on protein balance. We have examined the effects of HMB (200 mg/kg/day via osmotic pump for 7 days) on rats with diabetes induced by streptozotocin (STZ, 100 mg/kg intraperitoneally). STZ induced severe diabetes associated with muscle wasting, decreased ATP in the liver, and increased α-ketoglutarate in muscles. In plasma, liver, and muscles increased branched-chain amino acids (BCAAs; valine, isoleucine, and leucine) and decreased serine. The decreases in mass and protein content of muscles and increases in BCAA concentration were more pronounced in extensor digitorum longus (fast-twitch muscle) than in soleus muscle (slow-twitch muscle). HMB infusion to STZ-treated animals increased glycemia and serine in the liver, decreased BCAAs in plasma and muscles, and decreased ATP in the liver and muscles. The effects of HMB on the weight and protein content of tissues were nonsignificant. We concluded that fast-twitch muscles are more sensitive to STZ than slow-twitch muscles and that HMB administration to STZ-treated rats has dual effects. Adjustments of BCAA concentrations in plasma and muscles and serine in the liver can be considered beneficial, whereas the increased glycemia and decreased ATP concentrations in the liver and muscles are detrimental.


Assuntos
Aminoácidos/farmacologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Fígado/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Valeratos/farmacologia , Aminoácidos/administração & dosagem , Animais , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/metabolismo , Injeções Intraperitoneais , Injeções Subcutâneas , Fígado/metabolismo , Masculino , Músculo Esquelético/metabolismo , Ratos , Ratos Wistar , Estreptozocina/administração & dosagem , Valeratos/administração & dosagem
9.
Nutrients ; 12(10)2020 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-33050579

RESUMO

Branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) are increased in starvation and diabetes mellitus. However, the pathogenesis has not been explained. It has been shown that BCAA catabolism occurs mostly in muscles due to high activity of BCAA aminotransferase, which converts BCAA and α-ketoglutarate (α-KG) to branched-chain keto acids (BCKAs) and glutamate. The loss of α-KG from the citric cycle (cataplerosis) is attenuated by glutamate conversion to α-KG in alanine aminotransferase and aspartate aminotransferase reactions, in which glycolysis is the main source of amino group acceptors, pyruvate and oxaloacetate. Irreversible oxidation of BCKA by BCKA dehydrogenase is sensitive to BCKA supply, and ratios of NADH to NAD+ and acyl-CoA to CoA-SH. It is hypothesized that decreased glycolysis and increased fatty acid oxidation, characteristic features of starvation and diabetes, cause in muscles alterations resulting in increased BCAA levels. The main alterations include (i) impaired BCAA transamination due to decreased supply of amino groups acceptors (α-KG, pyruvate, and oxaloacetate) and (ii) inhibitory influence of NADH and acyl-CoAs produced in fatty acid oxidation on citric cycle and BCKA dehydrogenase. The studies supporting the hypothesis and pros and cons of elevated BCAA concentrations are discussed in the article.


Assuntos
Aminoácidos de Cadeia Ramificada/metabolismo , Diabetes Mellitus/metabolismo , Inanição/metabolismo , Alanina/metabolismo , Ácidos Graxos/metabolismo , Feminino , Glicólise , Humanos , Insulina/metabolismo , Resistência à Insulina , Ácidos Cetoglutáricos/metabolismo , Masculino , Músculos/enzimologia , Músculos/metabolismo , Obesidade/metabolismo , Oxirredução , Piruvatos/farmacocinética , Transaminases/metabolismo
10.
Int J Exp Pathol ; 101(5): 171-182, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32869427

RESUMO

A feared adverse effect of dyslipidaemia therapy by fibrates is myopathy. We examined the effect of fenofibrate (FF) on protein and amino acid metabolism. Rats received a low (50 mg/kg, LFFD) or high (300 mg/kg, HFFD) dose of FF or vehicle daily by oral gavage. Blood plasma, liver, and soleus and extensor digitorum longus muscles were analysed after 10 days. The FF-treated rats developed hepatomegaly associated with increased hepatic carnitine and ATP and AMP concentrations, decreased protein breakdown, and decreased concentrations of DNA and triglycerides. HFFD increased plasma ALT and AST activities. The weight and protein content of muscles in the HFFD group were lower compared with controls. In muscles of the LFFD group there were increased ATP and decreased AMP concentrations; in the HFFD group AMP was increased. In both FF-treated groups there were increased glycine, phenylalanine, and citrulline and decreased arginine and branched-chain keto acids (BCKA) in blood plasma. After HFFD there were decreased levels of branched-chain amino acids (BCAA; valine, leucine and isoleucine), methionine, and lysine and increased homocysteine. Decreased arginine and increased glycine concentrations were found in both muscles in FF-treated animals; in HFFD-treated animals lysine, methionine, and BCAA were decreased. We conclude that FF exerts protein-anabolic effects on the liver and catabolic effects on muscles. HFFD causes signs of hepatotoxicity, impairs energy and protein balance in muscles, and decreases BCAA, methionine, and lysine. It is suggested that increased glycine and decreased lysine and methionine levels are due to activated carnitine synthesis; decreased BCAA and BCKA levels are due to increased BCAA oxidation.


Assuntos
Aminoácidos/metabolismo , Metabolismo Energético/efeitos dos fármacos , Fenofibrato/administração & dosagem , Hipolipemiantes/administração & dosagem , Proteínas/metabolismo , Aminoácidos/efeitos dos fármacos , Aminoácidos de Cadeia Ramificada/sangue , Animais , Carnitina/sangue , Glicina/metabolismo , Hepatomegalia/induzido quimicamente , Hepatomegalia/metabolismo , Humanos , Leucina/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Lisina/metabolismo , Masculino , Metionina/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Oxirredução , Proteínas/efeitos dos fármacos , Ratos , Ratos Wistar
11.
Metabolites ; 10(8)2020 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-32784821

RESUMO

In hyperammonemic states, such as liver cirrhosis, urea cycle disorders, and strenuous exercise, the catabolism of branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) is activated and BCAA concentrations decrease. In these conditions, BCAAs are recommended to improve mental functions, protein balance, and muscle performance. However, clinical trials have not demonstrated significant benefits of BCAA-containing supplements. It is hypothesized that, under hyperammonemic conditions, enhanced glutamine availability and decreased BCAA levels facilitate the amination of branched-chain keto acids (BCKAs; α-ketoisocaproate, α-keto-ß-methylvalerate, and α-ketoisovalerate) to the corresponding BCAAs, and that BCKA supplementation may offer advantages over BCAAs. Studies examining the effects of ketoanalogues of amino acids have provided proof that subjects with hyperammonemia can effectively synthesize BCAAs from BCKAs. Unfortunately, the benefits of BCKA administration have not been clearly confirmed. The shortcoming of most reports is the use of mixtures intended for patients with renal insufficiency, which might be detrimental for patients with liver injury. It is concluded that (i) BCKA administration may decrease ammonia production, attenuate cataplerosis, correct amino acid imbalance, and improve protein balance and (ii) studies specifically investigating the effects of BCKA, without the interference of other ketoanalogues, are needed to complete the information essential for decisions regarding their suitability in hyperammonemic conditions.

12.
Nutrients ; 12(3)2020 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-32235743

RESUMO

L-histidine (HIS) is an essential amino acid with unique roles in proton buffering, metal ion chelation, scavenging of reactive oxygen and nitrogen species, erythropoiesis, and the histaminergic system. Several HIS-rich proteins (e.g., haemoproteins, HIS-rich glycoproteins, histatins, HIS-rich calcium-binding protein, and filaggrin), HIS-containing dipeptides (particularly carnosine), and methyl- and sulphur-containing derivatives of HIS (3-methylhistidine, 1-methylhistidine, and ergothioneine) have specific functions. The unique chemical properties and physiological functions are the basis of the theoretical rationale to suggest HIS supplementation in a wide range of conditions. Several decades of experience have confirmed the effectiveness of HIS as a component of solutions used for organ preservation and myocardial protection in cardiac surgery. Further studies are needed to elucidate the effects of HIS supplementation on neurological disorders, atopic dermatitis, metabolic syndrome, diabetes, uraemic anaemia, ulcers, inflammatory bowel diseases, malignancies, and muscle performance during strenuous exercise. Signs of toxicity, mutagenic activity, and allergic reactions or peptic ulcers have not been reported, although HIS is a histamine precursor. Of concern should be findings of hepatic enlargement and increases in ammonia and glutamine and of decrease in branched-chain amino acids (valine, leucine, and isoleucine) in blood plasma indicating that HIS supplementation is inappropriate in patients with liver disease.


Assuntos
Suplementos Nutricionais , Histidina , Aminoácidos de Cadeia Ramificada/metabolismo , Amônia/metabolismo , Quelantes , Contraindicações , Dermatite Atópica/terapia , Proteínas Filagrinas , Sequestradores de Radicais Livres , Glutamina/metabolismo , Histamina , Histidina/efeitos adversos , Histidina/química , Histidina/fisiologia , Histidina/uso terapêutico , Humanos , Hipertrofia/etiologia , Fígado/metabolismo , Fígado/patologia , Hepatopatias/metabolismo , Síndrome Metabólica/terapia , Doenças do Sistema Nervoso/terapia , Soluções para Preservação de Órgãos
13.
Amino Acids ; 51(10-12): 1667-1680, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31712921

RESUMO

The unique capability of proton buffering is the rationale for using histidine (HIS) as a component of solutions for induction of cardiac arrest and myocardial protection in cardiac surgery. In humans, infusion of cardioplegic solution may increase blood plasma HIS from ~ 70 to ~ 21,000 µM. We examined the effects of a large intravenous dose of HIS on ammonia and amino acid concentrations and energy status of the body. Rats received 198 mM HIS intravenously (20 ml/kg) or vehicle. Samples of blood plasma, urine, liver, and soleus (SOL) and extensor digitorum longus (EDL) muscles were analysed at 2 or 24 h after treatment. At 2 h after HIS load, we found higher HIS concentration in all examined tissues, higher urea and ammonia concentrations in blood and urine, lower ATP content and higher AMP/ATP ratio in the liver and muscles, higher concentrations of almost all examined amino acids in urine, and lower glycine concentration in blood plasma, liver, and muscles when compared with controls. Changes in other amino acids were tissue dependent, markedly increased alanine and glutamate in the blood and the liver. At 24 h, the main findings were lower ATP concentrations in muscles, lower concentrations of branched-chain amino acids (BCAA; valine, leucine, and isoleucine) in blood plasma and muscles, and higher carnosine content in SOL when compared with controls. It is concluded that a load of large HIS dose results in increased ammonia levels and marked alterations in amino acid and energy metabolism. Pathogenesis is discussed in the article.


Assuntos
Nucleotídeos de Adenina/metabolismo , Aminoácidos/metabolismo , Amônia/metabolismo , Histidina/metabolismo , Administração Intravenosa , Aminoácidos/química , Animais , Soluções Cardioplégicas/química , Carnosina/metabolismo , Metabolismo Energético , Histidina/administração & dosagem , Histidina/análise , Ácidos Cetoglutáricos/metabolismo , Masculino , Especificidade de Órgãos , Ratos , Ratos Wistar , Distribuição Tecidual , Ureia/metabolismo
14.
Int J Exp Pathol ; 100(3): 175-183, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31321841

RESUMO

Beta-hydroxy-beta-methylbutyrate (HMB) is a leucine metabolite with protein anabolic effects. We examined the effects of an HMB-enriched diet in healthy rats and rats with liver cirrhosis induced by multiple doses of carbon tetrachloride (CCl4). HMB increased branched-chain amino acids (BCAAs; valine, leucine and isoleucine) in blood and BCAA and ATP in muscles of healthy animals. The effect on muscle mass and protein content was insignificant. In CCl4-treated animals alterations characteristic of liver cirrhosis were found with decreased ratio of the BCAA to aromatic amino acids in blood and lower muscle mass and ATP content when compared with controls. In CCl4-treated animals consuming HMB, we observed higher mortality, lower body weight, higher BCAA levels in blood plasma, higher ATP content in muscles, and lower ATP content and higher cathepsin B and L activities in the liver when compared with CCl4-treated animals without HMB. We conclude that (1) HMB supplementation has a positive effect on muscle mitochondrial function and enhances BCAA concentrations in healthy animals and (2) the effects of HMB on the course of liver cirrhosis in CCl4-treated rats are detrimental. Further studies examining the effects of HMB in other models of hepatic injury are needed to determine pros and cons of HMB in the treatment of subjects with liver cirrhosis.


Assuntos
Aminoácidos de Cadeia Ramificada/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Valeratos/farmacologia , Animais , Tetracloreto de Carbono/metabolismo , Suplementos Nutricionais , Leucina/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática/metabolismo , Ratos Wistar
15.
J Physiol Biochem ; 74(4): 523-530, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30058052

RESUMO

The aim was to determine the effects of enhanced availability of branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) on ammonia detoxification to glutamine (GLN) and protein metabolism in two types of skeletal muscle under hyperammonemic conditions. Isolated soleus (SOL, slow-twitch) and extensor digitorum longus (EDL, fast-twitch) muscles from the left leg of white rats were incubated in a medium with 1 mM ammonia (NH3 group), BCAAs at four times the concentration of the controls (BCAA group) or high levels of both ammonia and BCAA (NH3 + BCAA group). The muscles from the right leg were incubated in basal medium and served as paired controls. L-[1-14C]leucine was used to estimate protein synthesis and leucine oxidation, and 3-methylhistidine release was used to evaluate myofibrillar protein breakdown. We observed decreased protein synthesis and glutamate and α-ketoglutarate (α-KG) levels and increased leucine oxidation, GLN levels, and GLN release into medium in muscles in NH3 group. Increased leucine oxidation, release of branched-chain keto acids and GLN into incubation medium, and protein synthesis in EDL were observed in muscles in the BCAA group. The addition of BCAAs to medium eliminated the adverse effects of ammonia on protein synthesis and adjusted the decrease in α-KG found in the NH3 group. We conclude that (i) high levels of ammonia impair protein synthesis, activate BCAA catabolism, enhance GLN synthesis, and decrease glutamate and α-KG levels and (ii) increased BCAA availability enhances GLN release from muscles and attenuates the adverse effects of ammonia on protein synthesis and decrease in α-KG.


Assuntos
Aminoácidos de Cadeia Ramificada/metabolismo , Hiperamonemia/metabolismo , Fibras Musculares de Contração Rápida/metabolismo , Fibras Musculares de Contração Lenta/metabolismo , Amônia/intoxicação , Animais , Radioisótopos de Carbono , Ciclo do Ácido Cítrico/efeitos dos fármacos , Glutamina/agonistas , Glutamina/metabolismo , Hiperamonemia/enzimologia , Hiperamonemia/fisiopatologia , Técnicas In Vitro , Ácidos Cetoglutáricos/metabolismo , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Metilistidinas/metabolismo , Fibras Musculares de Contração Rápida/efeitos dos fármacos , Fibras Musculares de Contração Rápida/enzimologia , Fibras Musculares de Contração Lenta/efeitos dos fármacos , Fibras Musculares de Contração Lenta/enzimologia , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Especificidade de Órgãos , Concentração Osmolar , Oxirredução , Biossíntese de Proteínas/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Ratos Wistar
16.
Nutr Metab (Lond) ; 15: 33, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29755574

RESUMO

Branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) are essential amino acids with protein anabolic properties, which have been studied in a number of muscle wasting disorders for more than 50 years. However, until today, there is no consensus regarding their therapeutic effectiveness. In the article is demonstrated that the crucial roles in BCAA metabolism play: (i) skeletal muscle as the initial site of BCAA catabolism accompanied with the release of alanine and glutamine to the blood; (ii) activity of branched-chain keto acid dehydrogenase (BCKD); and (iii) amination of branched-chain keto acids (BCKAs) to BCAAs. Enhanced consumption of BCAA for ammonia detoxification to glutamine in muscles is the cause of decreased BCAA levels in liver cirrhosis and urea cycle disorders. Increased BCKD activity is responsible for enhanced oxidation of BCAA in chronic renal failure, trauma, burn, sepsis, cancer, phenylbutyrate-treated subjects, and during exercise. Decreased BCKD activity is the main cause of increased BCAA levels and BCKAs in maple syrup urine disease, and plays a role in increased BCAA levels in diabetes type 2 and obesity. Increased BCAA concentrations during brief starvation and type 1 diabetes are explained by amination of BCKAs in visceral tissues and decreased uptake of BCAA by muscles. The studies indicate beneficial effects of BCAAs and BCKAs in therapy of chronic renal failure. New therapeutic strategies should be developed to enhance effectiveness and avoid adverse effects of BCAA on ammonia production in subjects with liver cirrhosis and urea cycle disorders. Further studies are needed to elucidate the effects of BCAA supplementation in burn, trauma, sepsis, cancer and exercise. Whether increased BCAA levels only markers are or also contribute to insulin resistance should be known before the decision is taken regarding their suitability in obese subjects and patients with type 2 diabetes. It is concluded that alterations in BCAA metabolism have been found common in a number of disease states and careful studies are needed to elucidate their therapeutic effectiveness in most indications.

17.
Int J Exp Pathol ; 99(6): 274-281, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30637824

RESUMO

The aim of the study was to examine whether a rat model of liver cirrhosis induced by carbon tetrachloride (CCl4) is a suitable model of muscle wasting and alterations in amino acid metabolism in cirrhotic humans. Rats were treated by intragastric gavage of CCl4 or vehicle for 45 days. Blood plasma and different muscle types-tibialis anterior (mostly white fibres), soleus (red muscle) and extensor digitorum longus (white muscle) - were analysed at the end of the study. Characteristic biomarkers of impaired hepatic function were found in the plasma of cirrhotic animals. The weights and protein contents of all muscles of CCl4-treated animals were lower when compared with controls. Increased concentrations of glutamine (GLN) and aromatic amino acids (phenylalanine and tyrosine) and decreased concentrations of branched-chain amino acids (BCAA), glutamate (GLU), alanine and aspartate were found in plasma and muscles. In the soleus muscle, GLN increased more and GLU and BCAA decreased less than in the extensor digitorum and tibialis muscles. Increased chymotrypsin-like activity (indicating enhanced proteolysis) and decreased α-ketoglutarate and ATP levels were found in muscles of cirrhotic animals. ATP concentration also decreased in blood plasma. It is concluded that a rat model of CCl4-induced cirrhosis is a valid model for the investigation of hepatic cachexia that exhibits alterations in line with a theory of role of ammonia in pathogenesis of BCAA depletion, citric cycle and mitochondria dysfunction, and muscle wasting in cirrhotic subjects. The findings indicate more effective ammonia detoxification to GLN in red than in white muscles.


Assuntos
Trifosfato de Adenosina/deficiência , Aminoácidos de Cadeia Ramificada/metabolismo , Ácidos Cetoglutáricos/metabolismo , Cirrose Hepática/complicações , Sarcopenia/etiologia , Animais , Peso Corporal/efeitos dos fármacos , Tetracloreto de Carbono/farmacologia , Modelos Animais de Doenças , Ingestão de Alimentos/efeitos dos fármacos , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Tamanho do Órgão/efeitos dos fármacos , Ratos Wistar , Sarcopenia/metabolismo , Sarcopenia/patologia
18.
Lab Med ; 48(4): 339-345, 2017 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-29126300

RESUMO

OBJECTIVE: To determine the effect of presence of high concentrations of nicotinamide adenine dinucleotide (NADH)- and nicotinamide adenine dinucleotide phosphate (NADPH)-consuming enzymes on the accuracy of glutamate dehydrogenase (GLDH) assay for ammonia. METHODS: We measured ammonia concentrations using GLDH and NADH or NADPH in blood-plasma specimens and specimens deproteinized by sulfosalicylic acid from CCl4-treated or control rats. The nonspecific oxidation of NADH and NADPH was measured in mixtures without GLDH. RESULTS: We observed a gradual decrease (~0.5%) in absorbance in the plasma of controls after the addition of NADH but not after adding NADPH. The decrease in absorbance in plasma of CCl4-treated animals was 13.2% and 5.2% after the addition of NADH and NADPH, respectively. The decrease in absorbance was not detected in deproteinized specimens. The values of ammonia concentration were higher in the plasma specimens compared with the deproteinized ones. CONCLUSION: Deproteinization is necessary for accurate measurement of ammonia using GLDH assay in the blood plasma of subjects with liver injury.


Assuntos
Amônia/sangue , Análise Química do Sangue/métodos , Proteínas Sanguíneas/isolamento & purificação , Glutamato Desidrogenase/metabolismo , Hepatopatias/sangue , Animais , Análise Química do Sangue/normas , Humanos , Modelos Lineares , Hepatopatias/metabolismo , Masculino , NAD/metabolismo , NADP/metabolismo , Oxirredução , Ratos , Ratos Wistar
19.
Nutrition ; 41: 80-85, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28760433

RESUMO

Branched-chain amino acid (BCAA; valine, leucine, and isoleucine) supplementation is common for patients with liver cirrhosis due to decreased levels of BCAA in the blood plasma of these patients, which plays a role in pathogenesis of hepatic encephalopathy and cachexia. The unique pharmacologic properties of BCAA also are a factor for use as supplementation in this population. In the present article, BCAA is shown to provide nitrogen to alpha-ketoglutarate (α-KG) for synthesis of glutamate, which is a substrate for ammonia detoxification to glutamine (GLN) in the brain and muscles. The article also demonstrates that the favorable effects of BCAA supplementation might be associated with three adverse effects: draining of α-KG from tricarboxylic acid cycle (cataplerosis), increased GLN content and altered glutamatergic neurotransmission in the brain, and activated GLN catabolism to ammonia in the gut and kidneys. Cataplerosis of α-KG can be attenuated by dimethyl-α-ketoglutarate, l-ornithine-l-aspartate, and ornithine salt of α-KG. The pros and cons of GLN elimination from the body using phenylbutyrate (phenylacetate), which may impair liver regeneration and decrease BCAA levels, should be examined. The therapeutic potential of BCAA might be enhanced also by optimizing its supplementation protocol. It is concluded that the search for strategies attenuating adverse and increasing positive effects of the BCAA is needed to include the BCAA among standard medications for patients with cirrhosis of the liver.


Assuntos
Aminoácidos de Cadeia Ramificada/efeitos adversos , Aminoácidos de Cadeia Ramificada/uso terapêutico , Amônia/metabolismo , Suplementos Nutricionais , Ácidos Cetoglutáricos/metabolismo , Cirrose Hepática/tratamento farmacológico , Aminoácidos de Cadeia Ramificada/metabolismo , Humanos , Cirrose Hepática/metabolismo
20.
Int J Exp Pathol ; 98(3): 127-133, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28621016

RESUMO

Phenylbutyrate (PB) acts as chemical chaperone and histone deacetylase inhibitor, which is used to decrease ammonia in urea cycle disorders and has been investigated for use in the treatment of a number of lethal illnesses. We performed in vivo and in vitro experiments to examine the effects of PB on glutamine (GLN), branched-chain amino acid (BCAA; valine, leucine and isoleucine) and protein metabolism in rats. In the first study, animals were sacrificed one hour after three injections of PB (300mg/kg b.w.) or saline. In the second study, soleus (SOL, slow twitch) and extensor digitorum longus (EDL, fast twitch) muscles were incubated in a medium with or without PB (5 mM). L-[1-14 C] leucine was used to estimate protein synthesis and leucine oxidation, and 3-methylhistidine release was used to evaluate myofibrillar protein breakdown. PB treatment decreased GLN, BCAA and branched-chain keto acids (BCKAs) in blood plasma, decreased BCAA and increased GLN concentrations in muscles, and increased GLN synthetase activities in muscles. Addition of PB to incubation medium increased leucine oxidation (55% in EDL, 29% in SOL), decreased BCKA and increased GLN in medium of both muscles, increased GLN in muscles, decreased protein synthesis in SOL and increased proteolysis in EDL. It is concluded that PB decreases BCAA, BCKA and GLN in blood plasma, activates BCAA catabolism and GLN synthesis in muscle and exerts adverse effects on protein metabolism. The results indicate that BCAA and GLN supplementation is needed when PB is used therapeutically and that PB may be a useful prospective agent which could be effective in management of maple syrup urine disease.


Assuntos
Aminoácidos de Cadeia Ramificada/metabolismo , Glutamina/metabolismo , Proteínas Musculares/metabolismo , Músculo Esquelético/efeitos dos fármacos , Fenilbutiratos/farmacologia , Animais , Leucina/metabolismo , Masculino , Músculo Esquelético/metabolismo , Oxirredução/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Ratos Wistar , Técnicas de Cultura de Tecidos
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