支链氨基酸代谢机制研究进展

支链氨基酸是人体营养必需氨基酸。它们不仅是蛋白质的基本构成单位,而且作为调节糖脂代谢、细胞凋亡和自噬的信号分子发挥着重要的生理功能。除了合成代谢外,分解代谢在支链氨基酸代谢中也同样发挥着重要作用。支链氨基酸代谢异常与胰岛素抵抗、糖尿病、动脉粥样硬化、肿瘤等疾病的进展密切相关。然而其代谢机制并不十分清楚,本文现将支链氨基酸的代谢途径及各器官的分解代谢特点作一综述。     

肝硬化患者支链氨基酸的应用进展

氨基酸主要在肝脏代谢,肝硬化患者的蛋白质、糖类、脂肪代谢紊乱,体内氨基酸代谢失衡,继而引起全身多脏器、多系统的功能不全,出现肝性脑病、食管静脉曲张破裂出血、腹水等并发症,导致较高的病死率。总结了肝硬化患者氨基酸代谢特点及支链氨基酸在肝硬化治疗中的应用,指出支链氨基酸制剂在调整肝病患者的血清氨基酸谱,升高支链氨基酸与芳香族氨基酸的比值,预防肝硬化并发症,提高肝硬化患者生活质量方面具有重要作用。     

支链氨基酸与心血管疾病的研究进展

支链氨基酸是哺乳动物体内的重要营养物质，支链氨基酸代谢稳态对心功能的维持至关重要，同时参与多种疾病的发生发展过程。近年来也有越来越多的研究表明，支链氨基酸的代谢异常和心血管疾病及多种代谢性疾病有着紧密的联系。现对支链氨基酸代谢过程进行概述，就其在心力衰竭、急性心肌梗死、心肌缺血再灌注损伤、心律失常、糖尿病心肌病、高血压等心血管疾病中的研究进展进行综述，并对未来研究方向予以展望。     

支链氨基酸对脓毒性脑病患者血清神经元特异性烯醇化酶水平的影响

目的:探讨支链氨基酸对脓毒性脑病(SAE)患者血清神经元特异性烯醇化酶(NSE)水平的影响。方法:将82例SAE患者随机分为支链氨基酸组(40例)与常规组(42例)。常规组按照SAE指南的综合策略进行干预,支链氨基酸组在常规组基础上加用支链氨基酸进行干预。比较2组患者治疗7 d及14 d后精神状况GCS评分、血清学指标及脑脊液相关指标。结果:治疗14 d后,2组患者精神状况GCS评分均显著改善(均P0.05),支链氨基酸组血清NSE水平降低幅度及GCS评分升高幅度,均明显大于常规组(均P0.05);在第7天和14天,支链氨基酸组的脑脊液NSE水平显著低于常规组(P0.05)。结论:支链氨基酸能有效降低NSE水平,促进SAE患者的康复。     

BCAT1促进肿瘤发生发展的研究进展

支链氨基酸转移酶1(branched-chain amino acid transaminase 1,BCAT1)是催化支链氨基酸代谢的关键酶.国内外研究已证实BCAT1在多种恶性肿瘤中呈现高表达,并提示与肿瘤细胞增殖、转移及侵袭密切相关.本文拟就BCAT1的理化性质、生物学功能及其与肿瘤发生、发展的相关研究进行简要综述,为进一步研究BCAT1与恶性肿瘤的关系提供线索.     

支链氨基酸与葡萄糖治疗肝性脑病——65例肝硬化的双盲对照研究

肝性脑病患者常有血浆支链氨基酸(如缬氨酸、亮氨酸及异亮氨酸)浓度相对降低,而芳香氨基酸(如酪氨酸和苯丙氨酸)的浓度相对增高。照理,在这种情况下应用支链氨基酸含量高、芳香氨基酸含量低的溶液可改善病况,但若干研究结果出入颇大。本文旨在观察和比较支链氨基酸混合液及葡萄糖对肝硬化合并肝性脑病患者的治疗效果。65例患者被随机分成两组:32例(氨基酸组)每天接受8%(W/V)氨基酸溶液(含40%支链氨基酸)12.5毫升/公斤治疗,即每天氨基酸1克/公斤;33例(葡萄糖组)每天接受8%葡萄糖溶液12.5毫升/公斤,     

支链氨基酸在非酒精性脂肪性肝病发生发展中的作用

非酒精性脂肪性肝病是常见慢性肝病，有进展为非酒精性肝炎、肝纤维化和肝癌的风险，发病机制多样，其中支链氨基酸代谢异常可引起肝细胞氧化应激、自噬、线粒体功能障碍等，是导致非酒精性脂肪性肝病发生发展的最主要机制，对其进展进行综述，分析支链氨基酸代谢异常对非酒精性脂肪性肝病发生与发展的可能作用，以期提高临床认知与诊治水平。     

肝硬化肝性脑病过程中的血浆胰岛素和支链氨基酸研究

肝硬化肝性脑病过程中所观察到的血浆支链氨基酸(缬氨酸、亮氨酸、异亮氨酸)浓度的降低曾被认为是与周围性胰岛素升高有关,后者可能引起支链氨基酸在周围组织,尤其是肌肉内利用的增加。本研究的目的是通过对有肝性脑病的肝硬化病人分别研究股动脉和股静脉血中支链氨基酸(AAR)和胰岛素的血浆浓度,从而探讨上述假设的价值。研究对象25例病人,均无糖尿病家族史,亦无胰腺疾病史。其中有8例曾作门-腔静脉吻合术,其余17例中有13例于内窥镜检时可见食管静脉曲张。肝性     

肝昏迷时血浆氨基酸代谢紊乱及支链氨基酸的治疗作用

组成人体蛋白质的氨基酸有20多种,除支链氨基酸(缬氨酸、亮氨酸、异亮氨酸等)主要在骨骼肌肉分解外,其它必需氨基酸几乎均在肝内氧化代谢。1975年Fischer等发现肝昏迷时血浆氨基酸比率的改变,主要为支链氨基酸的一致性降低和芳香氨基酸(苯丙氨酸、酪氨酸等)的升高,后者可达正常的三倍。正常情况下,血浆中缬 亮 异亮/苯丙 酪的     

复方支链氨基酸颗粒剂治疗肝硬化低蛋白血症多中心临床观察

目的 观察口服复方支链氨基酸颗粒剂（商品名力维特,Livact)对肝硬化低蛋白血症的疗效和安全性。方法 上海地区6家医院共选择有低蛋白血症的肝硬化患者172例,其中治疗组120例,对照组52例,分别给予复方支链氨基酸颗粒剂和对照组药物复合氨基酸胶囊,治疗4周和9周后观察其临床太,血清总蛋白和白蛋白及Fisher比值的变化,评估其有效性和安全性。结果 复方支链氨基酸颗粒剂治疗组和对照组各项症状在治疗后均有显著改善（P＜0．05）,其中复方支链氨基酸颗粒剂对疲劳感的改善情况优于对照组（P＝0．03）。复方支链氨基酸颗粒剂组在治疗4周和9周后,血清总蛋白和白蛋白均显著升高（P均为0．0001）,Fisher比值复方支链氨基酸颗粒剂组治疗4周和9周后较前有显著改变（P分别为0．0005和0．0001）,对照组则无明显变化（P＝0．75）。治疗过程中,复方支链氨基酸颗粒剂组和对照组的不良反应发生率为分别为7．50％和3．85％,程度均较轻。结论 复方支链氨基酸颗粒剂是治疗肝硬化低蛋白血症有效而安全的药物。     

Branched-chain amino acid-enriched elemental diet in patients with cirrhosis of the liver. A double blind crossover trial

In 14 patients with cirrhosis of the liver and portal-systemic shunts the effect of a branched-chain amino acid-enriched elemental diet on portal systemic encephalopathy, routine laboratory parameters and plasma amino acids was investigated. In addition to the standard therapy including protein restriction (40 g/day) the patients received 44 g of an amino acid-protein mixture containing 30% of branched-chain amino acids and placebo over 3 months in a crossover regimen. Plasma valine and leucine increased significantly, whereas all other amino acids, including the ratio (formula: see text), remained unchanged. The electroencephalogram, number connection test, clinical state and laboratory parameters were not influenced by therapy with branched-chain amino acids. Thus, orally administered branched-chain amino acids probably have no influence on hepatic encephalopathy but are an adequate source of nitrogen in patients with cirrhosis of the liver.     

Influence of branched-chain amino acids and branched-chain keto acids on protein synthesis in isolated hepatocytes

We investigated the effects of the branched-chain amino acids--valine, leucine and isoleucine--or their keto analogs, the branched-chain keto acids--alpha-ketoisovaleric acid, alpha-ketoisocaproic acid and alpha-keto-beta-methylvaleric acid--on protein synthesis and secretion by monolayers of rabbit hepatocytes incubated with [35S] methionine in pulse-chase and steady-state experiments. The branched-chain amino acids (2.0 mM or 1.0 mM), in the presence or absence of insulin (2 X 10(-4) IU per dish) and in both types of experiments, reduced the trichloroacetic acid-precipitable 35S-protein secreted into the medium. The branched-chain keto acids (2.0 mM or 1.0 mM) had a stimulatory effect on secreted trichloroacetic acid-precipitable 35S-protein which was observed only by the pulse-chase technique in the presence of insulin. Immunoaffinity chromatography of medium demonstrated a slight inhibition by branched-chain amino acids and a slight stimulation by branched-chain keto acids on secretion of 35S-albumin and no effect of either treatment on secretion of 35S-fibrinogen. ELISA analysis of total (i.e., 35S-labeled and unlabeled) secreted albumin revealed an inhibitory effect of the branched-chain amino acids in both pulse-chase and steady-state experiments, and a small stimulatory effect, in steady-state experiments, of the branched-chain keto acids; both effects were insulin-dependent. Total secreted fibrinogen, under steady-state conditions, was increased by the branched-chain keto acids in the presence of insulin, while transferrin production was unaffected by any treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Branched-chain amino acids in the treatment of chronic hepatic encephalopathy.

The therapeutic efficacy of orally administered branched-chain amino acids in patients with liver cirrhosis and chronic encephalopathy was examined in a double blind, randomised crossover study. Seven patients with manifest hepatic cirrhosis and encephalopathy of six months' duration or longer ingested 30 g branched-chain amino acids or placebo during two 14-day periods. Psychometric tests and electroencephalograms were used to evaluate cerebral function. Neither clinical observations nor psychometric testing or electroencephalogram indicated a significant difference in the patients' response to branched-chain amino acids as compared with placebo. In four patients given branched-chain amino acids for longer periods (five to 22 weeks), psychometric tests also remained unchanged. The plasma concentrations of these acids after oral intake increased significantly, demonstrating adequate absorption. Basal plasma amino acid concentrations were unchanged, however, after branched-chain amino acid therapy. No side-effects were seen, which indicates that these amino acids are well tolerated as an extra protein supply in patients with chronic hepatic encephalopathy. As compared with placebo, however, no effect of branched-chain amino acids on the encephalopathy could be detected.     

Improvement of regional cerebral blood flow after treatment with branched-chain amino acid solutions in patients with cirrhosis

OBJECTIVE: The administration of solutions rich in branched-chain amino acids leads to mental recovery from acute hepatic encephalopathy in patients with liver cirrhosis. However, the mechanism of action of branched-chain amino acids remains unclear. The purpose of this study was to evaluate the effect of intravenous infusion of branched-chain amino acids on brain perfusion in patients with liver cirrhosis. METHODS: Single photon emission computed tomography scans were performed in 14 patients with liver cirrhosis before and after the administration of branched-chain amino acids in a single-day split-dose protocol. The per cent change in regional brain perfusion was calculated in high frontal, parietal, temporal, occipital lobes and cerebellum. Thereafter, statistical parametric mapping was performed to identify brain regions with abnormal cerebral perfusion. RESULTS: Intravenous infusion of solutions enriched with branched-chain amino acids induced a 13-20% increase in regional cerebral blood flow. Cirrhotic patients had regions of significant hypoperfusion, as determined by statistical parametric mapping, in the left superior parietal and posterior cingulate as compared to the control group. This hypoperfusion of parietal and cingulate regions was not detected after treatment with solutions of branched-chain amino acids. CONCLUSIONS: The results of the present study suggest that administration of solutions enriched with branched-chain amino acids improves cerebral perfusion in patients with cirrhosis.     

The dietary proportion of essential amino acids and Sir2 influence lifespan in the honeybee

Dietary essential amino acids have an important influence on the lifespan and fitness of animals. The expression of the NAD⁺-dependent histone deacetylase, Sir2, can be influenced by diet, but its role in the extension of lifespan has recently been challenged. Here, we used the honeybee to test how the dietary balance of carbohydrates and essential amino acids and/or Sir2 affected lifespan. Using liquid diets varying in their ratio of essential amino acids to carbohydrate (EAA:C), we found that adult worker bees fed diets high in essential amino acids (≥1:10) had shorter lifespans than bees fed diets containing low levels of dietary amino acids. Bees fed a 1:500 EAA:C diet lived longer and, in contrast to bees fed any of the other diets, expressed Sir2 at levels tenfold higher or more than bees fed a 1:5 EAA:C diet. When bees were fed the 1:500 diet, small interfering RNA (siRNA)-mediated knock-down of Sir2 expression shortened lifespan but did not reduce survival to the same extent as the 1:5 diet, indicating that Sir2 contributes to mechanisms that determine lifespan in response to differences in macronutrient intake but is not the sole determinant. These data show that the ratio of dietary amino acids to carbohydrate influences Sir2 expression and clearly demonstrate that Sir2 is one of the factors that can determine honeybee lifespan. We propose that effects of dietary amino acids and Sir2 on lifespan may depend on the simultaneous activation of multiple nutrient sensors that respond to relative levels of essential amino acids and carbohydrates.     

Long-term oral branched-chain amino acid treatment in chronic hepatic encephalopathy. A randomized double-blind casein-controlled trial. The Italian Multicenter Study Group

In a double blind randomized study, branched-chain amino acids and placebo (casein) were compared as a treatment for chronic hepatic encephalopathy in cirrhosis. After a 15-day run-in period with controlled diet (45-65 g protein), the patients were administered, in addition to their diet, branched-chain amino acids (0.24 g/kg, 30 patients) or an equinitrogenous amount of casein (34 patients). One patient on branched-chain amino acids and two on casein were lost to the study. After 3 months, the index of portal-systemic encephalopathy significantly improved in patients on active treatment (from 40 [S.D. 14]% to 21 [17]), but was not in subjects receiving casein (from 37 [13]% to 36 [12]). Two or more parameters of the index improved in 24 patients treated with amino acids (80%; confidence limits, 61-92%), and only in 12 receiving casein (35%; confidence limits, 20-54%; p less than 0.001). Patients who did not improve were given an alternative treatment for 3 more months. Casein-treated patients given branched-chain amino acids rapidly improved. The changes in neuropsychologic function were associated with an improvement in semiquantitative nitrogen balance, which became consistently positive in amino acid-treated subjects; there was also a mild improvement in nutritional parameters and in liver function tests. The supplementation of oral branched-chain amino acids to the diet is superior to casein as a treatment for providing adequate nitrogen supply and improving the mental state of cirrhotic patients with chronic encephalopathy.     

Branched-chain alpha-keto acids isolated as oxime derivatives: relationship to the corresponding hydroxy acids and amino acids in maple syrup urine disease

Branched-chain α-keto acids can be isolated from serum and urine with good recoveries when treated first with hydroxylamine. Silylation of the keto acid oximes then yields clearly identified peaks after gas chromatography. Serum branched-chain keto acids are increased ten fold above normal in patients with Maple Syrup Urine Disease (MSUD) due to branched-chain α-keto acid dehydrogenase deficiency, when the level of branched-chain amino acids are between the normal range (0.05-0.2 mM) and 1 mM. Keto acids rise another 10–20-fold (i.e., up to 200 times normal), when serum amino acid levels are permitted to rise only twofold above 0.8–1.0 mM. The acute clinical syndrome of MSUD coincides with the latter severe accumulation of keto acids. Removal of branched-chain keto acids by transamination in vivo to the corresponding amino acids seems to be most effective when serum amino acid concentrations are below 1 mM. Keto acids can also be excreted into urine, a mechanism in which they have preference over the corresponding amino and hydroxy acids. Accumulation of branched-chain α-hydroxy acids in MSUD is significant only for α-hydroxy-isovaleric acid, as reported previously by others. Thiamine-responsive MSUD is characterized by greater accumulation of α-keto-B-methyl-valerate relative to the two other branched-chain keto acids when compared with keto acid ratios in classical MSUD. It has been shown by Elsas et al.²¹ that thiamine preferentially stimulates the oxidation of isoleucine and its keto acid in cultured skin fibroblasts. Branched-chain keto acid concentrations are sufficient in uncontrolled MSUD to permit inhibition of pyruvate dehydrogenase according to current evidence in vitro. However, there is no abnormal retention of pyruvate or lactate in vivo in the acute clinical syndrome. Dietary control which permits serum branched-chain amino acids to rise above the normal range and yet remain below 0.8–1.0 mM may be as effective as more stringent dietary measures.     

Free amino acids in plasma and skeletal muscle of patients with liver cirrhosis

Free amino acids were measured under postabsorptive conditions in plasma and intracellular water of skeletal muscle obtained by needle biopsy in nine healthy controls and 14 subjects suffering from clinically stable liver cirrhosis. The aromatic amino acids phenylalanine and tyrosine in cirrhotics were elevated to the same extent in plasma and in muscle water. Branched-chain amino acids were uniformly reduced in plasma, but in muscle water only valine was significantly lower (222 +/- 92 mumoles per kg intracellular water vs. 368 +/- 82, p less than 0.001), while isoleucine (142 +/- 63 vs. 103 +/- 30), leucine (223 +/- 88 vs. 226 +/- 36) and branched-chain amino acids as a whole (589 +/- 186 vs. 681 +/- 88) were normal or elevated with an increased muscle:plasma ratio (3.12 +/- 2.03 vs. 1.41 +/- 0.37, p less than 0.05 for isoleucine; 3.00 +/- 1.28 vs. 1.85 +/- 0.27, p less than 0.025 for leucine; 2.24 +/- 0.64 vs. 1.69 +/- 0.13, p less than 0.05 for total branched-chain amino acids. Our data show that, in cirrhosis, plasma concentrations of branched-chain amino acids do not reflect their levels in muscle cellular water; only the intracellular pool of valine is severely depleted. This suggests that higher amounts of valine supplementation may be useful in nutritional treatment of liver cirrhosis. The elevated muscle:plasma gradients for branched-chain amino acids may result from abnormalities in their transport through muscle-plasma membrane.(ABSTRACT TRUNCATED AT 250 WORDS)     

Organic acids and branched-chain amino acids in body fluids before and after multiple exchange transfusions in maple syrup urine disease

We successfully treated a critically ill infant with the classical type of maple syrup urine disease by multiple exchange tranfusions via a peripheral artery and vein and with positive supplementation in the early stage of therapy. Clinical improvement was definite after the plasma leucine level fell below 1 mmol/l. There was a close linear correlation between plasma concentrations of branched-chain amino acids and their corresponding branched-chain α-keto acids and branched-chain α-hydroxy acids. α-Hydroxy acids were more easily excreted in the urine than α-keto acids and amino acids. Our studies on urinary organic acids supported the existence of minor metabolic pathways of branched-chain α-keto acids, although they were not though to be important in eliminating accumulated α-keto acids. Urinary excretion of succinic acid and α-ketoglutaric acid, which are components of the citric acid cycle, increased transiently during the patient's convalescence. The cerebrospinal fluid/plasma ratios for branched-chain amino acids, α-keto acids, and α-hydroxy acids were very high before the transfurions and decreased after improvement. The cerebrospinal fluid/plasma rations for 5-carvon acids, α-ketoisovaleric acid and α-hydroxyisiovaleric acid were much higher than for other branched-chain acids not only in the patients but also in normal controls. Cerebrospinal fluid levels of α-ketoisocaproic acid and α-hydroxyisovaleric acid were as high as 1 mmol/l in our patient.     

Effect of branched-chain amino acids on the plasma concentration of uridine does not occur via the action of glucagon or insulin

To examine whether branched-chain amino acids affect the plasma concentration of uridine, we administered branched-chain amino acids (L-isoleucine, 2.85 g, L-leucine 5.71 g, and L-valine, 3.43 g) orally to 6 healthy subjects. Plasma uridine and glucose decreased by 44% and 12%, respectively, together with an increase in plasma isoleucine, leucine, and valine 90 minutes after administration. However, branched-chain amino acids did not affect the plasma concentration and urinary excretion of purine bases (hypoxanthine, xanthine, and uric acid) and uridine or the plasma concentration of insulin, glucagon, and cyclic adenosine monophosphate (cAMP). Since small amounts of regular insulin, which were found to decrease plasma glucose more than the amino acids, did not decrease the plasma concentration of uridine, these results suggest that plasma uridine was decreased by a direct effect of the branched-chain amino acids on the cellular uptake and/or release of uridine.