Pharmacological activities of branched-chain amino acids: augmentation of albumin synthesis in liver and improvement of glucose metabolism in skeletal muscle

doi:10.1016/j.hepres.2004.08.006

Hepatology Research

Volume 30, Supplement, December 2004, Pages 19-24

https://doi.org/10.1016/j.hepres.2004.08.006 Get rights and content

Abstract

LIVACT granules, which is a branched-chain amino acid (BCAA) preparation, was developed for the purpose of improving hypoalbuminemia in patients with uncompensated liver cirrhosis in Japan. Recent clinical studies have shown that BCAA supplementation not only improves hypoalbuminemia, but also reduces the occurrence frequency of various complications of liver cirrhosis, which considerably affect mortality. In order to comprehend the significance of BCAA supplementation in patients with liver cirrhosis and to suggest better treatments, we conducted basic non-clinical studies mainly using animal models, clarified the molecular mechanism of the curative effect on hypoalbuminemia and emphasized the importance of mTOR signal transduction. Moreover, we found a new pharmacological action of BCAA, which improves glucose metabolism in skeletal muscles.

Introduction

The LIVACT granules (branched-chain amino acid granules) is an ethical drug that was developed for the purpose of improving hypoalbuminemia in patients with liver cirrhosis in Japan. It does this by correcting the Fischer's ratio by orally supplying three kinds of amino acids, which decrease the pathophysiological conditions of these patients, in appropriate proportion to each other (Leu:Val:Ile = 2:1.2:1). Recent post-marketing clinical studies have demonstrated that BCAA therapy prevents the development of complications in patients with liver cirrhosis, which considerably affect mortality. Therefore, we assumed that the effects of BCAA therapy include not only nutritional supplementation, but also include pharmacological activities. We hypothesized that BCAAs have evident pharmacological activities that improve the pathophysiological condition of patients with liver cirrhosis, and examined their effects in liver and skeletal muscle using a rat model of CCl₄-induced liver cirrhosis. As shown in Fig. 1, we had previously reported that BCAA supplementation improved hypoalbuminemia and survival of cirrhotic rats [1]. Moreover, we progressed our research using this model, demonstrated the mechanism of promoting albumin synthesis in liver and clarified the importance of mTOR, which is a signal transduction molecule for translational initiation. By examining the effect of BCAAs on organs other than the liver, we found that BCAAs have an improving effect on glucose metabolism in skeletal muscles. All these effects of BCAAs are expressed via particular cellular signal transductions and are considered to be novel effects of amino acids that differ from their effects as nutritious substrates or substrates for protein synthesis. In this article, our previous studies are summarized from the standpoints of albumin synthesis and the improvement of glucose metabolism in skeletal muscles.

Section snippets

Promotion of liver albumin synthesis

The significance of BCAA supplementation is to provide materials that are required for albumin synthesis as well as to nutritionally improve amino acids-imbalance that is one of the pathophysiological features of cirrhotic patients. BCAAs also improve protein metabolism by activating cellular signal transduction. Recently, the activation of mammalian target of rapamycin (mTOR) has attracted attention as the mechanism of this action. That is to say, BCAAs, such as leucine, have a characteristic

Curative effect on glucose metabolism in skeletal muscles

Insulin is the only hormone in the body that decreases blood glucose, and this hormone undergoes destructive metabolism in the liver. However, in patients with liver cirrhosis, decreased liver function deteriorates insulin clearance from the blood, and insulin resistance induced by chronic hyperinsulinemia causes pathophysiological conditions such as postprandial hyperglycemia, which are similarly observed in patients with diabetes mellitus. On the other hand, in patients with liver cirrhosis,

Future prospects

Recent studies have suggested that BCAA therapy has various effects in patients with liver cirrhosis, including not only the improvement of hypoalbuminemia, but also the improvement of energy metabolism in the whole body, cerebral blood circulation, biophylaxis and quality of life. Moreover, it is gradually becoming apparent that in addition to their role as nutritious substrates, BCAAs have a pharmacological effect that is expressed via signal transduction such as mTOR, which has been

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Effect of a high-protein, high-fiber diet plus supplementation with branched-chain amino acids on the nutritional status of patients with cirrhosis
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Los beneficios potenciales de los aminoácidos de cadena ramificada (AACR) en la cirrosis se extienden más allá de solo la mejora del estado nutricional. Sus efectos incluyen la mejora de la tolerancia a la glucosa, estrés oxidativo y los marcadores inflamatorios, como se ha mostrado en varios estudios. Un abordaje nutricional dual de una dieta alta en proteína y fibra más AACR en la cirrosis podría tener beneficios adicionales, comparado con los AACR por sí solos. Tal abordaje no se ha explorado, y por lo tanto el objetivo del presente estudio fue evaluar el efecto de la combinación de una dieta alta en proteína y fibra con la suplementación de AACR durante un periodo de 6 meses sobre el estado nutricional de los pacientes con cirrosis, así como su seguridad y tolerabilidad en dichos pacientes.
Se realizó un ensayo clínico aleatorizado abierto. Los pacientes se aleatorizaron en uno de 2 grupos: el grupo de intervención con dieta de AACR + APAF: una dieta alta en proteína y fibra con 1.2 g/kg de proteína y 30 g de fibra más la suplementación con aminoácidos de cadena ramificada orales 110 g diarios y el grupo de control con dieta APAF: una dieta alta en proteína y fibra con 1.2 g/kg de proteína y 30 g de fibra. Las diferencias entre los grupos de tratamiento se compararon utilizando la prueba «t» no pareada, y las diferencias al final del tratamiento se compararon utilizando la prueba «t» pareada.
Se incluyó un total de 72 pacientes, 37 en el grupo de intervención y 35 en el grupo de control. Al final del periodo de estudio no se mostró un incremento significativo en los niveles de amonio y glucosa en ambos grupos, reflejando la seguridad del suplemento con AACR. Aún más, se evaluó la masa muscular y la grasa por medio de la medición del espesor del pliegue cutáneo del tríceps y de la circunferencia muscular en la parte media del brazo. En el grupo con AACR hubo un incremento en masa muscular y una disminución en masa grasa, pero no en el grupo de control. Después de la intervención, no hubo cambios significativos en los resultados de puntajes en el puntaje psicométrico de encefalopatía hepática o en la frecuencia crítica de fusión en cualquiera de los grupos, y no se observaron episodios de encefalopatía hepática durante el periodo de tratamiento.
La suplementación con AACR más una dieta alta en proteína y fibra es una intervención segura en los pacientes con cirrosis. Ayuda al incremento de la masa muscular y no eleva los niveles de amonio o de glucosa, y tampoco se asocia con el desarrollo de encefalopatía hepática.
The potential benefits of branched-chain amino acids (BCAAs) in cirrhosis extend beyond just the improvement of nutritional status. Their effects include improvement of glucose tolerance, oxidative stress, and inflammatory markers, as has been shown in several studies. A dual nutritional approach of a high-protein, high-fiber diet plus BCAAs in cirrhosis could have additional benefits, compared with BCAAs alone. Such an approach has not been explored and therefore the aim of the present study was to evaluate the effect of a combination of a high-protein, high-fiber diet plus BCAA supplementation over a 6-month period of time on the nutritional status of patients with cirrhosis, as well as its safety and tolerability for those same patients.
An open, randomized clinical trial was conducted. Patients were randomized to one of two groups: the BCAAs + HPHF diet intervention group: a high-protein, high-fiber diet with 1.2 g/kg protein and 30 g of fiber plus supplementation with oral branched-chain amino acids 110 g daily and the HPHF diet control group: a high-protein, high-fiber diet with 1.2 g/kg protein and 30 g of fiber. The differences between the treatment groups were compared using the unpaired T test and the differences at the end of treatment were compared using the paired T test.
A total of 72 patients were included, 37 in the intervention group and 35 in the control group. At the end of the study period, ammonia and glucose levels showed no significant increase in either group, reflecting the safety of the BCAA supplement. Furthermore, muscle and fat mass were evaluated through triceps skinfold thickness and mid-arm muscle circumference measurements. There was an increase in muscle mass and a decrease in fat mass in the BCAA group, but not in the control group. After the intervention, there were no significant changes in the Psychometric Hepatic Encephalopathy Score or the Critical Flicker Frequency score results in either group, and no episodes of hepatic encephalopathy were observed during the treatment period.
Supplementation with branched-chain amino acids plus a high-fiber, high-protein diet is a safe intervention in patients with cirrhosis. It helps increase muscle mass and does not raise the levels of ammonia or glucose, nor is it associated with the development of hepatic encephalopathy.
Three targets of branched-chain amino acid supplementation in the treatment of liver disease
2010, Nutrition
Citation Excerpt :
Unfortunately, the resulting studies did not reveal a clear clinical benefit of BCAA supplementation in most disease states [12–15]. However, the positive results of several randomized trials from recent years have indicated their favorable effect in different forms of liver disease [16–20]. Three main targets of BCAA supplementation in the treatment of liver disease can be suggested: 1) prevention and treatment of hepatic encephalopathy, 2) repair and regeneration of hepatic tissue, and 3) prevention and treatment of hepatic cachexia.
The article explains the pathogenesis of disturbances in branched-chain amino acid (BCAA; valine, leucine, and isoleucine) and protein metabolism in various forms of hepatic injury and it is suggested that the main cause of decrease in plasma BCAA concentration in liver cirrhosis is hyperammonemia. Three possible targets of BCAA supplementation in hepatic disease are suggested: (1) hepatic encephalopathy, (2) liver regeneration, and (3) hepatic cachexia. The BCAA may ameliorate hepatic encephalopathy by promoting ammonia detoxification, correction of the plasma amino acid imbalance, and by reduced brain influx of aromatic amino acids. The influence of BCAA supplementation on hepatic encephalopathy could be more effective in chronic hepatic injury with hyperammonemia and low concentrations of BCAA in blood than in acute hepatic illness, where hyperaminoacidemia frequently develops. The favorable effect of BCAA on liver regeneration and nutritional state of the body is related to their stimulatory effect on protein synthesis, secretion of hepatocyte growth factor, glutamine production and inhibitory effect on proteolysis. Presumably the beneficial effect of BCAA on hepatic cachexia is significant in compensated liver disease with decreased plasma BCAA concentrations, whereas it is less pronounced in hepatic diseases with inflammatory complications and enhanced protein turnover. It is concluded that specific benefits associated with BCAA supplementation depend significantly on the type of liver disease and on the presence of inflammatory reaction. An important task for clinical research is to identify groups of patients for whom BCAA treatment can significantly improve the health-related quality of life and the prognosis of hepatic disease.
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Pharmacological activities of branched-chain amino acids: augmentation of albumin synthesis in liver and improvement of glucose metabolism in skeletal muscle

Abstract

Introduction

Section snippets

Promotion of liver albumin synthesis

Curative effect on glucose metabolism in skeletal muscles

Future prospects

J Biol Chem

Biochem Biophys Res Commun

Biochem Biophys Res Commun

J Hepatol

J Hepatol

Biochem Biophys Res Commun