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Why Are Branched-Chain Amino Acids Increased in Starvation and Diabetes?
Holeček, M
Nutrients. 2020;(10)
Abstract
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.
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2.
Coordinated Modulation of Energy Metabolism and Inflammation by Branched-Chain Amino Acids and Fatty Acids.
Ye, Z, Wang, S, Zhang, C, Zhao, Y
Frontiers in endocrinology. 2020;:617
Abstract
As important metabolic substrates, branched-chain amino acids (BCAAs) and fatty acids (FAs) participate in many significant physiological processes, such as mitochondrial biogenesis, energy metabolism, and inflammation, along with intermediate metabolites generated in their catabolism. The increased levels of BCAAs and fatty acids can lead to mitochondrial dysfunction by altering mitochondrial biogenesis and adenosine triphosphate (ATP) production and interfering with glycolysis, fatty acid oxidation, the tricarboxylic acid cycle (TCA) cycle, and oxidative phosphorylation. BCAAs can directly activate the mammalian target of rapamycin (mTOR) signaling pathway to induce insulin resistance, or function together with fatty acids. In addition, elevated levels of BCAAs and fatty acids can activate the canonical nuclear factor-κB (NF-κB) signaling pathway and inflammasome and regulate mitochondrial dysfunction and metabolic disorders through upregulated inflammatory signals. This review provides a comprehensive summary of the mechanisms through which BCAAs and fatty acids modulate energy metabolism, insulin sensitivity, and inflammation synergistically.
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3.
Emerging Roles for Branched-Chain Amino Acid Metabolism in Cancer.
Sivanand, S, Vander Heiden, MG
Cancer cell. 2020;(2):147-156
Abstract
Metabolic pathways must be adapted to support cell processes required for transformation and cancer progression. Amino acid metabolism is deregulated in many cancers, with changes in branched-chain amino acid metabolism specifically affecting cancer cell state as well as systemic metabolism in individuals with malignancy. This review highlights key concepts surrounding the current understanding of branched-chain amino acid metabolism and its role in cancer.
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4.
Nutrient Intake and Nutritional Status in Adult Patients with Inherited Metabolic Diseases Treated with Low-Protein Diets: A Review on Urea Cycle Disorders and Branched Chain Organic Acidemias.
Francini-Pesenti, F, Gugelmo, G, Lenzini, L, Vitturi, N
Nutrients. 2020;(11)
Abstract
UNLABELLED Low-protein diets (LPDs) are the main treatment for urea cycle disorders (UCDs) and organic acidemias (OAs). In most cases, LPDs start in childhood and must be continued into adulthood. The improved life expectancy of patients with UCDs and OAs raises the question of their consequences on nutritional status in adult subjects. As this topic has so far received little attention, we conducted a review of scientific studies that investigated the nutrient intake and nutritional status in adult patients with UCDs and branched chain organic acidemias (BCOAs) on LPD. METHODS The literature search was conducted in PubMed/MEDLINE, Scopus, EMBASE and Google Scholar from 1 January 2000 to 31 May 2020, focusing on nutrient intake and nutritional status in UCD and OA adult patients. RESULTS Despite protein restriction is recommended as the main treatment for UCDs and OAs, in these patients, protein intake ranges widely, with many patients who do not reach safety levels. When evaluated, micronutrient intake resulted below recommended values in some patients. Lean body mass resulted in most cases lower than normal range while fat body mass (FM) was often found normal or higher than the controls or reference values. Protein intake correlated inversely with FM both in adult and pediatric UCD patients. CONCLUSIONS The clinical management of adult patients with UCDs and BCOAs should include an accurate assessment of the nutritional status and body composition. However, as little data is still available on this topic, further studies are needed to better clarify the effects of LPDs on nutritional status in adult UCD and BCOA patients.
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5.
Brain Branched-Chain Amino Acids in Maple Syrup Urine Disease: Implications for Neurological Disorders.
Xu, J, Jakher, Y, Ahrens-Nicklas, RC
International journal of molecular sciences. 2020;(20)
Abstract
Maple syrup urine disease (MSUD) is an autosomal recessive disorder caused by decreased activity of the branched-chain α-ketoacid dehydrogenase complex (BCKDC), which catalyzes the irreversible catabolism of branched-chain amino acids (BCAAs). Current management of this BCAA dyshomeostasis consists of dietary restriction of BCAAs and liver transplantation, which aims to partially restore functional BCKDC activity in the periphery. These treatments improve the circulating levels of BCAAs and significantly increase survival rates in MSUD patients. However, significant cognitive and psychiatric morbidities remain. Specifically, patients are at a higher lifetime risk for cognitive impairments, mood and anxiety disorders (depression, anxiety, and panic disorder), and attention deficit disorder. Recent literature suggests that the neurological sequelae may be due to the brain-specific roles of BCAAs. This review will focus on the derangements of BCAAs observed in the brain of MSUD patients and will explore the potential mechanisms driving neurologic dysfunction. Finally, we will discuss recent evidence that implicates the relevance of BCAA metabolism in other neurological disorders. An understanding of the role of BCAAs in the central nervous system may facilitate future identification of novel therapeutic approaches in MSUD and a broad range of neurological disorders.
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6.
Branched chain amino acids: Passive biomarkers or the key to the pathogenesis of cardiometabolic diseases?
Siomkajło, M, Daroszewski, J
Advances in clinical and experimental medicine : official organ Wroclaw Medical University. 2019;(9):1263-1269
Abstract
The metabolomic approach to research on lifestyle diseases has led to the discovery of new potential biomarkers of pathological conditions as well as key metabolic pathways that may become targets of therapeutic intervention. Current evidence supports plasma branched chain amino acids (BCAAs) as potential diagnostic and prognostic biomarkers of cardiometabolic diseases. However, the biological mechanisms of the associations that have been identified are still not completely understood and should be clarified before implementing BCAA-based biomarkers in the clinical setting. The most crucial issue that needs to be solved first is determining whether BCAA plasma profile disturbances are only passive biomarkers or whether they facilitate dysmetabolic processes. In this context, further research is also warranted to investigate the role of dietary BCAAs. Gaining this knowledge would be significant progress in molecular nutrition research, providing perspective for target therapeutic and prophylactic interventions. This paper provides a comprehensive review of the main hypotheses and mechanistic models that consider circulating BCAAs both as passive biomarkers and as contributors to cardiometabolic diseases.
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7.
Dietary management and supplementation with branched-chain amino acids in cirrhosis of the liver.
Ruiz-Margáin, A, Méndez-Guerrero, O, Román-Calleja, BM, González-Rodríguez, S, Fernández-Del-Rivero, G, Rodríguez-Córdova, PA, Torre, A, Macías-Rodríguez, RU
Revista de gastroenterologia de Mexico (English). 2018;(4):424-433
Abstract
One of the most important characteristics of malnutrition is the loss of muscle mass and the severe depletion of the protein reserve, secondarily affecting energy metabolism. That impacts nutritional status and the progression of disease-related complications. Nutritional treatment is one of the main factors in the comprehensive management of those patients. Achieving adequate energy intake that provides the macronutrients and micronutrients necessary to prevent or correct malnutrition is attempted through dietary measures. ESPEN, the European Society for Clinical Nutrition and Metabolism, recommends a caloric intake of 30-40kcal/kg/day, in which carbohydrates provide 45-60% of the daily energy intake and proteins supply 1.0-1.5g/kg/day. The remaining portion of the total energy expenditure should be covered by lipids. The administration of branched-chain amino acids has been shown to be beneficial not only in counteracting malnutrition, but also as a coadjuvant treatment in specific complications, thus playing a favorable role in outcome and quality of life. Therefore, branched-chain amino acids should be considered part of nutritional treatment in patients with advanced stages of cirrhosis of the liver, particularly in the presence of complications.
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8.
Branching Out: Alterations in Bacterial Physiology and Virulence Due to Branched-Chain Amino Acid Deprivation.
Kaiser, JC, Heinrichs, DE
mBio. 2018;(5)
Abstract
The branched-chain amino acids (BCAAs [Ile, Leu, and Val]) represent important nutrients in bacterial physiology, with roles that range from supporting protein synthesis to signaling and fine-tuning the adaptation to amino acid starvation. In some pathogenic bacteria, the adaptation to amino acid starvation includes induction of virulence gene expression: thus, BCAAs support not only proliferation during infection, but also the evasion of host defenses. A body of research has accumulated over the years to describe the multifaceted physiological roles of BCAAs and the mechanisms bacteria use to maintain their intracellular levels. More recent studies have focused on understanding how fluctuations in their intracellular levels impact global regulatory pathways that coordinate the adaptation to nutrient limitation, especially in pathogenic bacteria. In this minireview, we discuss how these studies have refined the individual roles of BCAAs, shed light on how BCAA auxotrophy might promote higher sensitivity to exogenous BCAA levels, and revealed pathogen-specific responses to BCAA deprivation. These advancements improve our understanding of how bacteria meet their nutritional requirements for growth while simultaneously remaining responsive to changes in environmental nutrient availability to promote their survival in a range of environments.
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9.
A Role for Branched-Chain Amino Acids in the Pathophysiology of Diabetes: Using Data to Guide Discovery.
Katz, DH, Gerszten, RE
Clinical chemistry. 2018;(8):1250-1251
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10.
Branched-Chain Amino Acids as Critical Switches in Health and Disease.
Zhang, ZY, Monleon, D, Verhamme, P, Staessen, JA
Hypertension (Dallas, Tex. : 1979). 2018;(5):1012-1022