Role Of Branched-chain Amino Acids Research Articles

The Emerging Role of Branched-Chain Amino Acids in Liver Diseases.

Chronic liver diseases pose a substantial health burden worldwide, with approximately two million deaths each year. Branched-chain amino acids (BCAAs)—valine, leucine, and isoleucine—are a group of essential amino acids that are essential for human health. Despite the necessity of a dietary intake of BCAA, emerging data indicate the undeniable correlation between elevated circulating BCAA levels and chronic liver diseases, including non-alcoholic fatty liver diseases (NAFLD), cirrhosis, and hepatocellular carcinoma (HCC). Moreover, circulatory BCAAs were positively associated with a higher cholesterol level, liver fat content, and insulin resistance (IR). However, BCAA supplementation was found to provide positive outcomes in cirrhosis and HCC patients. This review will attempt to address the contradictory claims found in the literature, with a special focus on BCAAs’ distribution, key signaling pathways, and the modulation of gut microbiota. This should provide a better understanding of BCAAs’ possible contribution to liver health.

Randomised clinical trial: effect of adding branched chain amino acids to exercise and standard-of-care on muscle mass in cirrhotic patients with sarcopenia.

BackgroundThe role of branched-chain amino acids (BCAA) in improving muscle mass in cirrhosis is presently debatable.AimsTo evaluate the role of BCAA in improving muscle mass in a double-blind randomized placebo-controlled trial in patients with cirrhosis having sarcopenia.MethodsConsecutive patients with cirrhosis with Child–Pugh score < 10 and sarcopenia were randomized to receive either 12 g/day of BCAA orally or a placebo (1:1) for 6 months in addition to a home-based exercise program (30 min/day), dietary counselling and standard medical therapy. Sarcopenia was defined according to gender-specific axial skeletal muscle index (SMI) cut-offs. The primary endpoint was a change in muscle mass based on CT scan (SMI) after 6 months of supplementation.ResultsSixty patients [mean age 41.6 ± 9.9 years; males (66.6%) of predominantly viral (40%) and alcohol-related (31.7%) cirrhosis] were randomized. Baseline clinical and demographic characters were similar except MELD score (10.2 ± 2.8 vs. 12.2 ± 3.5, p = 0.02) and calorie intake (1838.1 kcal ± 631.5 vs. 2217.5 kcal ± 707.3, p = 0.03), both being higher in the placebo arm. After adjusting for both baseline confounders, baseline SMI and protein intake, the change in SMI at 6 months was similar in both groups [mean adjusted difference (MAD) + 0.84, CI − 2.9; + 1.2, p = 0.42] by intention-to-treat analysis. The secondary outcomes including change in handgrip strength (p = 0.65), 6-m gait speed (p = 0.20), 6-min walk distance (p = 0.39) were similar in both arms. Four patients had minor adverse events in each arm.ConclusionAddition of BCAA to exercise, dietary counselling and standard medical therapy did not improve muscle mass in patients with cirrhosis having sarcopenia. (CTRI/2019/05/019269).Trial registration numberCTRI/2019/05/019269 (Clinical Trials Registry of India).Supplementary InformationThe online version contains supplementary material available at 10.1007/s12072-022-10334-7.

Detrimental effects of branched-chain amino acids in glucose tolerance can be attributed to valine induced glucotoxicity in skeletal muscle

ObjectiveCurrent data regarding the roles of branched-chain amino acids (BCAA) in metabolic health are rather conflicting, as positive and negative effects have been attributed to their intake.MethodsTo address this, individual effects of leucine and valine were elucidated in vivo (C57BL/6JRj mice) with a detailed phenotyping of these supplementations in high-fat (HF) diets and further characterization with in vitro approaches (C2C12 myocytes).ResultsHere, we demonstrate that under HF conditions, leucine mediates beneficial effects on adiposity and insulin sensitivity, in part due to increasing energy expenditure—likely contributing partially to the beneficial effects of a higher milk protein intake. On the other hand, valine feeding leads to a worsening of HF-induced health impairments, specifically reducing glucose tolerance/insulin sensitivity. These negative effects are driven by an accumulation of the valine-derived metabolite 3-hydroxyisobutyrate (3-HIB). Higher plasma 3-HIB levels increase basal skeletal muscle glucose uptake which drives glucotoxicity and impairs myocyte insulin signaling.ConclusionThese data demonstrate the detrimental role of valine in an HF context and elucidate additional targetable pathways in the etiology of BCAA-induced obesity and insulin resistance.

Increased branched-chain amino acids at baseline and hours before a spontaneous seizure in the human epileptic brain.

The objective of this study was to monitor the extracellular brain chemistry dynamics at baseline and in relation to spontaneous seizures in human patients with refractory epilepsy. Thirty patients with drug-resistant focal epilepsy underwent intracranial electroencephalography and concurrent brain microdialysis for up to 8 continuous days. Extracellular brain glutamate, glutamine, and the branched-chain amino acids (BCAAs) valine, leucine, and isoleucine were quantified in the dialysis samples by liquid chromatography-tandem mass spectrometry. Extracellular BCAAs and glutamate were chronically elevated at baseline by approximately 1.5-3-fold in brain regions of seizure onset and propagation versus regions not involved by seizures. Moreover, isoleucine increased significantly above baseline as early as 3h before a spontaneous seizure. BCAAs play important roles in glutamatergic neurotransmission, mitochondrial function, neurodegeneration, and mammalian target of rapamycin signaling. Because all of these processes have been implicated in epilepsy, the results suggest a novel role of BCAAs in the pathogenesis of spontaneous seizures.

Branched chain amino acids exacerbate myocardial ischemia/reperfusion vulnerability via enhancing GCN2/ATF6/PPAR-α pathway-dependent fatty acid oxidation.

Rationale: Myocardial vulnerability to ischemia/reperfusion (I/R) injury is strictly regulated by energy substrate metabolism. Branched chain amino acids (BCAA), consisting of valine, leucine and isoleucine, are a group of essential amino acids that are highly oxidized in the heart. Elevated levels of BCAA have been implicated in the development of cardiovascular diseases; however, the role of BCAA in I/R process is not fully understood. The present study aims to determine how BCAA influence myocardial energy substrate metabolism and to further clarify the pathophysiological significance during cardiac I/R injury.Methods: Parameters of glucose and fatty acid metabolism were measured by seahorse metabolic flux analyzer in adult mouse cardiac myocytes with or without BCAA incubation. Chronic accumulation of BCAA was induced in mice receiving oral BCAA administration. A genetic mouse model with defective BCAA catabolism was also utilized. Mice were subjected to MI/R and the injury was assessed extensively at the whole-heart, cardiomyocyte, and molecular levels.Results: We confirmed that chronic accumulation of BCAA enhanced glycolysis and fatty acid oxidation (FAO) but suppressed glucose oxidation in adult mouse ventricular cardiomyocytes. Oral gavage of BCAA enhanced FAO in cardiac tissues, exacerbated lipid peroxidation toxicity and worsened myocardial vulnerability to I/R injury. Etomoxir, a specific inhibitor of FAO, rescued the deleterious effects of BCAA on I/R injury. Mechanistically, valine, leucine and their corresponding branched chain α-keto acid (BCKA) derivatives, but not isoleucine and its BCKA derivative, transcriptionally upregulated peroxisome proliferation-activated receptor alpha (PPAR-α). BCAA/BCKA induced PPAR-α upregulation through the general control nonderepresible-2 (GCN2)/ activating transcription factor-6 (ATF6) pathway. Finally, in a genetic mouse model with BCAA catabolic defects, chronic accumulation of BCAA increased FAO in myocardial tissues and sensitized the heart to I/R injury, which could be reversed by adenovirus-mediated PPAR-α silencing.Conclusions: We identify BCAA as an important nutrition regulator of myocardial fatty acid metabolism through transcriptional upregulation of PPAR-α. Chronic accumulation of BCAA, caused by either dietary or genetic factors, renders the heart vulnerable to I/R injury via exacerbating lipid peroxidation toxicity. These data support the notion that BCAA lowering methods might be potentially effective cardioprotective strategies, especially among patients with diseases characterized by elevated levels of BCAA, such as obesity and diabetes.

Concentration of Branched-Chain Amino Acids Is a Strong Risk Marker for Incident Hypertension.

The potential role of branched-chain amino acids (BCAAs) in the pathogenesis of cardiometabolic diseases is increasingly recognized, but the association of BCAAs with incident hypertension remains unknown. The aim of the present study was to explore the association of BCAAs with incident hypertension in a prospective population-based cohort study. We measured plasma concentrations of BCAAs by means of nuclear magnetic resonance spectroscopy in 4169 participants from the PREVEND (Prevention of Renal and Vascular End-stage Disease) study. We estimated the risk of incident hypertension using multivariable-adjusted Cox regression models. After a median follow-up of 8.6 years, incident hypertension was ascertained in 924 subjects. Cox regression analyses revealed a significant association between BCAAs and incident hypertension. The hazard ratio per one SD of BCAAs was 1.11 (95% CI, 1.02-1.20; P=0.01) after full adjustment for multiple clinical variables. Likewise, the fully adjusted association remained significant when evaluated as categorical variable (hazard ratio for upper quartile with lowest quartile as reference category, 1.36; 95% CI, 1.11-1.68; P=0.003). Furthermore, the net reclassification improvement assessment improved after addition of BCAAs to a traditional risk model (P<0.001). This prospective study revealed that high plasma concentrations of BCAAs are associated with an increased risk of newly developed hypertension. The association remained after adjusting for age, sex, body mass index, and lipid profile.

Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids.

Epidemiological studies indicate that insulin resistance (IR), a hallmark of type 2 diabetes, is associated with an increased risk of major depression. Here, we demonstrated that male mice fed a high-fat diet (HFD) exhibited peripheral metabolic impairments reminiscent of IR accompanied by elevated circulating levels of branched-chain amino acids (BCAAs), whereas both parameters were normalized by chronic treatment with metformin (Met). Given the role of BCAAs in the regulation of tryptophan influx into the brain, we then explored the activity of the serotonin (5-HT) system. Our results indicated that HFD-fed mice displayed impairment in the electrical activity of dorsal raphe 5-HT neurons, attenuated hippocampal extracellular 5-HT concentrations and anxiety, one of the most visible and early symptoms of depression. On the contrary, Met stimulated 5-HT neurons excitability and 5-HT neurotransmission while hindering HFD-induced anxiety. Met also promoted antidepressant-like activities as observed with fluoxetine. In light of these data, we designed a modified HFD in which BCAA dietary supply was reduced by half. Deficiency in BCAAs failed to reverse HFD-induced metabolic impairments while producing antidepressant-like activity and enhancing the behavioral response to fluoxetine. Our results suggest that Met may act by decreasing circulating BCAAs levels to favor serotonergic neurotransmission in the hippocampus and promote antidepressant-like effects in mice fed an HFD. These findings also lead us to envision that a diet poor in BCAAs, provided either alone or as add-on therapy to conventional antidepressant drugs, could help to relieve depressive symptoms in patients with metabolic comorbidities.SIGNIFICANCE STATEMENT Insulin resistance in humans is associated with increased risk of anxiodepressive disorders. Such a relationship has been also found in rodents fed a high-fat diet (HFD). To determine whether insulin-sensitizing strategies induce anxiolytic- and/or antidepressant-like activities and to investigate the underlying mechanisms, we tested the effects of metformin, an oral antidiabetic drug, in mice fed an HFD. Metformin reduced levels of circulating branched-chain amino acids, which regulate tryptophan uptake within the brain. Moreover, metformin increased hippocampal serotonergic neurotransmission while promoting anxiolytic- and antidepressant-like effects. Moreover, a diet poor in these amino acids produced similar beneficial behavioral property. Collectively, these results suggest that metformin could be used as add-on therapy to a conventional antidepressant for the comorbidity between metabolic and mental disorders.

Immunomodulatory role of branched-chain amino acids.

Branched-chain amino acids (BCAAs) have been associated with immunomodulation since the mid-1970s and 1980s and have been used in the nutritional therapy of critically ill patients. Evidence shows that BCAAs can directly contribute to immune cell function, aiding recovery of an impaired immune system, as well as improving the nutritional status in cancer and liver diseases. Branched-chain amino acids may also play a role in treatment of patients with sepsis or trauma, contributing to improved clinical outcomes and survival. Branched-chain amino acids, especially leucine, are activators of the mammalian target of rapamycin (mTOR), which, in turn, interacts with several signaling pathways involved in biological mechanisms of insulin action, protein synthesis, mitochondrial biogenesis, inflammation, and lipid metabolism. Although many in vitro and human and animal model studies have provided evidence for the biological activity of BCAAs, findings have been conflicting, and the mechanisms of action of these amino acids are still poorly understood. This review addresses several aspects related to BCAAs, including their transport, oxidation, and mechanisms of action, as well as their role in nutritional therapy and immunomodulation.

Intravenous and Oral Hyperammonemia Management

Hyperammonemia have significant morbidity and mortality. In this paper, we reviewed the latest research and evidence of both conventional and upcoming oral or intravenous treatments. New updates on the role of oral agents such as rifaximin, PEG, probiotics, glycerol phenylbutyrate, and zinc supplements in the management of both chronic hyperammonemia and overt hepatic encephalopathy have been discussed in this review. We discussed the recent findings on the role of branched-chain amino acids in patients with cirrhosis. Rifaximin role has expanded as mono or combination therapy in patients with hepatic encephalopathy. Probiotics and zinc might play a role in the prevention of overt hepatic encephalopathy. Newer oral agents such as activated carbon seem to be promising. Saline or albumin might play a role in diuretic-induced hyperammonemia but their role is yet to be determined. More research is needed for new interventions and treatment validation.

A Role for Branched-Chain Amino Acids in the Pathophysiology of Diabetes: Using Data to Guide Discovery.

Featured Article: Wang TJ, Larson MG, Vasan RS, Cheng S, Rhee EP, McCabe E, et al. Metabolite profiles and the risk of developing diabetes. Nature Med 2011;17:448–53.2 Over the past 10 years, the ability to quantify human biologic activity has grown exponentially. We now have the technology for high-throughput genomics, transcriptomics, proteomics, and metabolomics and the ability to interrogate the human biochemical system at every level (1). Indeed, hundreds of chemicals can now be measured in hundreds of individuals at reasonable cost. These advances have fueled analyses that drive medicine forward in a new way: instead of a hypothesis motivating the generation of new data, more and more discoveries are made when the data generate a new hypothesis. The article featured here exemplifies the power of this technique. The recent advent of metabolomic profiling was seen as a great opportunity to better understand type 2 diabetes mellitus (DM). Because DM is a disease of pathologic energy management, metabolite profiling is a natural tool for understanding the underlying pathophysiology …

Effect of Reduced Intake of Branched-Chain Amino Acids (BCAA) on Insulin Secretion and Sensitivity in Type 2 Diabetes

Circulating BCAA (valine, leucine, isoleucine) are increased in insulin resistant states and predict type 2 diabetes (T2D) suggesting a role of BCAA in the development of insulin resistance. Thus, we hypothesized that a dietary decrease of BCAA improves insulin sensitivity (IS) and oxidative phosphorylation in T2D and increases the levels of the hepatic metabolic regulator fibroblast-growth factor (FGF-21). In a randomized, placebo-controlled, double-blinded study, 12 patients (8 male, 4 female; age 54±4 years, body mass index 30.8±2.8 kg/m2, HbA1c 6.6±0.9%, 49±10 mmol/mol) with known T2D duration of &amp;lt;5 years, received a 4-week isocaloric diet with constant protein intake of 1 g/kg body weight. In a cross-over design, their diet comprised either the complete amino acid set (BCAA+) or a 60% reduction in BCAA (BCAA-) for 1 week. Whole body IS was assessed by hyperinsulinemic-euglycemic clamps and beta-cell function by mixed-meal tolerance tests (MMT). Mitochondrial efficiency was assessed from the respiratory control ratio (RCR) measured by high-resolution respirometry in muscle and adipose tissue. FGF-21 serum levels were quantified by ELISA. IS was lower after BCAA- diet (3.1±1.7 mg*kg-1*min-1) compared to BCAA+ diet (3.5±1.8 mg*kg-1*min-1, p&amp;lt;0.01). However, this difference disappeared after normalization for prevalent insulin levels. MMT showed lower increases in insulin and C-peptide after BCAA- than BCCA+ diet (incremental insulin area under the curve: 21±11 vs. 29±19 mU*ml-1*4 h-1, p&amp;lt;0.01). RCR in adipose tissue was 1.7-fold higher after BCAA- diet (p&amp;lt;0.05), but unchanged in skeletal muscle. The BCAA- diet also increased FGF-21 levels (from 323±189 to 405±233 pg/ml, p&amp;lt;0.05) which likely contributes to the effect on energy metabolism. In conclusion, short-term dietary reduction of BCAA decreases meal-induced insulin and C-peptide secretion, increases FGF-21 levels and stimulates mitochondrial efficiency in adipose tissue, but fails to improve IS in T2D. Disclosure Y. Karusheva: None. T. van Gemert: None. M. Simon: None. D.F. Markgraf: None. K. Strassburger: None. D. Schmoll: Employee; Self; Sanofi-Aventis Deutschland GmbH. V. Burkart: None. K. Müssig: None. J. Szendroedi: None. M. Roden: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi.

Synergistic renoprotective effect of a compiled branched-chain amino acids and Cymbopogon schoenanthus extract against experimentally induced oxido-nitrosative renal insult

Objective: To better investigate the protective role of branched-chain amino acids (BCAAs) and Cymbopogon schoenanthus (CS) extract against the potassium dichromate (PDC)-induced oxido-nitrosative nephrotoxic insult in the experimental rat model. Methods: Thirty male rats were randomly divided into five equal groups: The 1st group served as control; the 2 nd was injected with a single dose of PDC (15 mg/kg b.w i.p .); the 3 rd , 4 th , and 5 th groups were respectively treated with BCAAs, CS, and their combination for 15 d prior to induction of renal insult via PDC single dose (15 mg/kg b.w s.c .). The experimental period was terminated in all groups 2 d after induction of renal insult. The harvested kdney samples were divided for biochemical assays and histological examination. Results: The PDC-induced nephrotoxic effect caused a depletion of renal oxidative scavengers glutathione, superoxide dismutase with consequent lipo-oxidative cellular membrane deterioration manifested by a rise in malonaldehyde, oxidized glutathione, myeloperoxidase and the concomitant increase in inflammatory response elements tumor necrosis factor α, nitric oxide, and interleukin 1 β. Moreover, the comet assay and increased 8-hydroxy-2-deoxyguanosine proved an accelerated apoptotic DNA fragmentation. These local renal changes were met with global altered blood biochemistry. The BCAAs and CS or their compiled administration showed an ameliorative effect against PDC-induced nephrotoxic in a synergistic pattern. Conclusions: Both BCAAs and CS or their combined administration afford potential competitors against renal insult induced by polyvalent anion pollutants in experimentally studied animals model. As a route for novel drug discovery, further investigation should be attempted to optimize their augmenting reno-protecting potential.

Review on Application Prospects of Nutritional Supplement Branched-chain Amino Acids in Competitive Sports

The aim of this study is to review the role of branched-chain amino acids in competitive sports. The data in the existing literature indicated that winning the game not only depends on development of experience and physical ability but also synergetic efforts in such disciplines as physiology, psychology, nutrition, biology, material and athletic training. Only by considering the subjective and objective conditions comprehensively, can athletes constantly break their limits in competitive abilities. Among various measures and methods improving the sports performance, nutrition regulation is the one preferred by athletes and coaches. The supplement Branched-Chain Amino Acid (BCAA for short) has remarkable effects on rapidly relieving fatigue, replenishing energy and enhancing physical abilities after athletes’ high-speed and fiercely comprehensive sports. In view of this, this study makes a review on application prospects of BCAA in competitive sports, in hopes of providing theoretical references for analysis on nutritional supplements in athletic sports.

Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabolism

ObjectivePlasma levels of branched-chain amino acids (BCAA) are consistently elevated in obesity and type 2 diabetes (T2D) and can also prospectively predict T2D. However, the role of BCAA in the pathogenesis of insulin resistance and T2D remains unclear. MethodsTo identify pathways related to insulin resistance, we performed comprehensive gene expression and metabolomics analyses in skeletal muscle from 41 humans with normal glucose tolerance and 11 with T2D across a range of insulin sensitivity (SI, 0.49 to 14.28). We studied both cultured cells and mice heterozygous for the BCAA enzyme methylmalonyl-CoA mutase (Mut) and assessed the effects of altered BCAA flux on lipid and glucose homeostasis. ResultsOur data demonstrate perturbed BCAA metabolism and fatty acid oxidation in muscle from insulin resistant humans. Experimental alterations in BCAA flux in cultured cells similarly modulate fatty acid oxidation. Mut heterozygosity in mice alters muscle lipid metabolism in vivo, resulting in increased muscle triglyceride accumulation, increased plasma glucose, hyperinsulinemia, and increased body weight after high-fat feeding. ConclusionsOur data indicate that impaired muscle BCAA catabolism may contribute to the development of insulin resistance by perturbing both amino acid and fatty acid metabolism and suggest that targeting BCAA metabolism may hold promise for prevention or treatment of T2D.

The positive association of branched-chain amino acids and metabolic dyslipidemia in Chinese Han population.

BackgroundIt has been suggested that serum branched-chain amino acids (BCAAs) are associated with the incident, progression and prognostic of type 2 diabetes. However, the role of BCAAs in metabolic dyslipidemia (raised triglycerides (TG) and reduced high-density lipoprotein cholesterol (HDL-C)) remains poorly understood. This study aims to investigate 1) the association of serum BCAAs with total cholesterol (TC), TG, HDL-C and low-density lipoprotein cholesterol (LDL-C) and 2) the association between serum BCAAs levels and risk of metabolic dyslipidemia in a community population with different glucose homeostasis.MethodsDemographics data and blood samples were collected from 2251 Chinese subjects from the Huaian Diabetes Protective Program (HADPP) study. After exclusion for cardiovascular disease (CVD), serious hepatic or nephritic diseases and others, 1320 subjects remained for analysis (789 subjects with hemoglobin A1c (HbA1c) > 5.7, 521 with HbA1c ≤ 5.7). Serum BCAAs level was measured by liquid chromatography-tandem mass spectrometry (LC MS/MS). The association of BCAAs with lipids or with the risk of metabolic dyslipidemia was analyzed.ResultsElevated serum BCAAs (both total and individual BCAA) were positively associated with TG and inversely associated with HDL-C in the whole population. These correlations were still significant even after adjustment for confounding factors (r = 0.165, p < 0.001 for TG; and r = -0.126, p < 0.001 for HDL-C). For reduced HDL-C, we found higher odds risk (OR) of Valine (Val) in high HbA1c group than in the low one (OR = 1.055, p < 0.001 vs OR = 1.032, p = 0.059). Compared with that in the first quartile, the multivariable-adjusted OR (95 % CI) of the 4th quartile of serum total BCAAs level for reduced HDL-C was 3.689 (2.325, 5.854) in high HbA1c group and 2.329 (1.284, 4.227) in low group, for raised TG was 3.305 (2.120, 5.152) and 2.972 (1.706, 5.176), and for metabolic dyslipidemia was 3.703 (2.261, 6.065) and 3.702 (1.877, 7.304), respectively (all p < 0.01).ConclusionElevated serum BCAAs level are positively associated with incident metabolic dyslipidemia. In addition, glucose homeostasis could play a certain role in BCAAs-related dyslipidemia.

The Emerging Role of Branched-Chain Amino Acids in Insulin Resistance and Metabolism.

Insulin is required for maintenance of glucose homeostasis. Despite the importance of insulin sensitivity to metabolic health, the mechanisms that induce insulin resistance remain unclear. Branched-chain amino acids (BCAAs) belong to the essential amino acids, which are both direct and indirect nutrient signals. Even though BCAAs have been reported to improve metabolic health, an increased BCAA plasma level is associated with a high risk of metabolic disorder and future insulin resistance, or type 2 diabetes mellitus (T2DM). The activation of mammalian target of rapamycin complex 1 (mTORC1) by BCAAs has been suggested to cause insulin resistance. In addition, defective BCAA oxidative metabolism might occur in obesity, leading to a further accumulation of BCAAs and toxic intermediates. This review provides the current understanding of the mechanism of BCAA-induced mTORC1 activation, as well as the effect of mTOR activation on metabolic health in terms of insulin sensitivity. Furthermore, the effects of impaired BCAA metabolism will be discussed in detail.

Plasma Branched-Chain Amino Acids and Incident Cardiovascular Disease in the PREDIMED Trial.

The role of branched-chain amino acids (BCAAs) in cardiovascular disease (CVD) remains poorly understood. We hypothesized that baseline BCAA concentrations predict future risk of CVD and that a Mediterranean diet (MedDiet) intervention may counteract this effect. We developed a case-cohort study within the Prevención con Dieta Mediterránea (PREDIMED), with 226 incident CVD cases and 744 noncases. We used LC-MS/MS to measure plasma BCAAs (leucine, isoleucine, and valine), both at baseline and after 1 year of follow-up. The primary outcome was a composite of incident stroke, myocardial infarction, or cardiovascular death. After adjustment for potential confounders, baseline leucine and isoleucine concentrations were associated with higher CVD risk: the hazard ratios (HRs) for the highest vs lowest quartile were 1.70 (95% CI, 1.05-2.76) and 2.09 (1.27-3.44), respectively. Stronger associations were found for stroke. For both CVD and stroke, we found higher HRs across successive quartiles of BCAAs in the control group than in the MedDiet groups. With stroke as the outcome, a significant interaction (P = 0.009) between baseline BCAA score and intervention with MedDiet was observed. No significant effect of the intervention on 1-year changes in BCAAs or any association between 1-year changes in BCAAs and CVD were observed. Higher concentrations of baseline BCAAs were associated with increased risk of CVD, especially stroke, in a high cardiovascular risk population. A Mediterranean-style diet had a negligible effect on 1-year changes in BCAAs, but it may counteract the harmful effects of BCAAs on stroke.

BCAA Metabolism and NH3 Homeostasis.

The branched chain amino acids (BCAA) are essential amino acids required not only for growth and development, but also as nutrient signals and as nitrogen donors to neurotransmitter synthesis and glutamate/glutamine cycling. Transamination and oxidative decarboxylation of the BCAAs are catalysed by the branched-chain aminotransferase proteins (BCATm, mitochondrial and BCATc, cytosolic) and the branched-chain α-keto acid dehydrogenase enzyme complex (BCKDC), respectively. These proteins show tissue, cell compartmentation, and protein-protein interactions, which call for substrate shuttling or channelling and nitrogen transfer for oxidation to occur. Efficient regulation of these pathways is mediated through the redox environment and phosphorylation in response to dietary and hormonal stimuli. The wide distribution of these proteins allows for effective BCAA utilisation. We discuss how BCAT, BCKDC, and glutamate dehydrogenase operate in supramolecular complexes, allowing for efficient channelling of substrates. The role of BCAAs in brain metabolism is highlighted in rodent and human brain, where differential expression of BCATm indicates differences in nitrogen metabolism between species. Finally, we introduce a new role for BCAT, where a change in function is triggered by oxidation of its redox-active switch. Our understanding of how BCAA metabolism and nitrogen transfer is regulated is important as many studies now point to BCAA metabolic dysregulation in metabolic and neurodegenerative conditions.

Metabolomics for Improved Understanding and Prediction of Cardiometabolic Diseases—Recent Findings from Human Studies

Cardiometabolic dieases are the main causes of morbidity and mortality worldwide. Despite large clinical and basic research efforts to improve the understanding of the molecular mechanisms of these conditions and to develop prediagnostic markers still remains a challenge. Recently, targeted and untargeted metabolomics technique became available for comprehensive studies of small molecules in biological samples in large-scale studies. MS- or NMR-based techniques dominate and have recently been used extensively in studies to identify predictive biomarkers, monitoring therapeutic response as well as in basic mechanism studies of obesity, metabolic syndrome, type 2 diabetes, and heart disease. Here, we review the recent findings from such studies. Findings highlight the role of branched-chain amino acids, acyl carnitines and other lipid classes in these conditions. Putative biomarkers for disease conditions have been identified but mechanistic understanding of their role in the disease development and progression typically remains to be elucidated. Future studies should to a greater extent be designed to allow studies on causal mechanistic links between metabolites and disease.

Branched-chain amino acids modulate the expression of hepatic fatty acid metabolism-related genes in female broiler chickens.

The effects and roles of branched-chain amino acids (BCAAs) in hepatic fat metabolism are still unknown. Here, we used broiler chickens, in which lipogenesis occurs essentially in the liver as in human, to investigate the effects of three levels of BCAAs (control "C," low "L" and exogenous supplemented diet "L+S") on growth, carcass traits, immunity, and hepatic fat metabolism. Despite the same productive performance, immunity, and plasma BCAA levels between all groups, low BCAA levels significantly downregulated the hepatic expression of lipogenic genes particularly acetyl-CoA carboxylase alpha (ACCα) and stearoyl-coA desaturase 1 (p = 0.0036 and p = 0.0008, respectively) and upregulated the hepatic expression of mitochondrial β-oxidation- (uncoupling protein and NRF-1, p < 0.05) and dynamic-related genes (DNM1, p < 0.05). Concomitant with these changes, low BCAA levels increased the phosphorylation of AMP-activated protein kinase (AMPK)α(Thr172), ACCα(Ser79), and forkhead box protein O1 (FoxO1(Ser256)) and decreased the phosphorylation of mTOR(Ser2481) and P70 S6 kinase (Thr389). The mRNA abundance of the transcription factors SREBP1/2, peroxisome proliferator activated receptor alpha/beta, and FoxO1 were also increased in the liver of L group compared to the control. Together our data indicate that low BCAA levels inhibit fatty acid synthesis and enhanced fatty acid β-oxidation in the liver of female broiler chickens and these effects were probably mediated through AMPK-mTOR-FoxO1 pathway.