Branched-chain Amino Acid Metabolism Research Articles

Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson's disease after dietary supplementation with branched-chain amino acids.

The gut microbiota and microbial metabolites influence the enteric nervous system and the central nervous system via the microbial-gut-brain axis. Increasing body of evidence suggests that disturbances in the metabolism of peripheral branched-chain amino acids (BCAAs) can contribute to the development of neurodegenerative diseases through neuroinflammatory signaling. Preliminary research has shown that longitudinal changes in serum amino acid levels in mouse models of Parkinson's disease (PD) are negatively correlated with disease progression. Therefore, the aim of the present study was to determine the changes in serum levels of short-chain fatty acids (SCFAs) in a mouse model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD after dietary BCAA supplementation. In our research, gas chromatography-mass spectrometry was used to detect serum SCFA concentrations. The data were then analyzed with principal component analysis and orthogonal partial least squares discriminant analysis. Finally, the correlations of serum SCFA levels with gut and motor function in MPTP-induced PD mice were explored. Propionic acid, acetic acid, butyric acid, and isobutyric acid concentrations were elevated in MPTP + H-BCAA mice compared with MPTP mice. Propionic acid concentration was increased the most, while the isovaleric acid concentration was decreased. Propionic acid concentration was positively correlated with fecal weight and water content and negatively correlated with the pole-climbing duration. In conclusion, these results not only suggest that propionic acid may be a potential biomarker for PD, but also indicate the possibility that PD may be treated by altering circulating levels of SCFA.

Physiological 4-phenylbutyrate promotes mitochondrial biogenesis and metabolism in C2C12 myotubes

Type 2 diabetes is characterized by elevated circulating blood metabolites such as glucose, insulin, and branched chain amino acids (BCAA), which often coincide with reduced mitochondrial function. 4-Phenylbutyrate (PBA), an ammonia scavenger, has been shown to activate BCAA metabolism, resolve endoplasmic reticulum (ER) stress, and rescue BCAA-mediated insulin resistance. To determine the effect of PBA on the altered metabolic phenotype featured in type 2 diabetes, the present study investigated the effect of PBA on various metabolic parameters including mitochondrial metabolism and mitochondrial biogenesis. C2C12 myotubes were treated with PBA at 0.5 mM (representing physiologically attainable blood concentrations) or 10 mM (representing physiologically unattainable/proof-of-concept levels) for up to 24 h. Mitochondrial and glycolytic metabolism were assessed via oxygen consumption and extracellular acidification rate, respectively. Mitochondrial content, lipid content, and ER stress were measured by fluorescent staining. Metabolic gene expression was measured by qRT-PCR. Both doses of PBA increased expression of indicators of mitochondrial biogenesis, though only PBA at 0.5 mM increased mitochondrial function and content while 10 mM PBA reduced mitochondrial function and content. PBA at 0.5 mM also rescued reduced mitochondrial function during insulin resistance, though PBA also caused a reduced insulin stimulated pAkt expression during insulin resistance. PBA treatment also increased extracellular BCAA accumulation during insulin resistance despite unchanged pBCKDH expression. Taken together, PBA may increase mitochondrial biogenesis, content, and function in a dose-dependent fashion which may have implications for prevention or treatment of metabolic disease such as insulin resistance.

Branched chain amino acids metabolism in heart failure

As a terminal stage of various cardiovascular diseases, heart failure is of great concern due to its high mortality rate and limited treatment options. Researchers are currently focusing their efforts on investigating the metabolism of carbohydrates, fatty acids, and amino acids to enhance the prognosis of cardiovascular diseases. Simultaneously, branched-chain amino acids (BCAAs), including leucine, isoleucine, and valine, play significant roles in blood glucose regulation, protein synthesis, and insulin sensitivity. However, disrupted BCAAs metabolism has been associated with conditions such as hypertension, obesity, and atherosclerosis. This article explores intricate metabolic pathways, unveiling the connection between disrupted BCAAs metabolism and the progression of heart failure. Furthermore, the article discusses therapeutic strategies, assesses the impact of BCAAs on cardiac dysfunction, and examines the potential of modulating BCAAs metabolism as a treatment for heart failure. BCAAs and their metabolites are also considered as biomarkers for evaluating cardiac metabolic risk. In conclusion, this article elucidates the multifaceted roles of BCAAs in heart failure and cardiovascular health, providing guidance for future research and intervention measures.

Metabolomic Insights into the Mechanisms of Ganoderic Acid: Protection against α-Amanitin-Induced Liver Injury.

α-Amanitin is a representative toxin found in the Amanita genus of mushrooms, and the consumption of mushrooms containing α-Amanitin can lead to severe liver damage. In this study, we conduct toxicological experiments to validate the protective effects of Ganoderic acid A against α-amanitin-induced liver damage. By establishing animal models with different durations of Ganoderic acid A treatment and conducting a metabolomic analysis of the serum samples, we further confirmed the differences in serum metabolites between the AMA+GA and AMA groups. The analysis of differential serum metabolites after the Ganoderic acid A intervention suggests that Ganoderic acid A may intervene in α-amanitin-induced liver damage by participating in the regulation of retinol metabolism, tyrosine and tryptophan biosynthesis, fatty acid biosynthesis, sphingosine biosynthesis, spermidine and spermine biosynthesis, and branched-chain amino acid metabolism. This provides initial insights into the protective intervention mechanisms of GA against α-amanitin-induced liver damage and offers new avenues for the development of therapeutic drugs for α-Amanitin poisoning.

Branched-Chain Amino Acid Accumulation Fuels the Senescence-Associated Secretory Phenotype.

The essential branched-chain amino acids (BCAAs) leucine, isoleucine, and valine play critical roles in protein synthesis and energy metabolism. Despite their widespread use as nutritional supplements, BCAAs' full effects on mammalian physiology remain uncertain due to the complexities of BCAA metabolic regulation. Here a novel mechanism linking intrinsic alterations in BCAA metabolism is identified to cellular senescence and the senescence-associated secretory phenotype (SASP), both of which contribute to organismal aging and inflammation-related diseases. Altered BCAA metabolism driving the SASP is mediated by robust activation of the BCAA transporters Solute Carrier Family 6 Members 14 and 15 as well as downregulation of the catabolic enzyme BCAA transaminase 1 during onset of cellular senescence, leading to highly elevated intracellular BCAA levels in senescent cells. This, in turn, activates the mammalian target of rapamycin complex 1 (mTORC1) to establish the full SASP program. Transgenic Drosophila models further indicate that orthologous BCAA regulators are involved in the induction of cellular senescence and age-related phenotypes in flies, suggesting evolutionary conservation of this metabolic pathway during aging. Finally, experimentally blocking BCAA accumulation attenuates the inflammatory response in a mouse senescence model, highlighting the therapeutic potential of modulating BCAA metabolism for the treatment of age-related and inflammatory diseases.

Impaired cardiac BCAA catabolism associated with impaired myocardial efficiency during exercise in a porcine model with multiple risk factors

Abstract Background Diabetes mellitus (DM), chronic kidney disease (CKD) and consumption of a high-fat diet (HFD), are well known risk factors for diastolic heart failure. We recently developed a multiple comorbidity swine model (MCS), with DM (streptozotocin), HFD and CKD (kidney embolization), and showed that 6 months of sustained hyperglycemia, hypercholesterolemia and kidney dysfunction resulted in inflammation and oxidative stress associated with coronary microvascular dysfunction and left ventricular diastolic dysfunction. Additionally, MCS animals showed impaired myocardial efficiency during exercise as demonstrated by increased myocardial oxygen consumption (Fig. A), suggesting an impairment in myocardial mitochondrial function. Purpose Here we used a combined omics (single nuclei RNA sequencing and proteomics) approach to study the molecular pathways involved in mitochondrial dysfunction. Methods 15 MCS and 10 healthy control female swine were included in the study. Proteome analysis and single nuclei RNA sequencing, was performed on frozen left ventricle myocardial samples. Results Proteome analysis of MCS hearts showed reduced expression of branched-chain amino acid (BCAA) catabolism proteins (Fig. B), most notably BCAT2, MCCC1 and MCCC2. Single nuclei RNA sequencing of a subgroup of the same animals demonstrated a downregulation of these genes specifically in cardiomyocyte subpopulations. Besides being a source of ATP, via oxidative phosphorylation in mitochondria, BCAAs, encompassing essential amino acids (leucine, valine and isoleucine), act as signaling molecules. Thus, increased BCAA levels reduce insulin sensitivity, modulate mitochondrial substrate utilization and impair mitochondrial function, resulting in increased mitochondrial production of reactive oxygen species (ROS). These findings are consistent with our data in the MCS swine indicating that impaired BCAA metabolism was found in the myocardium of animals with comorbidities and were associated with increased ROS levels (8-isoprostane 12.9±0.8 pg/mg protein in MCS vs 10.3±0.5 in healthy animals, P=0.02 by T-test) and impaired myocardial efficiency during exercise (Fig. A). Conclusion Taken together, these findings suggest an essential role of altered BCAA cardiomyocyte metabolism resulting in mitochondrial dysfunction, increased oxidative stress and subsequent alterations in the myocardial function.Fig.

Abstract 14967: Branching Out: Disrupted Branched Chain Amino Acid Metabolism Exacerbates Pulmonary Arterial Hypertension

Introduction: Valine, leucine, and isoleucine are essential branched chain amino acids (BCAA), and recent epidemiological studies report elevated BCAAs predict worse outcomes in several cardiovascular diseases with metabolic origins such as diabetes, heart failure, and hypertension. However, the role of BCAA metabolism in pulmonary arterial hypertension pathophysiology is relatively unexplored. Hypothesis: BCAAs are elevated in human PAH and reduction of BCAAs via small molecule activation of BCAA catabolism and dietary interventions combats PAH severity in preclinical PAH. Methods: Literature search of human PAH metabolomics studies was conducted. For rodent studies, male Sprague Dawley rats were divided into three groups: control (saline injection), monocrotaline (MCT) vehicle (MCT-V), or MCT-BT2, a small molecule inducer of BCAA catabolism. BT2 was administered at 20mg/kg/day. A low BCAA dietary intervention was implemented, with male Sprague Dawley rats divided into two groups: MCT-standard chow diet and MCT-low BCAA diet. To assess exercise capacity, rodents underwent a maximal exercise testing protocol before echocardiographic and hemodynamic assessments of PAH. Proteomic analysis of lung mitochondrial extracts was performed to define the molecular effects of BT2. Results: Of 11 studies evaluating human PAH metabolomics, 7 studies reported elevated BCAAs or BCAA metabolites in PAH. BT2 treatment improved exercise performance, reduced PA pressures, and augmented RV function. Moreover, the MCT-BT2 group possessed a distinct lung proteomic signature with changes in inflammatory and metabolic pathways. Finally, the low BCAA diet intervention modestly combatted PAH severity. Conclusions: BCAA metabolism is disrupted in human PAH and interventions that reduce circulating BCAAs display therapeutic potential in rodent PAH.

Abstract 16157: Impaired Branched Chain Amino Acid Metabolism in Porcine Right Atrial Dysfunction

Background: Right atrial (RA) dysfunction is prevalent and an early predictor of mortality in pulmonary arterial hypertension (PAH). At present, the underlying pathobiology of RA dysfunction is not well defined, and thus approaches are needed to delineate potential therapeutic pathways to hopefully improve outcomes in PAH. Methods: Surgical pulmonary artery banding induced right ventricular and right atrial dysfunction in male piglets. 6 weeks post-banding, cardiovascular magnetic resonance imaging quantified cardiac structure/function. Right atrial and ventricular tissue was subjected to quantitative proteomics and targeted metabolomics. Results: PAB piglets had decreased RA ejection fraction (RAEF) and increased RA end-systolic volume. Pathway analysis revealed proteins responsible for branched chain amino acid (BCAA) degradation, including MCEE (Methylmalonyl CoA Epimerase), DLD (Dihydrolipoamide Dehydrogenase), HIBADH (3-hydroxyisobutyrate Dehydrogenase), ACAT1 (Acetyl-CoA Acetyltransferase 1), and IVD (Isovaleryl-CoA Dehydrogenase), were reduced in PAB RAs, which was not observed in RV tissue. Targeted metabolomics analysis demonstrated BCAAs were elevated in the RA of PAB piglets and BCAA levels were strongly and inversely associated with RAEF. Conclusions: Deranged BCAA metabolism is uniquely observed in the dysfunctional RA, which offers a new therapeutic target for this important clinical problem.

Research progress on branched-chain amino acid aminotransferases.

Branched-chain amino acid aminotransferases, widely present in natural organisms, catalyze bidirectional amino transfer between branched-chain amino acids and branched-chain α-ketoacids in cells. Branched-chain amino acid aminotransferases play an important role in the metabolism of branched-chain amino acids. In this paper, the interspecific evolution and biological characteristics of branched-chain amino acid aminotransferases are introduced, the related research of branched-chain amino acid aminotransferases in animals, plants, microorganisms and humans is summarized and the molecular mechanism of branched-chain amino acid aminotransferase is analyzed. It has been found that branched-chain amino acid metabolism disorders are closely related to various diseases in humans and animals and plants, such as diabetes, cardiovascular diseases, brain diseases, neurological diseases and cancer. In particular, branched-chain amino acid aminotransferases play an important role in the development of various tumors. Branched-chain amino acid aminotransferases have been used as potential targets for various cancers. This article reviews the research on branched-chain amino acid aminotransferases, aiming to provide a reference for clinical research on targeted therapy for various diseases and different cancers.

The Effect of Altered Branched-Chain Amino Acid (BCAA) Metabolism on Proteinuria and Mesangial Expansion in db/db Mice Treated with SGLT2 Inhibitor

The Effect of Altered Branched-Chain Amino Acid (BCAA) Metabolism on Proteinuria and Mesangial Expansion in db/db Mice Treated with SGLT2 Inhibitor

Weight-loss Independent Clinical and Metabolic Biomarkers Associated with Type 2 Diabetes Remission Post-bariatric/metabolic Surgery

PurposeRemission of type 2 diabetes (T2D) can be achieved by many, but not all, people following bariatric/metabolic surgery. The mechanisms underlying T2D remission remain incompletely understood. This observational study aimed to identify novel weight-loss independent clinical, metabolic and genetic factors that associate with T2D remission using comprehensive phenotyping.Materials and MethodsTen patients without T2D remission (non-remitters) were matched to 10 patients with T2D remission (remitters) for age, sex, type of surgery, body weight, BMI, post-operative weight loss, duration from surgery and duration of T2D. Detailed body composition assessed using magnetic resonance imaging, gut hormones, serum metabolomics, insulin sensitivity, and genetic risk scores for T2D and anthropometric traits were assessed.ResultsRemitters had significantly greater β-cell function and circulating acyl ghrelin levels, but lower visceral adipose tissue (VAT): subcutaneous adipose tissue (SAT) ratio than non-remitters. Branched-chain amino acids (BCAAs) and VLDL particle size were the most discriminant metabolites between groups. A significant positive correlation between, VAT area, VAT:SAT ratio and circulating levels of BCAAs was observed, whereas a significant negative correlation between BCAAs and β-cell function was revealed.ConclusionWe highlight a potentially novel relationship between VAT and BCAAs, which may play a role in glucoregulatory control. Improvement in β-cell function, and the role ghrelin plays in its recovery, is likely another key factor influencing T2D remission post-surgery. These findings suggest that adjunctive approaches that target VAT loss and restoration of BCAA metabolism might achieve higher rates of long-term T2D remission post-surgery.Graphical

Genetic and Lifestyle-Related Factors Influencing Serum Hyper-Propionylcarnitine Concentrations and Their Association with Metabolic Syndrome and Cardiovascular Disease Risk.

The genetic and environmental determinants of serum propionylcarnitine concentrations (PC) remain largely unexplored. This study investigated the impact of genetic and environmental factors on serum propionylcarnitine levels in middle-aged and elderly participants from the Ansan/Ansung cohort of the Korean Genome and Epidemiology Study. Our goal was to understand the role of PC on the risk of metabolic syndrome (MetS) leading to cardiovascular disease, particularly concerning branched-chain amino acid (BCAA) metabolism. We analyzed participants' demographic, lifestyle, and biochemical data with and without MetS. Serum metabolite concentrations, including carnitine, acylcarnitine, and amino acid concentrations, were measured, and the components of MetS were evaluated. Genetic variants associated with low and high PC were selected using genome-wide association studies after adjusting for MetS-related parameters. Further, genetic variants and lifestyle factors that interacted with the polygenic risk score (PRS) were analyzed. Participants with MetS were older and less educated, and their alcohol intake was higher than non-MetS participants. PC was significantly associated with the MetS risk and increased the serum levels of BCAAs and other amino acids. Higher PC positively correlated with MetS components, insulin resistance, and cardiovascular risk factors. Intake of calcium, sodium, and vitamin D were inversely associated with PC, but coffee consumption was positively linked to PC. Multiple C2 And Transmembrane Domain Containing-1 (MCTP1)_rs4290997, Kinesin Family Member-7 (KIF7)_rs2350480, Coagulation Factor-II (F2)_rs2070850, Peroxisomal Biogenesis Factor-3 (PEX3)_rs223231, TBC1 Domain Family Member-22A (TBC1D22A)_rs910543, and Phospholipase A2 Group-IV-C (PLA2G4C)_rs7252136 interact with each other to have a threefold influence on PC. The PRS for the six-genetic variant model also interacted with age; the diet rich in beans, potato, and kimchi; and smoking status, influencing PC. In conclusion, elevated PC was associated with MetS and cardiovascular disease risk, suggesting their potential as disease biomarkers.

Combined metabolomic and lipidomic analysis uncovers metabolic profile and biomarkers for papillary thyroid carcinoma

Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy with a rapidly increasing incidence. The pathogenesis of PTC is unclear, but metabolic and lipidomic reprogramming may play a role in tumor growth. We applied ultra-performance liquid chromatography-tandem mass spectrometry to perform widely targeted metabolomics and lipidomics on plasma samples from 94 patients with PTC and 100 healthy controls. We identified 113 differential metabolites and 236 differential lipids, mainly involved in branched-chain amino acid metabolism, glutamate and glutamine metabolism, tricarboxylic acid cycle, and lipid metabolism. We also screened three potential metabolite biomarkers: sebacic acid, L-glutamine, and indole-3-carboxaldehyde. These biomarkers showed excellent diagnostic performance for PTC in both discovery and validation cohorts, with areas under the receiver operating characteristic curves of 0.994 and 0.925, respectively. Our findings reveal distinct metabolic and lipidomic features of PTC and provide novel targets for diagnosis and treatment.

Metabolomics in severe traumatic brain injury: a scoping review

BackgroundDiagnosis and prognostication of severe traumatic brain injury (sTBI) continue to be problematic despite years of research efforts. There are currently no clinically reliable biomarkers, though advances in protein biomarkers are being made. Utilizing Omics technology, particularly metabolomics, may provide new diagnostic biomarkers for sTBI. Several published studies have attempted to determine the specific metabolites and metabolic pathways involved; these studies will be reviewed.AimsThis scoping review aims to summarize the current literature concerning metabolomics in sTBI, review the comprehensive data, and identify commonalities, if any, to define metabolites with potential clinical use. In addition, we will examine related metabolic pathways through pathway analysis.MethodsScoping review methodology was used to examine the current literature published in Embase, Scopus, PubMed, and Medline. An initial 1090 publications were identified and vetted with specific inclusion criteria. Of these, 20 publications were selected for further examination and summary. Metabolic data was classified using the Human Metabolome Database (HMDB) and arranged to determine the ‘recurrent’ metabolites and classes found in sTBI. To help understand potential mechanisms of injury, pathway analysis was performed using these metabolites and the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Database.ResultsSeveral metabolites related to sTBI and their effects on biological pathways were identified in this review. Across the literature, proline, citrulline, lactate, alanine, valine, leucine, and serine all decreased in adults post sTBI, whereas both octanoic and decanoic acid increased. Hydroxy acids and organooxygen compounds generally increased following sTBI, while most carboxylic acids decreased. Pathway analysis showed significantly affected glycine and serine metabolism, glycolysis, branched-chain amino acid (BCAA) metabolism, and other amino acid metabolisms. Interestingly, no tricarboxylic acid cycle metabolites were affected.ConclusionAside from a select few metabolites, classification of a metabolic profile proved difficult due to significant ambiguity between study design, sample size, type of sample, metabolomic detection techniques, and other confounding variables found in sTBI literature. Given the trends found in some studies, further metabolomics investigation of sTBI may be useful to identify clinically relevant metabolites.

Relationship between serum amino acid levels and acne severity

AimAcne is a common skin disease in which metabolic factors have been suggested to play a role in its pathogenesis. The aim of this study was to evaluate the relationship between serum amino acid levels and acne and acne scar development. Material and methodsIn this cross-sectional study, 30 patients with scatricial acne, 30 patients with non-scatricial acne and 30 healthy subjects were included. Global acne scores and scar scores were calculated. Venous blood samples of the participants were analyzed by liquid chromatography-tandem mass spectrometry and serum levels of a total of 24 amino acids including nine essential amino acids, 11 nonessential amino acids and four other amino acids were measured. ResultsSerum levels of the branched chain amino acids leucine, isoleucine and valine were significantly higher in the cicatricial acne group (p: <0.001, 0.001, <0.001, respectively) and in the non-cicatricial acne group (p: 0.039, 0.045, 0.001, respectively) compared to healthy subjects. There were also significant positive correlations between the levels of these amino acids and global acne scores (p = 0.048, r = 0.255, p = 0.006, r = 0.354, p = 0.017, r = 0.307, respectively) and scar scores (p = 0.032, r = 0.392, p = 0.021, r = 0.424, p = 0.018, r = 0.427, respectively). Serum tryptophan levels were significantly lower in both scatricial and non-scatricial acne groups compared to healthy subjects (p = 0.033 and < 0.001, respectively). ConclusionImpaired metabolism of branched-chain amino acids and tryptophan may be associated with acne pathogenesis, acne severity and scarring.

Reactive nitrogen species inhibit branched chain alpha-ketoacid dehydrogenase complex and impact muscle cell metabolism

Branched chain α-ketoacid dehydrogenase complex (BCKDC) is the rate-limiting enzyme in branched chain amino acid (BCAA) catabolism, a metabolic pathway with great importance for human health. BCKDC belongs to the mitochondrial α-ketoacid dehydrogenase complex family, which also includes pyruvate dehydrogenase complex and oxoglutarate dehydrogenase complex. Here, we revealed that BCKDC can be substantially inhibited by reactive nitrogen species (RNS) via a mechanism similar to what we recently discovered with pyruvate dehydrogenase complex and oxoglutarate dehydrogenase complex-RNS can cause inactivating covalent modifications of the lipoic arm on its E2 subunit. In addition, we showed that such reaction between RNS and the lipoic arm of the E2 subunit can further promote inhibition of the E3 subunits of α-ketoacid dehydrogenase complexes. We examined the impacts of this RNS-mediated BCKDC inhibition in muscle cells, an important site of BCAA metabolism, and demonstrated that the nitric oxide production induced by cytokine stimulation leads to a strong inhibition of BCKDC activity and BCAA oxidation in myotubes and myoblasts. More broadly, nitric oxide production reduced the level of functional lipoic arms across the multiple α-ketoacid dehydrogenases and led to intracellular accumulation of their substrates (α-ketoacids), decrease of their products (acyl-CoAs), and a lower cellular energy charge. In sum, this work revealed a new mechanism for BCKDC regulation, demonstrated that RNS can generally inhibit all α-ketoacid dehydrogenases, which has broad physiological implications across multiple cell types, and elucidated the mechanistic connection between RNS-driven inhibitory modifications on the E2 and E3 subunits of α-ketoacid dehydrogenases.

BCAT2 promotes melanoma progression by activating lipogenesis via the epigenetic regulation of FASN and ACLY expressions.

Melanoma is the most lethal skin cancer originating from the malignant transformation of epidermal melanocyte. The dysregulation of cellular metabolism is a hallmark of cancer, including in melanoma. Aberrant branched-chain amino acids (BCAA) metabolism and related enzymes has been greatly implicated in the progression of multiple types of cancer, whereas remains far from understood in melanoma. Herein, we reported that the critical BCAA metabolism enzyme branched-chain amino acid transaminase 2 (BCAT2) is an oncogenic factor in melanoma by activating lipogenesis via the epigenetic regulation of fatty acid synthase (FASN) and ATP-citrate lyase (ACLY) expressions. Firstly, we found that BCAT2 expression was prominently increased in melanoma, and highly associated with clinical stage. Then, it was proved that the deficiency of BCAT2 led to impaired tumor cell proliferation, invasion and migration in vitro, and tumor growth and metastasis in vivo. Further, RNA sequencing technology and a panel of biochemical assays demonstrated that BCAT2 regulated de novo lipogenesis via the regulation of the expressions of both FASN and ACLY. Mechanistically, the inhibition of BCAT2 suppressed the generation of intracellular acetyl-CoA, mitigating P300-dependent histone acetylation at the promoter of FASN and ACLY, and thereby their transcription. Ultimately, zinc finger E-box binding homeobox 1 (ZEB1) was identified as the upstream transcriptional factor responsible for BCAT2 up-regulation in melanoma. Our results demonstrate that BCAT2 promotes melanoma progression by epigenetically regulating FASN and ACLY expressions via P300-dependent histone acetylation. Targeting BCAT2 could be exploited as a promising strategy to restrain tumor progression in melanoma.

THU136 Insulin Resistance, Insulin Secretion, And Body Fat In Youth: Associations With Branched-chain Amino-acids (BCAA), Branched-chain Keto-acids (BCKAs), Glutamate/Glutamine (Glx), And Kynurenine (KYN)

Abstract Disclosure: K. Blew: None. Q. Wang: None. H. Hong: None. O. Ilkayeva: None. M. Muehlbauer: None. M. Crawford: Employee; Self; Laboratory Corporations of America. Stock Owner; Self; Laboratory Corporations of America. R.P. Grant: Employee; Self; Laboratory Corporations of America. Stock Owner; Self; Laboratory Corporations of America. D.S. Hsia: None. J.R. Bain: None. M. Freemark: None. P. Gumus Balikcioglu: None. Objective: We recently showed that insulin resistance (IR) and Type 2 diabetes (T2D) in youth with obesity are associated with disordered metabolism of BCAA and diversion of tryptophan (TRP) metabolism from the serotonin to the kynurenine (KYN) pathway. In this study we determined if BCAAs, BCKAs, Glx and KYN/TRP correlate with metrics of obesity, insulin sensitivity, and insulin secretion. Methods: We performed frequently sampled oral glucose tolerance tests (OGTT) in 16 youth with normal weight and 16 non-diabetic youth with overweight/obesity and mild-moderate IR ages 18-21 yo. After an overnight fast of 8-12 hours, subjects underwent a 3-hour (1.75 g/kg, max 75 g) frequently sampled OGTT. Glucose (G) and insulin (I) were measured at times -15, 0, 10, 15, 30, 45, 60, 90, 120, and 180 minutes. Plasma metabolomic profiles were obtained at time 0. HOMA-S, HOMA-B, HOMA-IR, Matsuda Index, AUC glucose, AUC insulin, insulinogenic index (IGI) and disposition index (DI) at 10, 15 and 30 min were calculated. % Body fat was measured by TANITA. Results: Groups were comparable in age (19±1.2 vs 19.6±1.1 years), sex, race, ethnicity and pubertal status. Overweight/obese participants had higher BMI (22±2.3 vs 33.7±8.1), BF% (19.6±7.2 vs 37±9.2), leptin, and CRP and were more insulin resistant as evidenced by higher HOMA-IR and HOMA-B and lower HOMA-S and Matsuda Index. Glucose at 120’, insulin at -15’,0’,15’ and 120’, and IGI at 15’ were higher among overweight/obese subjects. AUC glucose, AUC insulin and DI were comparable across groups, as were fasting BCAA, BCAA/BCKA ratio, TRP, KYN, Kynurenic acid, and the KYN/TRP ratio. BCKA levels trended lower (p=0.05) in the overweight/obese group. Glx levels were higher among overweight/obese subjects (p=0.03) and correlated positively with BMI, % body fat, and metrics of hepatic IR including HOMA IR and ALT. BCAA levels correlated positively with fasting KYN and negatively with DI at 15’ and HMW-adiponectin, a metric of insulin sensitivity, but did not correlate with BMI or % body fat. The ratio of BCAA to BCKA correlated positively with KYN, KYN/TRP ratio and BMI. In contrast, BCKAs correlated negatively with BMI and % body fat but did not correlate with metrics of insulin sensitivity. KIV, the α-keto-acid of valine, associated negatively with metrics of insulin secretion including DI and IGI at 15’ and AUC glucose. Conclusions: In this cohort of non-diabetic youth, the levels of Glx correlated strongly with body fat mass and metrics of hepatic insulin resistance. The levels of BCAA and the ratio of BCAA/BCKA associated positively with KYN and negatively with HMW-adiponectin, a metric of insulin sensitivity, but did not correlate with % body fat. In contrast, BCKAs correlated negatively with % body fat and insulin secretion but did not correlate with metrics of IR. These findings suggest complex effects of fat deposition and insulin sensitivity on BCAA and glutamate metabolism. Presentation: Thursday, June 15, 2023

Use of Branched-Chain Amino Acids as a Potential Treatment for Improving Nutrition-Related Outcomes in Advanced Chronic Liver Disease.

Advanced chronic liver disease (ACLD) represents a complex and multifactorial clinical entity characterized by liver dysfunction and associated complications. In recent years, the significance of nutritional status in ACLD prognosis has gained considerable attention. This review article delves into the multifactorial pathogenesis of malnutrition in ACLD and its profound consequences for health outcomes. We explore the clinical implications of secondary sarcopenia in ACLD and highlight the critical relevance of frailty in both decompensated and compensated ACLD. A specific focus of this review revolves around branched-chain amino acids (BCAAs) and their pivotal role in managing liver disease. We dissect the intricate relationship between low Fischer's ratio and BCAA metabolism in ACLD, shedding light on the molecular mechanisms involved. Furthermore, we critically evaluate the existing evidence regarding the effects of BCAA supplementation on outcomes in ACLD patients, examining their potential to ameliorate the nutritional deficiencies and associated complications in this population.

Metabolic adaptations in pressure overload hypertrophic heart.

This review article offers a detailed examination of metabolic adaptations in pressure overload hypertrophic hearts, a condition that plays a pivotal role in the progression of heart failure with preserved ejection fraction (HFpEF) to heart failure with reduced ejection fraction (HFrEF). The paper delves into the complex interplay between various metabolic pathways, including glucose metabolism, fatty acid metabolism, branched-chain amino acid metabolism, and ketone body metabolism. In-depth insights into the shifts in substrate utilization, the role of different transporter proteins, and the potential impact of hypoxia-induced injuries are discussed. Furthermore, potential therapeutic targets and strategies that could minimize myocardial injury and promote cardiac recovery in the context of pressure overload hypertrophy (POH) are examined. This work aims to contribute to a better understanding of metabolic adaptations in POH, highlighting the need for further research on potential therapeutic applications.