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International Journal of Molecular... Mar 2018Branched chain amino acids (BCAAs), including leucine (Leu), isoleucine (Ile), and valine (Val), play critical roles in the regulation of energy homeostasis, nutrition... (Review)
Review
Branched chain amino acids (BCAAs), including leucine (Leu), isoleucine (Ile), and valine (Val), play critical roles in the regulation of energy homeostasis, nutrition metabolism, gut health, immunity and disease in humans and animals. As the most abundant of essential amino acids (EAAs), BCAAs are not only the substrates for synthesis of nitrogenous compounds, they also serve as signaling molecules regulating metabolism of glucose, lipid, and protein synthesis, intestinal health, and immunity via special signaling network, especially phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signal pathway. Current evidence supports BCAAs and their derivatives as the potential biomarkers of diseases such as insulin resistance (IR), type 2 diabetes mellitus (T2DM), cancer, and cardiovascular diseases (CVDs). These diseases are closely associated with catabolism and balance of BCAAs. Hence, optimizing dietary BCAA levels should have a positive effect on the parameters associated with health and diseases. This review focuses on recent findings of BCAAs in metabolic pathways and regulation, and underlying the relationship of BCAAs to related disease processes.
Topics: Amino Acids, Branched-Chain; Animals; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Isoleucine; Leucine; Metabolic Diseases; Signal Transduction; Valine
PubMed: 29570613
DOI: 10.3390/ijms19040954 -
Cell Research Oct 2019Recently, increasing evidence has suggested the association between gut dysbiosis and Alzheimer's disease (AD) progression, yet the role of gut microbiota in AD...
Recently, increasing evidence has suggested the association between gut dysbiosis and Alzheimer's disease (AD) progression, yet the role of gut microbiota in AD pathogenesis remains obscure. Herein, we provide a potential mechanistic link between gut microbiota dysbiosis and neuroinflammation in AD progression. Using AD mouse models, we discovered that, during AD progression, the alteration of gut microbiota composition leads to the peripheral accumulation of phenylalanine and isoleucine, which stimulates the differentiation and proliferation of pro-inflammatory T helper 1 (Th1) cells. The brain-infiltrated peripheral Th1 immune cells are associated with the M1 microglia activation, contributing to AD-associated neuroinflammation. Importantly, the elevation of phenylalanine and isoleucine concentrations and the increase of Th1 cell frequency in the blood were also observed in two small independent cohorts of patients with mild cognitive impairment (MCI) due to AD. Furthermore, GV-971, a sodium oligomannate that has demonstrated solid and consistent cognition improvement in a phase 3 clinical trial in China, suppresses gut dysbiosis and the associated phenylalanine/isoleucine accumulation, harnesses neuroinflammation and reverses the cognition impairment. Together, our findings highlight the role of gut dysbiosis-promoted neuroinflammation in AD progression and suggest a novel strategy for AD therapy by remodelling the gut microbiota.
Topics: Alzheimer Disease; Amino Acids; Animals; Anti-Bacterial Agents; Bacteria; Clinical Trials, Phase III as Topic; Cognitive Dysfunction; Disease Models, Animal; Disease Progression; Gastrointestinal Microbiome; Humans; Isoleucine; Mannose; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Oligosaccharides; Phenylalanine; Th1 Cells
PubMed: 31488882
DOI: 10.1038/s41422-019-0216-x -
Journal of Translational Medicine Oct 2022Although anxiety disorders are one of the most prevalent mental disorders, their underlying biological mechanisms have not yet been fully elucidated. In recent years,...
BACKGROUND
Although anxiety disorders are one of the most prevalent mental disorders, their underlying biological mechanisms have not yet been fully elucidated. In recent years, genetically determined metabolites (GDMs) have been used to reveal the biological mechanisms of mental disorders. However, this strategy has not been applied to anxiety disorders. Herein, we explored the causality of GDMs on anxiety disorders through Mendelian randomization study, with the overarching goal of unraveling the biological mechanisms.
METHODS
A two-sample Mendelian randomization (MR) analysis was implemented to assess the causality of GDMs on anxiety disorders. A genome-wide association study (GWAS) of 486 metabolites was used as the exposure, whereas four different GWAS datasets of anxiety disorders were the outcomes. Notably, all datasets were acquired from publicly available databases. A genetic instrumental variable (IV) was used to explore the causality between the metabolite and anxiety disorders for each metabolite. The MR Steiger filtering method was implemented to examine the causality between metabolites and anxiety disorders. The standard inverse variance weighted (IVW) method was first used for the causality analysis, followed by three additional MR methods (the MR-Egger, weighted median, and MR-PRESSO (pleiotropy residual sum and outlier) methods) for sensitivity analyses in MR analysis. MR-Egger intercept, and Cochran's Q statistical analysis were used to evaluate possible heterogeneity and pleiotropy. Bonferroni correction was used to determine the causative association features (P < 1.03 × 10). Furthermore, metabolic pathways analysis was performed using the web-based MetaboAnalyst 5.0 software. All statistical analysis were performed in R software. The STROBE-MR checklist for the reporting of MR studies was used in this study.
RESULTS
In MR analysis, 85 significant causative relationship GDMs were identified. Among them, 11 metabolites were overlapped in the four different datasets of anxiety disorders. Bonferroni correction showing1-linoleoylglycerophosphoethanolamine (OR = 1.04; 95% CI 1.021-1.06; P = 4.3 × 10) was the most reliable causal metabolite. Our results were robust even without a single SNP because of a "leave-one-out" analysis. The MR-Egger intercept test indicated that genetic pleiotropy had no effect on the results (intercept = - 0.0013, SE = 0.0006, P = 0.06). No heterogeneity was detected by Cochran's Q test (MR-Egger. Q = 7.68, P = 0.742; IVW. Q = 12.12, P = 0.436). A directionality test conducted by MR Steiger confirmed our estimation of potential causal direction (P < 0.001). In addition, two significant pathways, the "primary bile acid biosynthesis" pathway (P = 0.008) and the "valine, leucine, and isoleucine biosynthesis" pathway (P = 0.03), were identified through metabolic pathway analysis.
CONCLUSION
This study provides new insights into the causal effects of GDMs on anxiety disorders by integrating genomics and metabolomics. The metabolites that drive anxiety disorders may be suited to serve as biomarkers and also will help to unravel the biological mechanisms of anxiety disorders.
Topics: Humans; Mendelian Randomization Analysis; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Leucine; Isoleucine; Anxiety Disorders; Valine; Bile Acids and Salts
PubMed: 36266699
DOI: 10.1186/s12967-022-03691-2 -
Cell Metabolism May 2021Low-protein diets promote metabolic health in rodents and humans, and the benefits of low-protein diets are recapitulated by specifically reducing dietary levels of the...
Low-protein diets promote metabolic health in rodents and humans, and the benefits of low-protein diets are recapitulated by specifically reducing dietary levels of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Here, we demonstrate that each BCAA has distinct metabolic effects. A low isoleucine diet reprograms liver and adipose metabolism, increasing hepatic insulin sensitivity and ketogenesis and increasing energy expenditure, activating the FGF21-UCP1 axis. Reducing valine induces similar but more modest metabolic effects, whereas these effects are absent with low leucine. Reducing isoleucine or valine rapidly restores metabolic health to diet-induced obese mice. Finally, we demonstrate that variation in dietary isoleucine levels helps explain body mass index differences in humans. Our results reveal isoleucine as a key regulator of metabolic health and the adverse metabolic response to dietary BCAAs and suggest reducing dietary isoleucine as a new approach to treating and preventing obesity and diabetes.
Topics: Adipose Tissue, White; Amino Acids, Branched-Chain; Animals; Body Mass Index; Diet; Energy Metabolism; Fibroblast Growth Factors; Humans; Isoleucine; Liver; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Protein Serine-Threonine Kinases; Uncoupling Protein 1; Valine
PubMed: 33887198
DOI: 10.1016/j.cmet.2021.03.025 -
Cancer Cell Feb 2020Metabolic pathways must be adapted to support cell processes required for transformation and cancer progression. Amino acid metabolism is deregulated in many cancers,... (Review)
Review
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.
Topics: Amino Acids, Branched-Chain; Epigenomics; Humans; Intracellular Signaling Peptides and Proteins; Isoleucine; Leucine; Neoplasms
PubMed: 32049045
DOI: 10.1016/j.ccell.2019.12.011 -
Molecular Cell Jan 2022Quantitative subcellular metabolomic measurements can explain the roles of metabolites in cellular processes but are subject to multiple confounding factors. We... (Comparative Study)
Comparative Study
Quantitative subcellular metabolomic measurements can explain the roles of metabolites in cellular processes but are subject to multiple confounding factors. We developed stable isotope labeling of essential nutrients in cell culture-subcellular fractionation (SILEC-SF), which uses isotope-labeled internal standard controls that are present throughout fractionation and processing to quantify acyl-coenzyme A (acyl-CoA) thioesters in subcellular compartments by liquid chromatography-mass spectrometry. We tested SILEC-SF in a range of sample types and examined the compartmentalized responses to oxygen tension, cellular differentiation, and nutrient availability. Application of SILEC-SF to the challenging analysis of the nuclear compartment revealed a nuclear acyl-CoA profile distinct from that of the cytosol, with notable nuclear enrichment of propionyl-CoA. Using isotope tracing, we identified the branched chain amino acid isoleucine as a major metabolic source of nuclear propionyl-CoA and histone propionylation, thus revealing a new mechanism of crosstalk between metabolism and the epigenome.
Topics: Acyl Coenzyme A; Animals; Cell Compartmentation; Cell Differentiation; Cell Nucleus; Chromatography, Liquid; Cytosol; Energy Metabolism; Epigenesis, Genetic; Hep G2 Cells; Histones; Humans; Isoleucine; Metabolome; Metabolomics; Mice; Mitochondria; Oxygen; Protein Processing, Post-Translational; Spectrometry, Mass, Electrospray Ionization
PubMed: 34856123
DOI: 10.1016/j.molcel.2021.11.006 -
Gastroenterology Feb 2022Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with altered gut microbiota...
BACKGROUND AND AIMS
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with altered gut microbiota composition. Phylogenetic groups of gut bacteria involved in the metabolism of short chain fatty acids (SCFAs) were depleted in SARS-CoV-2-infected patients. We aimed to characterize a functional profile of the gut microbiome in patients with COVID-19 before and after disease resolution.
METHODS
We performed shotgun metagenomic sequencing on fecal samples from 66 antibiotics-naïve patients with COVID-19 and 70 non-COVID-19 controls. Serial fecal samples were collected (at up to 6 times points) during hospitalization and beyond 1 month after discharge. We assessed gut microbial pathways in association with disease severity and blood inflammatory markers. We also determined changes of microbial functions in fecal samples before and after disease resolution and validated these functions using targeted analysis of fecal metabolites.
RESULTS
Compared with non-COVID-19 controls, patients with COVID-19 with severe/critical illness showed significant alterations in gut microbiome functionality (P < .001), characterized by impaired capacity of gut microbiome for SCFA and L-isoleucine biosynthesis and enhanced capacity for urea production. Impaired SCFA and L-isoleucine biosynthesis in gut microbiome persisted beyond 30 days after recovery in patients with COVID-19. Targeted analysis of fecal metabolites showed significantly lower fecal concentrations of SCFAs and L-isoleucine in patients with COVID-19 before and after disease resolution. Lack of SCFA and L-isoleucine biosynthesis significantly correlated with disease severity and increased plasma concentrations of CXCL-10, NT- proB-type natriuretic peptide, and C-reactive protein (all P < .05).
CONCLUSIONS
Gut microbiome of patients with COVID-19 displayed impaired capacity for SCFA and L-isoleucine biosynthesis that persisted even after disease resolution. These 2 microbial functions correlated with host immune response underscoring the importance of gut microbial functions in SARS-CoV-2 infection pathogenesis and outcome.
Topics: Adult; Biomarkers; COVID-19; Case-Control Studies; Fatty Acids, Volatile; Feces; Female; Gastrointestinal Microbiome; Humans; Immunity; Isoleucine; Male; Metagenomics; Middle Aged; Phylogeny; SARS-CoV-2; Severity of Illness Index
PubMed: 34687739
DOI: 10.1053/j.gastro.2021.10.013 -
Hepatology (Baltimore, Md.) Jan 2018Plasma concentrations of amino acids (AAs), in particular, branched chain AAs (BCAAs), are often found increased in nonalcoholic fatty liver disease (NAFLD); however, if... (Comparative Study)
Comparative Study
UNLABELLED
Plasma concentrations of amino acids (AAs), in particular, branched chain AAs (BCAAs), are often found increased in nonalcoholic fatty liver disease (NAFLD); however, if this is due to increased muscular protein catabolism, obesity, and/or increased insulin resistance (IR) or impaired tissue metabolism is unknown. Thus, we evaluated a) if subjects with NAFLD without obesity (NAFLD-NO) compared to those with obesity (NAFLD-Ob) display altered plasma AAs compared to controls (CTs); and b) if AA concentrations are associated with IR and liver histology. Glutamic acid, serine, and glycine concentrations are known to be altered in NAFLD. Because these AAs are involved in glutathione synthesis, we hypothesized they might be related to the severity of NAFLD. We therefore measured the AA profile of 44 subjects with NAFLD without diabetes and who had a liver biopsy (29 NAFLD-NO and 15 NAFLD-Ob) and 20 CTs without obesity, by gas chromatography-mass spectrometry, homeostasis model assessment of insulin resistance, hepatic IR (Hep-IR; Hep-IR = endogenous glucose production × insulin), and the new glutamate-serine-glycine (GSG) index (glutamate/[serine + glycine]) and tested for an association with liver histology. Most AAs were increased only in NAFLD-Ob subjects. Only alanine, glutamate, isoleucine, and valine, but not leucine, were increased in NAFLD-NO subjects compared to CTs. Glutamate, tyrosine, and the GSG-index were correlated with Hep-IR. The GSG-index correlated with liver enzymes, in particular, gamma-glutamyltransferase (R = 0.70), independent of body mass index. Ballooning and/or inflammation at liver biopsy were associated with increased plasma BCAAs and aromatic AAs and were mildly associated with the GSG-index, while only the new GSG-index was able to discriminate fibrosis F3-4 from F0-2 in this cohort.
CONCLUSION
Increased plasma AA concentrations were observed mainly in subjects with obesity and NAFLD, likely as a consequence of increased IR and protein catabolism. The GSG-index is a possible marker of severity of liver disease independent of body mass index. (Hepatology 2018;67:145-158).
Topics: Adult; Age Factors; Amino Acids; Biomarkers; Case-Control Studies; Disease Progression; Female; Glutamic Acid; Humans; Insulin Resistance; Isoleucine; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Obesity; Prognosis; Reference Values; Retrospective Studies; Risk Assessment; Severity of Illness Index; Sex Factors; Tyrosine
PubMed: 28802074
DOI: 10.1002/hep.29465 -
Clinical Nutrition (Edinburgh, Scotland) Dec 2023Studies have suggested a possible relevance between branched-chain amino acid (BCAA) catabolic enzymes and cancers. However, few studies have explored the variation in...
BACKGROUND
Studies have suggested a possible relevance between branched-chain amino acid (BCAA) catabolic enzymes and cancers. However, few studies have explored the variation in circulating concentrations of BCAAs. Our study used bi-directional, two-sample Mendelian randomization (MR) analysis for predicting the causality between the BCAA levels and 9 types of cancers.
METHODS
The largest genome-wide association studies (GWAS) provided data for total BCAAs, valine, leucine, and isoleucine from the UK Biobank. Data on multiple cancer endpoints were collected from various sources, such as the International Lung Cancer Consortium (ILCCO), the Pancreatic Cancer Cohort Consortium 1 (PanScan1), the Breast Cancer Association Consortium (BCAC), the FinnGen Biobank, and the Ovarian Cancer National Alliance (OCAC). The mainly analysis method was the inverse-variance-weighted (IVW). For assessing horizontal pleiotropy, the researchers performed MR-Egger regression and MR-PRESSO global test. Finally, the Cochran's Q test served for evaluating the heterogeneity.
RESULTS
Circulating total BCAAs levels (OR 1.708, 95%CI 1.168, 2.498; p = 0.006), valine levels (OR 1.747, 95%CI 1.217, 2.402; p < 0.001), leucine levels (OR 1.923, 95%CI 1.279, 2.890; p = 0.002) as well as isoleucine levels (OR 1.898, 95%CI 1.164, 3.094; p = 0.010) positively correlated with the squamous cell lung cancer risk. Nevertheless, no compelling evidence was found to support a causal link between BCAAs and any other examined cancers.
CONCLUSIONS
Increased circulating total-BCAAs levels, leucine levels, isoleucine levels and valine levels had higher hazard of squamous cell lung cancer. No such associations were found for BCAAs with other cancers.
Topics: Humans; Female; Isoleucine; Mendelian Randomization Analysis; Leucine; Genome-Wide Association Study; Amino Acids, Branched-Chain; Valine; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Lung Neoplasms
PubMed: 37922693
DOI: 10.1016/j.clnu.2023.10.019 -
Aging Cell Jun 2022The proportion of humans suffering from age-related diseases is increasing around the world, and creative solutions are needed to promote healthy longevity. Recent work... (Review)
Review
The proportion of humans suffering from age-related diseases is increasing around the world, and creative solutions are needed to promote healthy longevity. Recent work has clearly shown that a calorie is not just a calorie-and that low protein diets are associated with reduced mortality in humans and promote metabolic health and extended lifespan in rodents. Many of the benefits of protein restriction on metabolism and aging are the result of decreased consumption of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Here, we discuss the emerging evidence that BCAAs are critical modulators of healthy metabolism and longevity in rodents and humans, as well as the physiological and molecular mechanisms that may drive the benefits of BCAA restriction. Our results illustrate that protein quality-the specific composition of dietary protein-may be a previously unappreciated driver of metabolic dysfunction and that reducing dietary BCAAs may be a promising new approach to delay and prevent diseases of aging.
Topics: Amino Acids, Branched-Chain; Diet, Protein-Restricted; Isoleucine; Leucine
PubMed: 35526271
DOI: 10.1111/acel.13626