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Targeting branched-chain amino acids alleviates pulmonary fibrosis

ABSTRACT: Purpose: To determine whether BCAAs regulate H3K36me3 modification on collagen genes via KDM4A. Methods: We transfected two KDM4A siRNAs into MLF cells. After 24 h of transfection, the cells were treated with 20 ng/mL TGF-β1 for 48 h, followed by CUT&Tag assay for H3K36me3. Conclusions: BCAAs promote H3K36me3 modification on collagen genes via KDM4A.

ORGANISM(S): Mus musculus

PROVIDER: GSE325209 | GEO | 2026/03/18

REPOSITORIES: GEO

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BCAT1 activation reprograms branched-chain amino acids (BCAAs) metabolism and epigenetically promotes inflammation in diabetic retinopathy

Project description:Branched-chain amino acids (BCAAs) metabolism is dysregulated in diabetic retinopathy. Retina Müller cells maintain various metabolic processes and immune homeostasis. Here, we found that branched-chain aminotransferase 1 (BCAT1), which catalyzes the first step of BCAAs metabolism, was predominantly expressed in retina Müller cells. Under diabetic conditions, BCAT1 showed increased enzymatic activity in Müller cells, which drove the remodeling of BCAAs catabolism, and upregulated the expression of inflammatory genes such as interleukin 6 (IL6) and tumor necrosis factor-α (TNF-α). Mechanistically, BCAT1 activity was negatively regulated by Polo-like kinase 4 (PLK4) via phosphorylation at threonine 333. Increased BCAT1 activity further reduced α-ketoglutarate (α-KG) levels, a critical substrate for histone demethylation, resulting in higher H3K4me3 levels at inflammatory gene promoters, and further upregulated inflammation genes. Treatment with chemical BCAT inhibitor significantly reduced inflammatory gene expression and vascular leakage in diabetic retinas in vivo. These findings reveal a crucial role of BCAT1 in metabolic remodeling and inflammatory regulation, which indicates that BCAT1 could be used as a target for diabetic retinopathy.

2025-06-25 | GSE282215 | GEO

Branched chain amino acids impact health and lifespan indirectly via amino acid balance and appetite control

Project description:Elevated branched chain amino acids (BCAAs) are associated with obesity and insulin resistance. How long-term dietary BCAAs impact late-life health and lifespan is unknown. Here, we show that when dietary BCAAs are varied against a fixed, isocaloric macronutrient background, long-term exposure to high BCAA diets led to hyperphagia, obesity and reduced lifespan. These effects were not due to elevated BCAA per se or hepatic mTOR activation, but rather the shift in balance between dietary BCAAs and other AAs, notably tryptophan and threonine. Increasing the ratio of BCAAs to these AAs resulted in hyperphagia and was linked to central serotonin depletion. Preventing hyperphagia by calorie restriction or pair-feeding averted the health costs of a high BCAA diet. Our data highlight a role for amino acid quality in energy balance and show that health costs of chronic high BCAA intakes were not due to intrinsic toxicity; rather, to hyperphagia driven by AA imbalance.

2019-03-11 | GSE114855 | GEO

Genome-wide maps of H3K27me3 chromatin modification status regulated by branched chain amino acids (BCAA) metabolism in human acute leukemia

Project description:The branched-chain amino acid (BCAA) metabolism plays pleiotropic roles in homeostasis. Here we show that human acute leukemia-initiating cells (LICs), but not normal hematopoietic stem cells, are heavily addicted to the BCAA metabolism, irrespective of myeloid or lymphoid types. Human acute leukemia cells had a high level of BCAAs, transporting free BCAAs into the cytoplasm. Functional inhibition of BCAA transaminase-1 (BCAT1), a catalytic enzyme for BCAAs, induced apoptosis of human LICs, and suppressed reconstitution of human leukemia in xenograft models. Furthermore, deprivation of BCAAs from daily diet in mice transplanted with human LICs strongly inhibited their expansion and self-renewal in vivo. The BCAT1 inhibition inactivates the PRC2 function for epigenetic maintenance of stem cell signatures via downregulation of EZH2 and EED, critical PRC2 components, and inhibited the mTORC1 signaling for leukemia propagation. Thus, targeting the BCAA metabolism should be a powerful approach to erase cancer stemness in human acute leukemias.

2019-08-01 | GSE132512 | GEO

Targeting branched-chain amino acids alleviates pulmonary fibrosis [ATAC-seq]

2026-03-17 | GSE295423 | GEO

Accumulation of branched-chain amino acids reprograms glucose metabolism in CD8+ T cells with enhanced effector function and anti-tumor responses

Project description:Branched-chain amino acids (BCAAs) provide nutrient signals for cell survival and growth. How BCAAs affecting CD8+ T cell functions remains unexplored. Herein we reported that accumulation of BCAAs in CD8+ T cells due to the impairment of BCAA degradation in 2C-type serine/threonine protein phosphatase (PP2Cm) deficient mice leads to hyper-activity of CD8+ T cells and enhanced anti-tumor immunity. CD8+ T cells from PP2Cm-/- mice upregulate glucose transporter Glut1 expression in a FoxO1-dependent manner with more glucose uptake as well as increased glycolysis and oxidative phosphorylation. Moreover, BCAA supplementation recapitulates CD8+ T cell hyper-functions and synergizes with anti-PD-1, supported by a better prognosis in NSCLC patients harboring high BCAAs when receiving anti-PD-1 therapy. Our finding thus reveals that accumulation of BCAAs promotes effector function and anti-tumor immunity of CD8+ T cells through reprogramming glucose metabolism, making BCAAs alternative supplementary components to increase the clinical efficacy of anti-PD-1 immunotherapy against tumors.

2023-02-06 | GSE224250 | GEO

Targeting branched-chain amino acids alleviates pulmonary fibrosis [CUT&Tag, histone_modification]

2026-03-17 | GSE295425 | GEO

Targeting branched-chain amino acids alleviates pulmonary fibrosis [RNA-seq]

Project description:Purpose: Previous studies demonstrated that BCAA metabolic reprogramming induces idiopathic pulmonary fibrosis (IPF). This study investigates BCAA-mediated gene expression regulation in primary mouse lung fibroblasts (MLFs). Methods: In vitro: MLFs were cultured in three media conditions: complete medium (Complete), BCAA-free medium (Free), or BCAA-free medium supplemented with BCAAs (Free+BCAA) or BCKA (Free+BCKA) for 24 hours prior to TGF-β1 (20 ng/mL) stimulation for 48 hours. Triplicate RNA-seq analyses were conducted on treated MLFs. In vivo: Comparative RNA-seq profiling was performed on lung tissues from three experimental groups: PBS-treated controls, bleomycin (BLM)-exposed mice, and BLM-treated mice receiving BCAA supplementation (3 mmol/L in drinking water) or BCAA-free diets or BT2 treatment. Conclusions: BCAA metabolism is essential for myofibroblast activation and mechanistically promotes lung fibrogenesis in both in vitro and in vivo models.

2026-03-17 | GSE295426 | GEO

Distinct effects of restricting individual branched-chain amino acids on the development and progression of Alzheimer’s disease in 3xTg mice

Project description:Dietary protein is a critical regulator of metabolic health and aging in diverse species, and many of the benefits of low-protein diets are recapitulated by restriction of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. In mouse models of Alzheimer’s disease (AD), dietary supplementation with BCAAs worsens AD neuropathology, while restriction of any of the BCAAs improves cognitive deficits. We recently discovered that each BCAA has distinct metabolic effects, with the restriction of isoleucine alone being sufficient to improve metabolic health and extend lifespan and healthspan in genetically diverse mice. Here, we investigate the effect of restricting each individual BCAA on metabolic health and the development and progression of AD in the 3xTg mouse model. We find that restriction of isoleucine and valine, but not leucine, promotes metabolic health. Restricting any of the three BCAAs improved short-term memory in males, with isoleucine restriction having the strongest effect, while restricting valine has the greatest cognitive benefits in females. Restriction of each BCAA had distinct effects on AD pathology, mTOR signaling, autophagy, and survival. Transcriptomic analysis of the brain revealed both distinct and shared, and highly sex-specific, molecular impacts of restricting each BCAA, and we identify a set of significantly altered pathways strongly associated with reduced AD pathology and improved cognitive performance in males. Our findings suggest that restricting any of the BCAAs, particularly isoleucine or valine, may form the basis of a novel sex-specific approach to prevent or delay the progression of AD.

2025-07-30 | GSE299928 | GEO

Comparison of RNA-seq of Actinobacillus pleuropneumoniae (WT and (p)ppGpp0) under the absence of branched chain amino acids

Project description:(p)ppGpp is a key player in reprogramming transcriptomes to respond to nutritional challenges. Here, we present a transcriptional and phenotypic differences of A. pleuropneumoniae grown in different chemically defined media in the absence of (p)ppGpp. We show that the deprivation of branch-chain amino acids (BCAAs) does not elicit a change in the basal level (p)ppGpp, but this level is sufficient to regulate the expression of BCAA biosynthesis. The mechanism found in A. pleuropneumoniae is different to that of the model organism Escherichia coli, but similar to that found in some Gram-positive bacteria. This study not only broadens the research scope of (p)ppGpp, but also further validates the complexity and multiplicity of (p)ppGpp regulation in microorganisms that occupy different biological niches.

2019-11-28 | E-MTAB-8514 | biostudies-arrayexpress

Branched-Chain Amino Acids Contribute to Diabetic Kidney Disease Progression via PKM2-Mediated Podocyte Metabolic Reprogramming and Apoptosis

Project description:Approximately 30-40% of people living with diabetes develop diabetic kidney disease (DKD). It is of great importance to identify the “decisive factors” for DKD initiation. Recently, high levels of plasma and urinary branched-chain animo acid (BCAA) metabolites were shown to predict the future risk of DKD. Here, we observed that glomerular podocytes in male and female patients with DKD and db/db mice specifically displayed BCAA catabolic defects. Podocyte-specific knockout of PP2Cm, a key enzyme involved in BCAA catabolism, or exogenous supplementation of BCAAs induced DKD phenotypes in high-fat (HF) diet-fed male mice as manifested by podocyte dysfunction and apoptosis, glomerular pathological changes, and proteinuria. Mechanistically, BCAAs promoted PKM2 depolymerization and inactivation in podocytes. Depolymerized PKM2 suppressed glucose oxidative phosphorylation (OXPHOS) and promoted a shift in glucose metabolism to serine and folate biosynthesis. Depolymerized PKM2 is also cotransported to the nucleus with DDIT3, acting as a novel cotranscriptional factor to increase DDIT3 transcriptional activity, which promotes Chac1 and Trib3 expression and directly induces podocyte apoptosis. We concluded that BCAA catabolic defects may be one of the missing factors that determine DKD initiation. Targeting BCAA catabolism or PKM2 activation is a promising strategy for preventing DKD progression.

2025-06-13 | GSE283568 | GEO

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