bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2025–02–09
seven papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine
  1. Lactate homeostasis is maintained through regulation of glycolysis and lipolysis.
  2. GDH1-dependent α-ketoglutarate promotes HBV transcription by modulating histone methylations on the cccDNA minichromosome.
  3. Inhibition of ATP-citrate lyase by bempedoic acid protects against abdominal aortic aneurysm formation in mice.
  4. Nutrient metabolism shapes epigenetic landscape of T cells.
  5. LDHA- Mediated Histone Lactylation Promotes the Nonalcoholic Fatty Liver Disease Progression Through Targeting The METTL3/ YTHDF1/SCD1 m6A Axis.
  6. Metabolic deficiencies underlie reduced plasmacytoid dendritic cell IFN-I production following viral infection.
  7. NLRP3-mediated glutaminolysis controls microglial phagocytosis to promote Alzheimer's disease progression.
  1. Cell Metab. 2025 Jan 29. pii: S1550-4131(24)00491-1. [Epub ahead of print]
    Lactate homeostasis is maintained through regulation of glycolysis and lipolysis.
    Won Dong Lee, Daniel R Weilandt, Lingfan Liang, Michael R MacArthur, Natasha Jaiswal, Olivia Ong, Charlotte G Mann, Qingwei Chu, Craig J Hunter, Rolf-Peter Ryseck, Wenyun Lu, Anna M Oschmann, Alexis J Cowan, Tara A TeSlaa, Caroline R Bartman, Cholsoon Jang, Joseph A Baur, Paul M Titchenell, Joshua D Rabinowitz.
      Lactate is among the highest flux circulating metabolites. It is made by glycolysis and cleared by both tricarboxylic acid (TCA) cycle oxidation and gluconeogenesis. Severe lactate elevations are life-threatening, and modest elevations predict future diabetes. How lactate homeostasis is maintained, however, remains poorly understood. Here, we identify, in mice, homeostatic circuits regulating lactate production and consumption. Insulin induces lactate production by upregulating glycolysis. We find that hyperlactatemia inhibits insulin-induced glycolysis, thereby suppressing excess lactate production. Unexpectedly, insulin also promotes lactate TCA cycle oxidation. The mechanism involves lowering circulating fatty acids, which compete with lactate for mitochondrial oxidation. Similarly, lactate can promote its own consumption by lowering circulating fatty acids via the adipocyte-expressed G-protein-coupled receptor hydroxycarboxylic acid receptor 1 (HCAR1). Quantitative modeling suggests that these mechanisms suffice to produce lactate homeostasis, with robustness to noise and perturbation of individual regulatory mechanisms. Thus, through regulation of glycolysis and lipolysis, lactate homeostasis is maintained.
    Keywords:  HCAR1 signaling; TCA cycle; competitive catabolism; diabetes mellitus; insulin resistance; insulin signaling; lactate metabolism; metabolic flux; metabolic homeostasis; quantitative modeling
    DOI:  https://doi.org/10.1016/j.cmet.2024.12.009
  2. Clin Mol Hepatol. 2025 Feb 05.
    GDH1-dependent α-ketoglutarate promotes HBV transcription by modulating histone methylations on the cccDNA minichromosome.
    Sheng-Tao Cheng, Wei-Xian Chen, Hai-Jun Deng, Xin He, Hui Zhang, Ming Tan, Hai-Bo Yu, Zhen-Zhen Zhang, Ji-Hua Ren, Min-Li Yang, Da-Peng Zhang, Zhi-Hong Li, Juan Chen.
       Background: Hepatitis B virus (HBV) hijacks host cell metabolism, especially host glutamine metabolism, to support its replication. Glutamate dehydrogenase 1 (GDH1), a mitochondrial enzyme crucial for glutamine metabolism, can interact with histone demethylases to regulate gene expression through histone methylation. However, the mechanisms underlying GDH1-mediated glutamine metabolism reprogramming and the roles of key metabolites during HBV infection remain unclear.
    Methods: Transcriptomic and metabolomic analyses of HBV-infected cell were performed. Both HBV-infected cells and humanized liver chimeric mice were used to elucidate the effect of glutamine metabolism on HBV.
    Results: HBV infection leads to the abnormal activation of glutamine metabolism, including upregulation of key enzymes and metabolites involved in glutamine metabolism. The viral core protein (HBc) mediates the translocation of GDH1 into the nucleus, where GDH1 activates covalently closed circular DNA (cccDNA) transcription by converting glutamate to α-ketoglutarate (αKG). Mechanistically, the promoting effect of GDH1-derived αKG on cccDNA transcription is independent of its conventional role. Rather, αKG directly interacts with the lysine-specific demethylase KDM4A and enhances KDM4A demethylase activity to regulate αKG-dependent histone demethylation, controlling cccDNA transcription.
    Conclusions: Our findings highlight the importance of glutamine metabolism in HBV transcription and suggest that glutamine deprivation is a potential strategy for silencing cccDNA transcription.
    Keywords:   GDH1; Methylation; cccDNA; αKG; Glutamine
    DOI:  https://doi.org/10.3350/cmh.2024.0694
  3. Biomed Pharmacother. 2025 Jan 30. pii: S0753-3322(25)00070-8. [Epub ahead of print]184 117876
    Inhibition of ATP-citrate lyase by bempedoic acid protects against abdominal aortic aneurysm formation in mice.
    Lídia Puertas-Umbert, Judith Alonso, Laia Blanco-Casoliva, Rafael Almendra-Pegueros, Mercedes Camacho, Antonio Rodríguez-Sinovas, María Galán, Nuria Roglans, Juan Carlos Laguna, José Martínez-González, Cristina Rodríguez.
      Abdominal aortic aneurysm (AAA) is a prevalent degenerative disease characterized by an exacerbated inflammation and destructive vascular remodeling. Unfortunately, effective pharmacological tools for the treatment of this disease remain a challenge. ATP-citrate lyase (ACLY), the primary enzyme responsible for acetyl-CoA biosynthesis, is a key regulator of inflammatory signaling in macrophages and lymphocytes. Here, we found increased levels of the active (phosphorylated) form of ACLY (p-ACLY) in the inflammatory infiltrate of AAA from patients and in aneurysmal lesions from angiotensin II (Ang II)-infused apolipoprotein E-deficient mice (ApoE-/-). Furthermore, plasma ACLY levels positively correlates with IL6 and IFNγ levels in patients with AAA, while inflammatory stimuli strongly upregulated ACLY expression in macrophages and Jurkat cells. The administration of the ACLY inhibitor bempedoic acid (BemA) protected against Ang II-induced AAA formation in ApoE-/- mice, limiting the progression of aortic dilatation and reducing mortality due to aortic rupture. BMS-303141, another ACLY inhibitor, also ameliorated AAA formation, although to a lesser extent. BemA attenuated vascular remodeling and the disorganization and rupture of elastic fibers induced by Ang II, as well as vascular inflammation, decreasing the recruitment of macrophages (CD68 +) and neutrophils (Ly-6G+) into the aortic wall. Moreover, BemA shifted splenic monocytes toward a functionally anti-inflammatory phenotype, and increased the percentage of CD4+CD69+ cells. Taken together, these results support the contribution of ACLY to AAA and point to BemA as a promising tool to be considered for future clinical trials addressing the management of this disease which is quite often associated with disorders of lipoprotein metabolism.
    Keywords:  ATP-citrate lyase; Abdominal aortic aneurysm; Bempedoic acid; Vascular inflammation
    DOI:  https://doi.org/10.1016/j.biopha.2025.117876
  4. Nat Immunol. 2025 Jan 31.
    Nutrient metabolism shapes epigenetic landscape of T cells.
    Annika Poch, Daniel T Utzschneider.
      
    DOI:  https://doi.org/10.1038/s41590-025-02080-3
  5. Physiol Res. 2024 Dec 31. 73(6): 985-999
    LDHA- Mediated Histone Lactylation Promotes the Nonalcoholic Fatty Liver Disease Progression Through Targeting The METTL3/ YTHDF1/SCD1 m6A Axis.
    J Meng, C Yan, J Liu.
      Nonalcoholic fatty liver disease (NAFLD) is characterized by elevated hepatic lipids caused by nonalcoholic factors, where histone lactylation is lately discovered as a modification driving disease progression. This research aimed to explore the role of histone 3 lysine 18 lactylation (H3K18lac) in NAFLD progression using a high-fat diet (HFD)-treated mouse model and free fatty acids (FFA)-treated L-02 cell lines. Lipids accumulation was screened via Oil Red O staining, real-time quantitative polymerase chain reaction (RT-qPCR), western blotting, and commercially available kits. Similarly, molecular mechanism was analyzed using immunoprecipitation (IP), dual-luciferase reporter assay, and RNA decay assay. Results indicated that FFA upregulated lactate dehydrogenase A (LDHA) and H3K18lac levels in L-02 cells. Besides, LDHA-mediated H3K18lac was enriched on the proximal promoter of methyltransferase 3 (METTL3), translating into an increased expression. Moreover, METTL3 or LDHA knockdown relieved lipid accumulation, decreased total cholesterol (TC) and triglyceride (TG) levels, and downregulated lipogenesis-related proteins in FFA-treated L-02 cell lines, in addition to enhancing the m6A and mRNA levels of stearoyl-coenzyme A desaturase 1 (SCD1). The m6A modification of SCD1 was recognized by YTH N6-methyladenosine RNA binding protein F1 (YTHDF1), resulting in enhanced mRNA stability. LDHA was found to be highly expressed in HFD-treated mice, where knocking down LDHA attenuated HFD-induced hepatic steatosis. These findings demonstrated that LDHA-induced H3K18lac promoted NAFLD progression, where LDHA-induced H3K18lac in METTL3 promoter elevated METTL3 expression, thereby promoting m6A methylation and stabilizing SCD1 via a YTHDF1-dependent manner. Keywords: Nonalcoholic fatty liver disease, LDHA, METTL3, YTHDF1, Histone lactylation.
  6. Nat Commun. 2025 Feb 07. 16(1): 1460
    Metabolic deficiencies underlie reduced plasmacytoid dendritic cell IFN-I production following viral infection.
    Trever T Greene, Yeara Jo, Carolina Chiale, Monica Macal, Ziyan Fang, Fawziyah S Khatri, Alicia L Codrington, Katelynn R Kazane, Elizabeth Akbulut, Shobha Swaminathan, Yu Fujita, Patricia Fitzgerald-Bocarsly, Thekla Cordes, Christian Metallo, David A Scott, Elina I Zúñiga.
      Type I Interferons (IFN-I) are central to host protection against viral infections, with plasmacytoid dendritic cells (pDC) being the most significant source, yet pDCs lose their IFN-I production capacity following an initial burst of IFN-I, resulting in susceptibility to secondary infections. The underlying mechanisms of these dynamics are not well understood. Here we find that viral infection reduces the capacity of pDCs to engage both oxidative and glycolytic metabolism. Mechanistically, we identify lactate dehydrogenase B (LDHB) as a positive regulator of pDC IFN-I production in mice and humans; meanwhile, LDHB deficiency is associated with suppressed IFN-I production, pDC metabolic capacity, and viral control following infection. In addition, preservation of LDHB expression is sufficient to partially retain the function of otherwise exhausted pDCs, both in vitro and in vivo. Furthermore, restoring LDHB in vivo in pDCs from infected mice increases IFNAR-dependent, infection-associated pathology. Our work thus identifies a mechanism for balancing immunity and pathology during viral infections, while also providing insight into the highly preserved infection-driven pDC inhibition.
    DOI:  https://doi.org/10.1038/s41467-025-56603-5
  7. Immunity. 2025 Jan 31. pii: S1074-7613(25)00032-9. [Epub ahead of print]
    NLRP3-mediated glutaminolysis controls microglial phagocytosis to promote Alzheimer's disease progression.
    Róisín M McManus, Max P Komes, Angelika Griep, Francesco Santarelli, Stephanie Schwartz, Juan Ramón Perea, Johannes C M Schlachetzki, David S Bouvier, Michelle-Amirah Khalil, Mario A Lauterbach, Lea Heinemann, Titus Schlüter, Mehran Shaban Pour, Marta Lovotti, Rainer Stahl, Fraser Duthie, Juan F Rodríguez-Alcázar, Susanne V Schmidt, Jasper Spitzer, Peri Noori, Alberto Maillo, Andreas Boettcher, Brian Herron, John McConville, David Gomez-Cabrero, Jesper Tegnér, Christopher K Glass, Karsten Hiller, Eicke Latz, Michael T Heneka.
      Activation of the NLRP3 inflammasome has been implicated in the pathogenesis of Alzheimer's disease (AD) via the release of IL-1β and ASC specks. However, whether NLRP3 is involved in pathways beyond this remained unknown. Here, we found that Aβ deposition in vivo directly triggered NLRP3 activation in APP/PS1 mice, which model many features of AD. Loss of NLRP3 increased glutamine- and glutamate-related metabolism and increased expression of microglial Slc1a3, which was associated with enhanced mitochondrial and metabolic activity. The generation of α-ketoglutarate during this process impacted cellular function, including increased clearance of Aβ peptides as well as epigenetic and gene transcription changes. This pathway was conserved between murine and human cells. Critically, we could mimic this effect pharmacologically using NLRP3-specific inhibitors, but only with chronic NLRP3 inhibition. Together, these data demonstrate an additional role for NLRP3, where it can modulate mitochondrial and metabolic function, with important downstream consequences for the progression of AD.
    Keywords:  Alzheimer’s disease; NLRP3; amyloid-β; dementia; glutamine metabolism; inflammasome; microglia; phagocytosis; α-ketoglutarate
    DOI:  https://doi.org/10.1016/j.immuni.2025.01.007
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