bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2024–11–03
nine papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine
  1. Bempedoic acid suppresses diet-induced hepatic steatosis independently of ATP-citrate lyase.
  2. A hierarchical hepatic de novo lipogenesis substrate supply network utilizing pyruvate, acetate, and ketones.
  3. Stimulation of neutral lipid synthesis via viral growth factor signaling and ATP citrate lyase during vaccinia virus infection.
  4. The mitochondrial citrate carrier SLC25A1 regulates metabolic reprogramming and morphogenesis in the developing heart.
  5. Glucose-dependent glycosphingolipid biosynthesis fuels CD8+ T cell function and tumor control.
  6. Methylmalonic acid induces metabolic abnormalities and exhaustion in CD8+ T cells to suppress anti-tumor immunity.
  7. The post-translational modification O-GlcNAc is a sensor and regulator of metabolism.
  8. Rewiring Lysine Catabolism in Cancer Leads to Increased Histone Crotonylation and Immune Escape.
  9. Metabolic regulation of the glioblastoma stem cell epitranscriptome by malate dehydrogenase 2.
  1. Cell Metab. 2024 Oct 26. pii: S1550-4131(24)00410-8. [Epub ahead of print]
    Bempedoic acid suppresses diet-induced hepatic steatosis independently of ATP-citrate lyase.
    Joyce Y Liu, Ramya S Kuna, Laura V Pinheiro, Phuong T T Nguyen, Jaclyn E Welles, Jack M Drummond, Nivitha Murali, Prateek Sharma, Julianna G Supplee, Mia Shiue, Steven Zhao, Aimee T Farria, Avi Kumar, Mauren L Ruchhoeft, Christina Demetriadou, Daniel S Kantner, Adam Chatoff, Emily Megill, Paul M Titchenell, Nathaniel W Snyder, Christian M Metallo, Kathryn E Wellen.
      ATP citrate lyase (ACLY) synthesizes acetyl-CoA for de novo lipogenesis (DNL), which is elevated in metabolic dysfunction-associated steatotic liver disease. Hepatic ACLY is inhibited by the LDL-cholesterol-lowering drug bempedoic acid (BPA), which also improves steatosis in mice. While BPA potently suppresses hepatic DNL and increases fat catabolism, it is unclear if ACLY is its primary molecular target in reducing liver triglyceride. We show that on a Western diet, loss of hepatic ACLY alone or together with the acetyl-CoA synthetase ACSS2 unexpectedly exacerbates steatosis, linked to reduced PPARα target gene expression and fatty acid oxidation. Importantly, BPA treatment ameliorates Western diet-mediated triacylglyceride accumulation in both WT and liver ACLY knockout mice, indicating that its primary effects on hepatic steatosis are ACLY independent. Together, these data indicate that hepatic ACLY plays an unexpected role in restraining diet-dependent lipid accumulation and that BPA exerts substantial effects on hepatic lipid metabolism independently of ACLY.
    Keywords:  ACLY; ACSS2; PPARα; bempedoic acid; lipid metabolism; metabolic dysfunction-associated steatotic liver disease
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.014
  2. Cell Metab. 2024 Oct 25. pii: S1550-4131(24)00409-1. [Epub ahead of print]
    A hierarchical hepatic de novo lipogenesis substrate supply network utilizing pyruvate, acetate, and ketones.
    Adam J Rauckhorst, Ryan D Sheldon, Daniel J Pape, Adnan Ahmed, Kelly C Falls-Hubert, Ronald A Merrill, Reid F Brown, Kshitij Deshmukh, Thomas A Vallim, Stanislaw Deja, Shawn C Burgess, Eric B Taylor.
      Hepatic de novo lipogenesis (DNL) is a fundamental physiologic process that is often pathogenically elevated in metabolic disease. Treatment is limited by incomplete understanding of the metabolic pathways supplying cytosolic acetyl-CoA, the obligate precursor to DNL, including their interactions and proportional contributions. Here, we combined extensive 13C tracing with liver-specific knockout of key mitochondrial and cytosolic proteins mediating cytosolic acetyl-CoA production. We show that the mitochondrial pyruvate carrier (MPC) and ATP-citrate lyase (ACLY) gate the major hepatic lipogenic acetyl-CoA production pathway, operating in parallel with acetyl-CoA synthetase 2 (ACSS2). Given persistent DNL after mitochondrial citrate carrier (CiC) and ACSS2 double knockout, we tested the contribution of exogenous and leucine-derived acetoacetate to acetoacetyl-CoA synthetase (AACS)-dependent DNL. CiC knockout increased acetoacetate-supplied hepatic acetyl-CoA production and DNL, indicating that ketones function as mitochondrial-citrate reciprocal DNL precursors. By delineating a mitochondrial-cytosolic DNL substrate supply network, these findings may inform strategies to therapeutically modulate DNL.
    Keywords:  AACS; ACLY; ACSS2; ATP-citrate lyase; CiC; DNL; MPC; acetoacetyl-CoA synthetase; acetyl-CoA synthetase 2; de novo lipogenesis; liver; metabolomics; mitochondrial citrate carrier; mitochondrial pyruvate carrier; stable isotope tracers
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.013
  3. J Virol. 2024 Oct 30. e0110324
    Stimulation of neutral lipid synthesis via viral growth factor signaling and ATP citrate lyase during vaccinia virus infection.
    Anil Pant, Djamal Brahim Belhaouari, Lara Dsouza, Zhilong Yang.
      Fatty acid metabolism can provide various products essential for viral infections. How vaccinia virus (VACV), the prototype of poxviruses, modulates fatty acid metabolism is not well understood. Here, we show that VACV infection results in increased neutral lipid droplet synthesis, the organelles that play a crucial role in storing and mobilizing fatty acids for energy production via β-oxidation. Citrate is the first tricarboxylic acid (TCA) cycle intermediate that can be transported to the cytosol to be converted to acetyl-CoA for de novo fatty acid biosynthesis. We found that VACV infection stimulates the S455 phosphorylation of ATP citrate lyase (ACLY), a pivotal enzyme that links citrate metabolism with lipid metabolism. We demonstrate that the inhibition of neutral lipid droplet synthesis and ACLY severely suppresses VACV replication. Remarkably, we found that virus growth factor (VGF)-induced signaling is essential for the VACV-mediated upregulation of ACLY phosphorylation and neutral lipid droplets. Finally, we report that VGF-induced EGFR-Akt pathway and ACLY phosphorylation are important for VACV stimulation of neutral lipid synthesis. These findings identified a new way of rewiring cell metabolism by a virus and a novel function for VGF in the governance of virus-host interactions through the induction of a key enzyme at the crossroads of the TCA cycle and fatty acid metabolism. Our study also provides a mechanism for the role played by VGF and its downstream signaling cascades in the modulation of lipid metabolism in VACV-infected cells.IMPORTANCENeutral lipid droplets are vital players in cellular metabolism. Here, we showed that VACV induces neutral lipid droplet synthesis in infected primary human foreskin fibroblasts and identified the cellular and viral factors needed. We identified VACV encoded growth factor (VGF) as an essential viral factor that induces cellular EGFR-Akt signaling to increase lipid droplets. Interestingly, VACV increases the S455 phosphorylation of ACLY, a key metabolic enzyme that sits at the crossroads of carbohydrate and lipid metabolism in a VGF-EGFR-Akt-dependent manner. We also found that ACLY is vital for VACV-induced lipid droplet synthesis. Our findings identified the modulation of ACLY by a virus and identified it as a potential target for antiviral development against pathogenic poxviruses. Our study also expands the role of growth factor signaling in boosting VACV replication by targeting fatty acid metabolism.
    Keywords:  ATP citrate lyase; EGFR; fatty acids; lipid droplets; metabolism; poxvirus; vaccinia virus
    DOI:  https://doi.org/10.1128/jvi.01103-24
  4. Commun Biol. 2024 Oct 31. 7(1): 1422
    The mitochondrial citrate carrier SLC25A1 regulates metabolic reprogramming and morphogenesis in the developing heart.
    Chiemela Ohanele, Jessica N Peoples, Anja Karlstaedt, Joshua T Geiger, Ashley D Gayle, Nasab Ghazal, Fateemaa Sohani, Milton E Brown, Michael E Davis, George A Porter, Victor Faundez, Jennifer Q Kwong.
      The developing mammalian heart undergoes an important metabolic shift from glycolysis towards mitochondrial oxidation that is critical to support the increasing energetic demands of the maturing heart. Here, we describe a new mechanistic link between mitochondria and cardiac morphogenesis, uncovered by studying mitochondrial citrate carrier (SLC25A1) knockout mice. Slc25a1 null embryos displayed impaired growth, mitochondrial dysfunction and cardiac malformations that recapitulate the congenital heart defects observed in 22q11.2 deletion syndrome, a microdeletion disorder involving the SLC25A1 locus. Importantly, Slc25a1 heterozygous embryos, while overtly indistinguishable from wild type, exhibited an increased frequency of these defects, suggesting Slc25a1 haploinsuffiency and dose-dependent effects. Mechanistically, SLC25A1 may link mitochondria to transcriptional regulation of metabolism through epigenetic control of gene expression to promote metabolic remodeling in the developing heart. Collectively, this work positions SLC25A1 as a novel mitochondrial regulator of cardiac morphogenesis and metabolic maturation, and suggests a role in congenital heart disease.
    DOI:  https://doi.org/10.1038/s42003-024-07110-8
  5. bioRxiv. 2024 Oct 14. pii: 2024.10.10.617261. [Epub ahead of print]
    Glucose-dependent glycosphingolipid biosynthesis fuels CD8+ T cell function and tumor control.
    Joseph Longo, Lisa M DeCamp, Brandon M Oswald, Robert Teis, Alfredo Reyes-Oliveras, Michael S Dahabieh, Abigail E Ellis, Michael P Vincent, Hannah Damico, Kristin L Gallik, Shelby E Compton, Colt D Capan, Kelsey S Williams, Corinne R Esquibel, Zachary B Madaj, Hyoungjoo Lee, Dominic G Roy, Connie M Krawczyk, Brian B Haab, Ryan D Sheldon, Russell G Jones.
      Glucose is essential for T cell proliferation and function, yet its specific metabolic roles in vivo remain poorly defined. Here, we identify glycosphingolipid (GSL) biosynthesis as a key pathway fueled by glucose that enables CD8+ T cell expansion and cytotoxic function in vivo. Using 13C-based stable isotope tracing, we demonstrate that CD8+ effector T cells use glucose to synthesize uridine diphosphate-glucose (UDP-Glc), a precursor for glycogen, glycan, and GSL biosynthesis. Inhibiting GSL production by targeting the enzymes UGP2 or UGCG impairs CD8+ T cell expansion and cytolytic activity without affecting glucose-dependent energy production. Mechanistically, we show that glucose-dependent GSL biosynthesis is required for plasma membrane lipid raft integrity and aggregation following TCR stimulation. Moreover, UGCG-deficient CD8+ T cells display reduced granzyme expression and tumor control in vivo. Together, our data establish GSL biosynthesis as a critical metabolic fate of glucose-independent of energy production-required for CD8+ T cell responses in vivo.
    Keywords:  CD8+ T cells; UGCG; cytotoxic function; glucose; glycosphingolipids; immunometabolism; lipid rafts; lipidomics; metabolomics; nucleotide sugar metabolism
    DOI:  https://doi.org/10.1101/2024.10.10.617261
  6. Oncogene. 2024 Oct 29.
    Methylmalonic acid induces metabolic abnormalities and exhaustion in CD8+ T cells to suppress anti-tumor immunity.
    Joanne D Tejero, Rebecca S Hesterberg, Stanislav Drapela, Didem Ilter, Devesh Raizada, Felicia Lazure, Hossein Kashfi, Min Liu, Leonardo Silvane, Dorina Avram, Juan Fernández-García, John M Asara, Sarah-Maria Fendt, John L Cleveland, Ana P Gomes.
      Systemic levels of methylmalonic acid (MMA), a byproduct of propionate metabolism, increase with age and MMA promotes tumor progression via its direct effects in tumor cells. However, the role of MMA in modulating the tumor ecosystem remains to be investigated. The proliferation and function of CD8+ T cells, key anti-tumor immune cells, declines with age and in conditions of vitamin B12 deficiency, which are the two most well-established conditions that lead to increased systemic levels of MMA. Thus, we hypothesized that increased circulatory levels of MMA would lead to a suppression of CD8+ T cell immunity. Treatment of primary CD8+ T cells with MMA induced a dysfunctional phenotype characterized by robust immunosuppressive transcriptional reprogramming and marked increases in the expression of the exhaustion regulator, TOX. Accordingly, MMA treatment upregulated exhaustion markers in CD8+ T cells and decreased their effector functions, which drove the suppression of anti-tumor immunity in vitro and in vivo. Mechanistically, MMA-induced CD8+ T cell exhaustion was associated with a suppression of NADH-regenerating reactions in the TCA cycle and concomitant defects in mitochondrial function. Thus, MMA has immunomodulatory roles, thereby highlighting MMA as an important link between aging, immune dysfunction, and cancer.
    DOI:  https://doi.org/10.1038/s41388-024-03191-1
  7. Open Biol. 2024 Oct;14(10): 240209
    The post-translational modification O-GlcNAc is a sensor and regulator of metabolism.
    Murielle M Morales, Matthew R Pratt.
      Cells must rapidly adapt to changes in nutrient conditions through responsive signalling cascades to maintain homeostasis. One of these adaptive pathways results in the post-translational modification of proteins by O-GlcNAc. O-GlcNAc modifies thousands of nuclear and cytoplasmic proteins in response to nutrient availability through the hexosamine biosynthetic pathway. O-GlcNAc is highly dynamic and can be added and removed from proteins multiple times throughout their life cycle, setting it up to be an ideal regulator of cellular processes in response to metabolic changes. Here, we describe the link between cellular metabolism and O-GlcNAc, and we explore O-GlcNAc's role in regulating cellular processes in response to nutrient levels. Specifically, we discuss the mechanisms of elevated O-GlcNAc levels in contributing to diabetes and cancer, as well as the role of decreased O-GlcNAc levels in neurodegeneration. These studies form a foundational understanding of aberrant O-GlcNAc in human disease and provide an opportunity to further improve disease identification and treatment.
    Keywords:  O-GlcNAc; metabolism; modifications; post-translational; regulators; sensor
    DOI:  https://doi.org/10.1098/rsob.240209
  8. Chembiochem. 2024 Oct 27. e202400638
    Rewiring Lysine Catabolism in Cancer Leads to Increased Histone Crotonylation and Immune Escape.
    Kosta Besermenji, Rita Petracca.
      Crotonyl-CoA (cr-CoA) is a metabolite derived directly from the catabolism of lysine (Lys) and tryptophan (Trp) or from the β-oxidation of fatty acids. In glioblastoma stem cells (GSCs), histone H4 crotonylation levels are significantly elevated, which appears to positively correlate with tumor growth. This increase in crotonyl-CoA production is attributed to the overexpression of specific Lys transporters on the cell membrane, leading to higher free lysine levels. Additionally, the overexpression of glutaryl-CoA dehydrogenase (GCDH), the enzyme responsible for crotonyl-CoA production, further contributes to this increase. When GCDH is depleted or under a lysine-restricted diet, genes involved in type I interferon (IFN) signaling are upregulated, resulting in tumor growth suppression. Type I interferons are a group of cytokines critical for antiviral responses and immunoregulation. This highlights how cancer cells exploit crotonylation to modulate the immune response. This work opens up new avenues for investigating how cancer cells rewire their metabolism to increase crotonylation and evade the immune system.
    Keywords:  Crotonylation; cancer; immune escape; metabolic reprogramming
    DOI:  https://doi.org/10.1002/cbic.202400638
  9. Cell Metab. 2024 Oct 19. pii: S1550-4131(24)00396-6. [Epub ahead of print]
    Metabolic regulation of the glioblastoma stem cell epitranscriptome by malate dehydrogenase 2.
    Deguan Lv, Deobrat Dixit, Andrea F Cruz, Leo J Y Kim, Likun Duan, Xin Xu, Qiulian Wu, Cuiqing Zhong, Chenfei Lu, Zachary C Gersey, Ryan C Gimple, Qi Xie, Kailin Yang, Xiaojing Liu, Xiaoguang Fang, Xujia Wu, Reilly L Kidwell, Xiuxing Wang, Shideng Bao, Housheng H He, Jason W Locasale, Sameer Agnihotri, Jeremy N Rich.
      Tumors reprogram their metabolism to generate complex neoplastic ecosystems. Here, we demonstrate that glioblastoma (GBM) stem cells (GSCs) display elevated activity of the malate-aspartate shuttle (MAS) and expression of malate dehydrogenase 2 (MDH2). Genetic and pharmacologic targeting of MDH2 attenuated GSC proliferation, self-renewal, and in vivo tumor growth, partially rescued by aspartate. Targeting MDH2 induced accumulation of alpha-ketoglutarate (αKG), a critical co-factor for dioxygenases, including the N6-methyladenosine (m6A) RNA demethylase AlkB homolog 5, RNA demethylase (ALKBH5). Forced expression of MDH2 increased m6A levels and inhibited ALKBH5 activity, both rescued by αKG supplementation. Reciprocally, targeting MDH2 reduced global m6A levels with platelet-derived growth factor receptor-β (PDGFRβ) as a regulated transcript. Pharmacological inhibition of MDH2 in GSCs augmented efficacy of dasatinib, an orally bioavailable multi-kinase inhibitor, including PDGFRβ. Collectively, stem-like tumor cells reprogram their metabolism to induce changes in their epitranscriptomes and reveal possible therapeutic paradigms.
    Keywords:  ALKBH5; MDH2; PDGFRβ; alpha-ketoglutarate; cancer stem cell; epitranscriptomics; glioblastoma; m6A; malate-aspartate shuttle; metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2024.09.014
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