bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2023–02–26
two papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine
  1. p53 protects against alcoholic fatty liver disease via ALDH2 inhibition.
  2. CD40 signal rewires fatty acid and glutamine metabolism for stimulating macrophage anti-tumorigenic functions.
  1. EMBO J. 2023 Feb 24. e112304
    p53 protects against alcoholic fatty liver disease via ALDH2 inhibition.
    Pengbo Yao, Zhenxi Zhang, Hongchao Liu, Peng Jiang, Wei Li, Wenjing Du.
      The tumor suppressor p53 is critical for tumor suppression, but the regulatory role of p53 in alcohol-induced fatty liver remains unclear. Here, we show a role for p53 in regulating ethanol metabolism via acetaldehyde dehydrogenase 2 (ALDH2), a key enzyme responsible for the oxidization of alcohol. By repressing ethanol oxidization, p53 suppresses intracellular levels of acetyl-CoA and histone acetylation, leading to the inhibition of the stearoyl-CoA desaturase-1 (SCD1) gene expression. Mechanistically, p53 directly binds to ALDH2 and prevents the formation of its active tetramer and indirectly limits the production of pyruvate that promotes the activity of ALDH2. Notably, p53-deficient mice exhibit increased lipid accumulation, which can be reversed by ALDH2 depletion. Moreover, liver-specific knockdown of SCD1 alleviates ethanol-induced hepatic steatosis caused by p53 loss. By contrast, overexpression of SCD1 in liver promotes ethanol-induced fatty liver development in wild-type mice, while it has a mild effect on p53-/- or ALDH2-/- mice. Overall, our findings reveal a previously unrecognized function of p53 in alcohol-induced fatty liver and uncover pyruvate as a natural regulator of ALDH2.
    Keywords:  ALDH2; alcoholic fatty liver; histone acetylation; p53; protein-protein interaction
    DOI:  https://doi.org/10.15252/embj.2022112304
  2. Nat Immunol. 2023 Feb 23.
    CD40 signal rewires fatty acid and glutamine metabolism for stimulating macrophage anti-tumorigenic functions.
    Pu-Ste Liu, Yi-Ting Chen, Xiaoyun Li, Pei-Chun Hsueh, Sheue-Fen Tzeng, Hsi Chen, Pei-Zhu Shi, Xin Xie, Sweta Parik, Mélanie Planque, Sarah-Maria Fendt, Ping-Chih Ho.
      Exposure of lipopolysaccharide triggers macrophage pro-inflammatory polarization accompanied by metabolic reprogramming, characterized by elevated aerobic glycolysis and a broken tricarboxylic acid cycle. However, in contrast to lipopolysaccharide, CD40 signal is able to drive pro-inflammatory and anti-tumorigenic polarization by some yet undefined metabolic programming. Here we show that CD40 activation triggers fatty acid oxidation (FAO) and glutamine metabolism to promote ATP citrate lyase-dependent epigenetic reprogramming of pro-inflammatory genes and anti-tumorigenic phenotypes in macrophages. Mechanistically, glutamine usage reinforces FAO-induced pro-inflammatory and anti-tumorigenic activation by fine-tuning the NAD+/NADH ratio via glutamine-to-lactate conversion. Genetic ablation of important metabolic enzymes involved in CD40-mediated metabolic reprogramming abolishes agonistic anti-CD40-induced antitumor responses and reeducation of tumor-associated macrophages. Together these data show that metabolic reprogramming, which includes FAO and glutamine metabolism, controls the activation of pro-inflammatory and anti-tumorigenic polarization, and highlight a therapeutic potential of metabolic preconditioning of tumor-associated macrophages before agonistic anti-CD40 treatments.
    DOI:  https://doi.org/10.1038/s41590-023-01430-3
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