bims-meprid 2023-08-06 papers

Immunity. 2023 Jul 20. pii: S1074-7613(23)00314-X. [Epub ahead of print]

Ketolysis drives CD8+ T cell effector function through effects on histone acetylation.

Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. Here, we identified ketone bodies (KBs)-including β-hydroxybutyrate (βOHB) and acetoacetate (AcAc)-as essential fuels supporting CD8+ T cell metabolism and effector function. βOHB directly increased CD8+ T effector (Teff) cell cytokine production and cytolytic activity, and KB oxidation (ketolysis) was required for Teff cell responses to bacterial infection and tumor challenge. CD8+ Teff cells preferentially used KBs over glucose to fuel the tricarboxylic acid (TCA) cycle in vitro and in vivo. KBs directly boosted the respiratory capacity and TCA cycle-dependent metabolic pathways that fuel CD8+ T cell function. Mechanistically, βOHB was a major substrate for acetyl-CoA production in CD8+ T cells and regulated effector responses through effects on histone acetylation. Together, our results identify cell-intrinsic ketolysis as a metabolic and epigenetic driver of optimal CD8+ T cell effector responses.

Keywords: CD8(+) T cells; TCA cycle; acetyl-CoA; cancer immunology; effector function; epigenetics; ketolysis; ketone bodies; metabolism

DOI: https://doi.org/10.1016/j.immuni.2023.07.002

Dev Cell. 2023 Jul 25. pii: S1534-5807(23)00335-0. [Epub ahead of print]

Fatty acid synthesis and oxidation regulate human endoderm differentiation by mediating SMAD3 nuclear localization via acetylation.

Ying Yi, Xianchun Lan, Yinglei Li, Chenchao Yan, Jing Lv, Tianzhe Zhang, Wei Jiang.

Metabolic remodeling is one of the earliest events that occur during cell differentiation. Here, we define fatty acid metabolism as a key player in definitive endoderm differentiation from human embryonic stem cells. Fatty acid β-oxidation is enhanced while lipogenesis is decreased, and this is due to the phosphorylation of lipogenic enzyme acetyl-CoA carboxylase by AMPK. More importantly, inhibition of fatty acid synthesis by either its inhibitors or AMPK agonist significantly promotes human endoderm differentiation, while blockade of fatty acid oxidation impairs differentiation. Mechanistically, reduced de novo fatty acid synthesis and enhanced fatty acid β-oxidation both contribute to the accumulation of intracellular acetyl-CoA, which guarantees the acetylation of SMAD3 and further causes nuclear localization to promote endoderm differentiation. Thus, our current study identifies a fatty acid synthesis/oxidation shift during early differentiation and presents an instructive role for fatty acid metabolism in regulating human endoderm differentiation.

Keywords: SMAD3 acetylation; embryonic stem cell; fatty acid metabolism; fatty acid synthesis; human endoderm differentiation

DOI: https://doi.org/10.1016/j.devcel.2023.07.005

Pharmacol Res. 2023 Jul 28. pii: S1043-6618(23)00225-6. [Epub ahead of print] 106869

Demethylzeylasteral targets lactate to suppress the tumorigenicity of liver cancer stem cells: It is attributed to histone lactylation?

Hang Gong, Hui-Mei Xu, Yao-Hui Ma, De-Kui Zhang.

Keywords: Glycolysis; Histone lactylation; Lactate; Liver cancer; Tumorigenicity

DOI: https://doi.org/10.1016/j.phrs.2023.106869

Curr Opin Biotechnol. 2023 Jul 27. pii: S0958-1669(23)00086-1. [Epub ahead of print]83 102976

2-hydroxyglutarate rides the cancer-immunity cycle.

Iosifina P Foskolou, Lukas Bunse, Jan Van den Bossche.

2-hydroxyglutarate (2HG) is a biproduct of the Krebs cycle, which exists in a D- and L- enantiomer and is structurally similar to α-ketoglutarate. Both 2HG enantiomers have been described to accumulate in diverse cancer and immune cells and can influence cell fate and function. While D-2HG was originally considered as an 'oncometabolite' that aberrantly builds up in certain cancers, it is becoming clear that it also physiologically accumulates in immune cells and regulates immune function. Conversely, L-2HG is considered as an 'immunometabolite' due to its induction and regulatory function in T cells, but it can also be induced in certain cancers. Here, the authors review the effects of both 2HG enantiomers on immune cells within the tumor microenvironment.

DOI: https://doi.org/10.1016/j.copbio.2023.102976