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  • Investigating these possibilities will illuminate whether

    2024-06-22

    Investigating these possibilities will illuminate whether Lesinurad possess mechanisms to differentially detect ACLY-generated versus ACSS2-generated acetyl-CoA as well as define the functional relationship between histone acetylation levels and cellular functions and phenotypes. Given that ACLY dominates in nutrient- and oxygen-replete conditions, whereas ACSS2 becomes important in nutrient- and oxygen-poor conditions (Gao et al., 2016, Schug et al., 2015), having mechanisms such as different acetylation substrates to distinguish between acetyl-CoA produced by each enzyme could be advantageous to cells. For example, such mechanisms could potentially cue cells to grow when ACLY serves as the acetyl-CoA source and to mediate adaptive responses when ACSS2 is the primary acetyl-CoA source. The roles of these enzymes in gene regulation appear to be complex, and in-depth analysis of the respective roles of ACLY and ACSS2 in genome-wide histone acetylation and acetylation of other protein substrates is needed to begin addressing these questions. Recent work has shown that the PDC is present in the nucleus and is able to convert pyruvate to acetyl-CoA for use in histone acetylation (Sutendra et al., 2014), raising the question of how the findings of the present study can be aligned with the described role of nuclear PDC. We suggest two potential models that are consistent both with our data and with a role for nuclear PDC in histone acetylation. In the first model, ACLY is the primary acetyl-CoA producer for regulation of global levels of histone acetylation, while PDC (and, potentially, other nuclear acetyl-CoA sources such as CrAT) could participate in mediating histone acetylation at specific target genes but not globally. A recent report that PDC forms a complex with PKM2, p300, and the arylhydrocarbon receptor (AhR) to facilitate histone acetylation at AhR target genes is consistent with such a possibility (Matsuda et al., 2015). In the second model, the role of ACLY in glucose-dependent histone acetylation regulation could be context dependent, with a larger role for PDC emerging in certain conditions or cell types. This possibility is supported by observations that PDC nuclear translocation is stimulated by conditions such as growth factor stimulation and mitochondrial stress (Sutendra et al., 2014). Further investigation will be needed to evaluate these models.
    Experimental Procedures
    Author Contributions The project was conceptualized and designed by S.Z. and K.E.W. S.Z. performed the majority of cell culture experiments and GC-MS metabolite analysis. A.T. generated Acly mice and performed the majority of animal experiments. R.A.H., Y.-M.K., and A.J.A. conducted mass spectrometry analysis of histone acetylation. S.T., A.J.F., I.A.B., and N.W.S. conducted acyl-CoA measurements by LC-MS. J.V.L., S.L.C., and J.M.V. conducted experiments. A.C. generated Acly MEFs and assisted with mouse experiments. A.S. and A.M.W. conducted NMR acetate measurements. M.W., N.M., and C.M.M. analyzed tissue rates of DNL from D2O-labeled mice. S.Z. and A.M.T. prepared figures. K.E.W. guided the study, analyzed data, and wrote the manuscript. All authors read and provided feedback on manuscript and figures.
    Acknowledgments This work was supported by grant R01CA174761, a Pew Biomedical Scholar Award, an American Diabetes Association Junior Faculty Award (7-12-JF-59), and the Linda Pechenik Montague Investigator Award to K.E.W. S.Z. is supported by predoctoral training grant 5T32CA115299. A.T. is supported by Penn-PORT IRACDA postdoctoral fellowship K12 GM081259. J.V.L. is supported by predoctoral fellowship F31 CA189744. I.A.B. is supported by NIH grant P30ES013508. K.E.W. and I.A.B. also acknowledge support from the Abramson Cancer Center Basic Science Center of Excellence in Cancer Metabolism. A.J.A. is supported by NIH grant GM102503. N.W.S. is supported by grants K22ES26235 and R21HD087866. C.M.M. acknowledges grant R01CA188652. We thank Tobias Raabe from the Penn Gene Targeting Core and Jean Richa from the Transgenic and Chimeric Mouse Core for generation of the embryonic stem cells and chimeric mice that were used to produce the Acly mice. We thank Tony Mancuso from the AFCRI Quantitative Metabolomics Core for guidance on GC-MS metabolite analysis. We thank James Alwine, Chi Dang, and K.E.W. lab members for helpful discussions during the preparation of this manuscript.