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    • Kifunensine In considering the roles of

    2023-05-17

    In considering the roles of these enzymes in normal physiology, given the importance of GLUT4-dependent glucose uptake and glucose-dependent fatty Kifunensine synthesis for systemic metabolic homeostasis (Herman and Kahn, 2006, Herman et al., 2012), deletion of Acly in adipocytes results in a surprisingly mild phenotype, with no overt metabolic dysfunction observed for mixed-background mice on a regular chow diet. Nevertheless, larger adipocytes and reduced expression of genes, such as Glut4, observed in this model are also characteristic of obesity and are associated with poorer metabolic function. This suggests that Acly mice may be more susceptible to metabolic dysfunction when nutritionally stressed, for example, with high fructose feeding. Another interesting question is whether these mice will exhibit exacerbated metabolic phenotypes under conditions that alter acetate availability in the bloodstream, such as ethanol consumption or antibiotic treatment. The differential impact of ACLY on SWAT and VWAT also warrants further investigation. It is not clear why SWAT, but not VWAT, exhibits reduced histone acetylation and de novo fatty acid synthesis, despite evidence for compensatory mechanisms such as FASN upregulation. One possible explanation relates to an overall greater fraction of fatty acids that are de novo synthesized in SWAT, as compared to VWAT (Figures S6E and S6F), placing a greater demand for acetyl-CoA. Potentially, in a tissue with a lower DNL rate, acetate may be more readily able to compensate in both DNL and histone acetylation. Distribution of fatty acids in Acly WAT depots is also altered; SWAT, in particular, exhibits increased levels of monounsaturated and essential fatty acids (Figure S6B). Palmitoleate, which has been implicated as an insulin-sensitizing lipokine (Cao et al., 2008), is elevated in ACLY-deficient SWAT, raising questions about how altered levels of bioactive lipid species in the absence of ACLY may influence metabolic phenotypes. More mechanistic work is also clearly needed to elucidate the relationship between ACLY and gene regulation. The relationship between global histone acetylation and gene expression is not entirely consistent between VWAT and SWAT, possibly reflecting gene regulatory mechanisms that are specific to ACLY. A noteworthy observation in this study is that acetyl-CoA and histone acetylation levels appear to become uncoupled in the absence of ACLY, suggesting that acetate-derived acetyl-CoA may not be efficiently used for histone acetylation. Several possible mechanisms could account for this. First, it may be that, in MEFs, an insufficient amount of ACSS2 is present in the nucleus to efficiently drive histone acetylation. ACSS2 has been found to localize prominently to the nucleus in some conditions (Chen et al., 2015, Comerford et al., 2014, Xu et al., 2014); thus, investigation of whether acetate more readily contributes to overall histone acetylation levels in these contexts will be informative. However, potentially arguing against this possibility, hypoxia promotes ACSS2 nuclear localization (Xu et al., 2014); yet, although acetate does regulate histone acetylation in hypoxic cells, a high level of acetate (∼2.5 mM) is required (Gao et al., 2016). A second possibility is that, within the nucleus, acetyl-CoA producing enzymes are channeled, compartmentalized into niches, or sequestered with particular binding partners. Through such a mechanism, acetylation of specific proteins may be regulated not only by the relevant acetyltransferase but also by a specific acetyl-CoA-producing enzyme. Consistent with this possibility, acetylation of HIF2α was shown to be exclusively dependent on ACSS2 as a source of acetyl-CoA (Chen et al., 2015, Xu et al., 2014). A third possibility is that ACLY-deficient conditions may result in altered lysine acetyltransferase (KAT) or HDAC (histone deacetylase) activity. Finally, a fourth possibility is that lower use of acetyl-CoA for histone acetylation could be a feature of slow proliferation in the absence of ACLY (i.e., secondary to the proliferation defect). However, prior findings that histone acetylation is sensitive to glucose availability over a range that did not impact proliferation (Lee et al., 2014) and that the TCA cycle (which supplies ACLY substrate citrate) and mitochondrial membrane potential have distinct and separate roles in regulating histone acetylation and proliferation, respectively (Martínez-Reyes et al., 2016), as well as data in the present article showing that histone acetylation can be boosted by high acetate without a corresponding rescue of proliferation, argue against this as a sole explanation. Nevertheless, elucidation of the mechanisms that constrain proliferation in the absence of ACLY could help to definitively address this.