Nutrient-driven histone acetylation underlies energy storage and mobilization

In natural settings, energy storage and mobilization maintain a dynamic balance in response to recurrent overfeeding and fasting. Imbalanced energy storage and mobilization lead to a variety of metabolic dysfunctions. However, whether the metabolic status directly couples with epigenetic modifications and transcriptional outputs remains unclear. Here, we aimed to investigate the epigenetic mechanism underlying this adaptive balance and observed that, in an overfeeding state, increased glucose availability is associated with enhanced histone acetylation coinciding with acetyl-CoA production in an acyl-CoA short-chain synthetase 2 (ACSS2)-dependent manner, contributing to energy storage (e.g., lipogenesis); in contrast, in the fasting state, elevated D-β-hydroxybutyrate levels are associated with altered histone acetylation distribution and transcriptional programs, supporting a metabolic shift from anabolism to catabolism, such as fatty acid oxidation. In both overfeeding and fasting states, acetylated lysines in the histone require BRD4 to recognize and initiate transcriptional regulation. Inhibition of BRD4 leads to context-dependent phenotypic effects: it ameliorates non-alcoholic fatty liver disease (NAFLD) pathology induced by a high-fat diet, while it exacerbates hepatic steatosis in fasted mice or mice fed a ketogenic diet. Thus, these findings highlights that epigenetic regulation of energy storage and mobilization is closely linked to the availability of glucose, and ketone bodies. Moreover, our study revealed that modulation of ACSS2-associated pathway may represent a potential strategy for treatment of metabolic diseases, such as NAFLD. Glucose-derived acetyl-CoA is associated with an “active” mode of histone acetylation, which coincides with the expression of genes involved in energy storage; in parallel, overfeeding is accompanied by chronic metaflammation. By contrast, BHB sustains a “passive” mode of histone acetylation and is associated with the expression of genes related to energy mobilization, while fasting is accompanied by a dampened acute inflammatory response. Both “active” and “passive” histone acetylation were recognized by BRD4 to execute transcription regulatory effects. BRD4 inhibition improved high-fat diet-induced nonalcoholic fatty liver diseases pathology but aggravated hepatic steatosis in fasted mice or mice fed with the ketogenic diet. • D-β-hydroxybutyrate enhances histone “passive acetylation” to support energy mobilization • Glucose enhances histone “active acetylation” to support energy storage • ACSS2 is required for in vitro and in vivo lipogenesis