Diets low in carbohydrates and proteins and enriched in fat stimulate the hepatic synthesis of ketone bodies (KB). These molecules are used as alternative fuel for energy production in target tissues. The synthesis and utilization of KB are tightly regulated both at transcriptional and hormonal levels. The nuclear receptor peroxisome proliferator activated receptor α (PPARα), currently recognized as one of the master regulators of ketogenesis, integrates nutritional signals to the activation of transcriptional networks regulating fatty acid β-oxidation and ketogenesis. New factors, such as circadian rhythms and paracrine signals, are emerging as important aspects of this metabolic regulation. However, KB are currently considered not only as energy substrates but also as signaling molecules. β-hydroxybutyrate has been identified as class I histone deacetylase inhibitor, thus establishing a connection between products of hepatic lipid metabolism and epigenetics. Ketogenic diets (KD) are currently used to treat different forms of infantile epilepsy, also caused by genetic defects such as Glut1 and Pyruvate Dehydrogenase Deficiency Syndromes. However, several researchers are now focusing on the possibility to use KD in other diseases, such as cancer, neurological and metabolic disorders. Nonetheless, clear-cut evidence of the efficacy of KD in other disorders remains to be provided in order to suggest the adoption of such diets to metabolic-related pathologies.

White adipose tissue (WAT) can undergo a phenotypic switch, known as browning, in response to environmental stimuli such as cold. Post-translational modifications of histones have been shown to regulate cellular energy metabolism, but their role in white adipose tissue physiology remains incompletely understood. Here we show that histone deacetylase 3 (HDAC3) regulates WAT metabolism and function. Selective ablation of Hdac3 in fat switches the metabolic signature of WAT by activating a futile cycle of de novo fatty acid synthesis and β-oxidation that potentiates WAT oxidative capacity and ultimately supports browning. Specific ablation of Hdac3 in adipose tissue increases acetylation of enhancers in Pparg and Ucp1 genes, and of putative regulatory regions of the Ppara gene. Our results unveil HDAC3 as a regulator of WAT physiology, which acts as a molecular brake that inhibits fatty acid metabolism and WAT browning.

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Over the past decade, epigenetics has emerged as a new layer of regulation of gene expression. Several investigations demonstrated that nutrition and lifestyle regulate lipid metabolism by influencing epigenomic remodeling. Studies on animal models highlighted the role of epigenome modifiers in specific metabolic contexts and established clear links between dysregulation of epigenetic mechanisms and metabolic dysfunction. The relevance of findings in animal models has been translated to humans, as epigenome-wide association studies (EWAS) deeply investigated the relationship between lifestyle and epigenetics in human populations. In this review, we will provide an outlook of recent studies addressing the link between epigenetics and lipid metabolism, by comparing results obtained in animal models and in human subjects.

IntroductionCastration resistant prostate cancer (CRPC) is an aggressive tumour with still limited therapeutic outcomes. Tocotrienols (TT), vitamin E derivatives, were reported to exert anticancer activity in different tumours. The aim of this study was to assess the effects of δ-TT on human CRPC cells growth and the molecular mechanisms associated with its activity.Material and methodsIn human normal prostate (RWPE-1) and CRPC (PC3 and DU145) cell lines the effect of δ-TT on cell viability was evaluated by MTT assay; in PC3 and DU145 cells Trypan blue exclusion and colony formation assays were also performed. The expression of apoptosis-, ER stress- and autophagy-related proteins was analysed by Western blot and immunofluorescence assays, and the cytotoxic effect of δ-TT was also assessed using specific inhibitors of these pathways. The effect on mitochondrial metabolism was evaluated analysing the expression of the OXPHOS complexes (Western blot), the mitochondrial activity and mass (flow cytometry), the oxygen consumption (Clark-type oxygen electrode) and the ATP production (colorimetric assay).Results and discussionsWe demonstrated that δ-TT exerts a cytotoxic effect on PC3 and DU145 but not on RWPE-1 cells. In particular, δ-TT induces caspase 3 and PARP cleavage and cytochrome c release from mitochondria, and its cytotoxic effect is partially blocked by co-treatment with the pan-caspase inhibitor z-VAD-FMK, confirming that δ-TT exerts a pro-apoptotic effect on CRPC cells.We also observed that δ-TT significantly increases the expression of ER stress (BiP, IRE1α, PERK, pEIF2α, ATF4 and CHOP) and autophagy mediators (LC3-II and p62). Using the ER stress inhibitors salubrinal and 4-phenylbutyrate (4-PBA) and the autophagic flux inhibitors 3-methyladenine and chloroquine, we confirmed that the effect of δ-TT is mediated by both these mechanisms. In addition, treatment with salubrinal or 4-PBA impairs δ-TT-induced LC3-II expression, demonstrating that this compound triggers the ER stress-autophagy axis.Finally, we observed that δ-TT severely alters mitochondrial metabolism: the expression of the OXPHOS protein complexes, the mitochondrial activity/mass ratio, the oxygen consumption and the ATP production were significantly reduced after δ-TT treatment.ConclusionThese results demonstrate that δ-TT exerts a selective pro-apoptotic effect on human CRPC cells through the activation of the ER stress-autophagy axis and the rewiring of mitochondrial metabolism.