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  • The hyperacetylation of histone proteins by HATs is

    2022-05-12

    The hyperacetylation of histone proteins by HATs is known to be associated with gene activation [51]. In particular, p300, which is a transcription factor having HAT activity, links activators to the transcription machinery at promoters [52]. The p300/CBP complex dynamically regulates hundreds of different transcription factors, including SREBP-1c and PPARγ [53], [54]. Glucose-induced p300/CBP activation contributes to the development of NAFLD through enhanced activation of lipogenic genes [55]. Indeed, numerous studies have shown the relationship between lipogenic gene expression and NAFLD, as well as the preventive effects of natural compounds [56], [57]. Our data indicated that the mRNA expression of lipogenic genes was increased during lipid accumulation in vitro and in vivo. In addition, consistent with some previous studies [48], [58], [59], we observed that TA downregulated the mRNA expression of lipogenic genes. Importantly, in contrast to previous studies, we provide direct evidence to explain the observed responses based on an epigenetic mechanism. A recent study showed that the HAT enzyme p300, bound to the FASN promoter, increases histone acetylation in this region, and eventually increases mRNA expression of the FASN gene [60]. Consistent with these observations, our data also showed that histone acetylation was increased in the FASN promoter during lipogenesis and, using ChIP assays, we further demonstrated that TA modulated this process. These findings provide important evidence in support of our hypothesis. Unexpectedly, however, not only was the recruitment of p300 to the SRE region of the ACLY promoter not inhibited but also acetylation of H3K9 and H3K36 was not significantly abrogated by treatment with 10 μM of TA, suggesting that the ACLY gene is less vulnerable to epigenetic regulation by TA. Another plausible explanation is that increased ACLY expression promotes histone acetylation by generating acetyl-CoA [61], which plays an essential role in determining the overall status of histone acetylation in mammalian sphingosine kinase [46], [62]. Finally, we adopted a WD-induced NAFLD model to confirm whether TA-induced inhibition of HAT activity prevents development of the pathogenic features of NAFLD. Two previous studies have reported that histone acetylation is influenced by a WD [63], [64], suggesting the possibility of preventing WD-induced diseases through the regulation of HAT activity. As previously mentioned, our results showed that dietary TA supplementation not only ameliorated WD-induced hyperacetylation of histone and non-histone proteins in the liver tissues but also attenuated NAFLD-induced phenotypes and clinicopathological characters, even though food intake was increased in the TA-fed mice, thereby supporting our hypothesis that WD-induced disease could be regulated by the control of HAT activity. Animals fed high-TA-containing diets have a higher total feed intake than those fed a low-TA-containing diet, and the groups on high-TA diets showed a significant decrease in weight gain [65], [66]. In this regard, a study on the biochemical mechanism underlying the activity of TA demonstrated that the major effect of TA was not related to the inhibition of food consumption. Instead, it has been demonstrated that the effects of TA are mediated via the efficiency with which digested and absorbed nutrients are converted into new body substances [67], indicating that this phenomenon could be due to a direct inhibitory effect on a key metabolic pathway or indirect effect related to the diversion of metabolism by TA. On the basis of the findings of these previous studies and our present data, it can be postulated that the preventive effects of TA on the development of NAFLD in vivo are related to TA-induced epigenetic regulation of lipid metabolic pathways. We have also demonstrated a feasible mechanism by which the relative occupancy of p300 in the promoter regions of SREBP1c-regulated genes determines overall FASN- or ACLY-mediated mRNA expression, indicating that TA, as a novel HATi, has the important effect of regulating lipid metabolism. By extension, to explain the mode of action of TA as a HATi, we predicted a possible p300-TA docking model (Figure 7, and Supplemental Figures 3–6). The results showed that TA interacts with a catalytic pocket, bromodomain, and RING domain in p300, and regulates gene transcription by binding directly to histone H3 and negatively regulates itself via an autoinhibitory function [28], indicating that TA may interrupt the function of p300 by inducing a conformational change. Taken together, the results of this study suggest the potential application of a new class of TA nutraceuticals having HATi activity.