Tannic acid, a novel histone acetyltransferase inhibitor, prevents non-alcoholic fatty liver disease both in vivo and in vitro model

Min-Yu Chung, Ji-Hye Song, Jinhyuk Lee, Eun Ju Shin, Jae Ho Park, Seung-Hyun Lee, Jin-Taek Hwang, Hyo-Kyoung Choi

Non-alcoholic fatty liver disease (NAFLD) development is influenced by environmental as well as genetic factors. The environment influences gene expression by altering histone acetylation patterns in the chromatin, which is regulated by histone acetyltransferases (HATs) and deacetylases. Chung et al. identified tannic acid as a novel HAT inhibitor and demonstrated that tannic acid prevented the development of NAFLD via its HAT inhibition activity, both in vitro and in vivo.

Objective: We examined the potential of tannic acid (TA) as a novel histone acetyltransferase inhibitor (HATi) and demonstrated that TA prevents non-alcoholic fatty liver disease (NAFLD) by inhibiting HAT activity.

Methods: The anti-HAT activity of TA was examined using HAT activity assays. An in vitro NAFLD model was generated by treating HepG2 cells with oleic and palmitic acids. Male C57BL/6J mice were fed a control diet (CD) or Western diet (WD) with or without supplementation with either 1% or 3% TA (w/w) for 12 weeks. Finally, the possibility of interacting p300 and TA was simulated.

Results: TA suppressed HAT activity both in vitro and in vivo. Interestingly, TA abrogated occupancy of p300 on the sterol regulatory element in the fatty acid synthase and ATP-citrate lyase promoters, eventually inducing hypoacetylation of H3K9 and H3K36. Furthermore, TA decreased acetylation at lysine residues 9 and 36 of histone H3 protein and that of total proteins. Consequently, TA decreased the mRNA expression of lipogenesis-related genes and attenuated lipid accumulation in vivo. We observed that NAFLD features, including body weight, liver mass, fat mass, and lipid profile in serum, were improved by TA supplementation in vivo. Finally, we demonstrated the possibility that TA directly binds to p300 through docking simulation between ligand and protein.

Conclusions: Our findings demonstrate that TA, a novel HATi, has potential application for the prevention of NAFLD.