Activation of TAF9 via Danshensu-Induced Upregulation of HDAC1 Expression Alleviates Non-alcoholic Fatty Liver Disease

Ruiwen Wang; Zhecheng Wang; Ruimin Sun; Rong Fu; Yu Sun; Meiyang Zhu; Yunfei Geng; Dongyan Gao; Xiaofeng Tian; Yan Zhao; Jihong Yao

doi:10.3389/fphar.2021.775528

Activation of TAF9 via Danshensu-Induced Upregulation of HDAC1 Expression Alleviates Non-alcoholic Fatty Liver Disease

Front Pharmacol. 2021 Dec 2:12:775528. doi: 10.3389/fphar.2021.775528. eCollection 2021.

Authors

Ruiwen Wang¹, Zhecheng Wang¹, Ruimin Sun¹, Rong Fu¹, Yu Sun¹, Meiyang Zhu¹, Yunfei Geng¹, Dongyan Gao¹, Xiaofeng Tian², Yan Zhao¹, Jihong Yao¹

Affiliations

¹ Department of Pharmacology, Dalian Medical University, Dalian, China.
² Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China.

Abstract

Fatty acid β-oxidation is an essential pathogenic mechanism in nonalcoholic fatty liver disease (NAFLD), and TATA-box binding protein associated factor 9 (TAF9) has been reported to be involved in the regulation of fatty acid β-oxidation. However, the function of TAF9 in NAFLD, as well as the mechanism by which TAF9 is regulated, remains unclear. In this study, we aimed to investigate the signaling mechanism underlying the involvement of TAF9 in NAFLD and the protective effect of the natural phenolic compound Danshensu (DSS) against NAFLD via the HDAC1/TAF9 pathway. An in vivo model of high-fat diet (HFD)-induced NAFLD and a palmitic acid (PA)-treated AML-12 cell model were developed. Pharmacological treatment with DSS significantly increased fatty acid β-oxidation and reduced lipid droplet (LD) accumulation in NAFLD. TAF9 overexpression had the same effects on these processes both in vivo and in vitro. Interestingly, the protective effect of DSS was markedly blocked by TAF9 knockdown. Mechanistically, TAF9 was shown to be deacetylated by HDAC1, which regulates the capacity of TAF9 to mediate fatty acid β-oxidation and LD accumulation during NAFLD. In conclusion, TAF9 is a key regulator in the treatment of NAFLD that acts by increasing fatty acid β-oxidation and reducing LD accumulation, and DSS confers protection against NAFLD through the HDAC1/TAF9 pathway.

Keywords: Danshensu; FATTY ACID β-OXIDATION; HDAC1; LD accumulation; NAFLD; TAF9.