2. Academic Validation
  3. Sirt1-mediated deacetylation of PGC-1α alleviated hepatic steatosis in type 2 diabetes mellitus via improving mitochondrial fatty acid oxidation

Sirt1-mediated deacetylation of PGC-1α alleviated hepatic steatosis in type 2 diabetes mellitus via improving mitochondrial fatty acid oxidation

  • Cell Signal. 2024 Dec:124:111478. doi: 10.1016/j.cellsig.2024.111478.
Jiale Pang 1,  Longxiang Yin 2,  Wenjie Jiang 2,  Haiyan Wang 3,  Qian Cheng 2,  Zhenzhou Jiang 4,  Yanjuan Cao 2,  Xia Zhu 2,  Baojing Li 5,  Sitong Qian 2,  Xiaoxing Yin 2,  Tao Wang 6,  Qian Lu 7,  Tingting Yang 8
Affiliations

Affiliations

  • 1 Department of Pharmacy, Jintan Affiliated Hospital of Jiangsu University, Changzhou 213200, China.
  • 2 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.
  • 3 Department of Biochemistry, Graduate School of Inovative Life Science, University of Toyama, Toyama 930-0194, Japan.
  • 4 New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China, Pharmaceutical University, Nanjing 210009, China.
  • 5 College of Traditional Chinese Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China.
  • 6 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China; Department of Pharmacy, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, China. Electronic address: Misswt2011@126.com.
  • 7 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China. Electronic address: luqian@xzhmu.edu.cn.
  • 8 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China. Electronic address: tty@xzhmu.edu.cn.
PMID: 39428026 DOI: 10.1016/j.cellsig.2024.111478
Abstract

Being activated by deacetylation, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) has become an important regulator of metabolic-related diseases. The activation of Sirtuin 1 (SIRT1) by resveratrol was likely to deacetylate PGC-1α. However, the role of deacetylated PGC-1α in the alleviation of activated SIRT1 on type 2 diabetes mellitus (T2DM)-related fatty liver disease (FLD) remained unexplored. The aim of this study was to investigate the potential impact of Sirt1-mediated deacetylation of PGC-1α on T2DM-associated FLD and its underlying mechanisms. Our findings revealed that, along with the decreased SIRT1, the levels of acetylated PGC-1α were up-regulated in hepatocytes co-stimulated with high glucose (HG) and free fatty acids (FFA). Down-regulated SIRT1 inactivated PGC-1α by inhibiting its deacetylation, while activating SIRT1 improved hepatic injury by reducing lipid droplet accumulation through the deacetylation of PGC-1α. However, the beneficial effects of SIRT1 activation on hepatic steatosis were inhibited by PGC-1α antagonist in vitro. Mechanistically, activating SIRT1 enhanced mitochondrial function by promoting PGC-1α activity, thereby facilitating hepatic fatty acid oxidation (FAO). In conclusion, Sirt1-mediated deacetylation of PGC-1α mitigated hepatic lipotoxicity by enhancing mitochondrial FAO, which contributed to the restoration of mitochondrial function in T2DM. The activation of Sirt1-mediated PGC-1α deacetylation might represent a promising therapeutic approach for T2DM-associated FLD.

Keywords

Mitochondrial FAO; PGC-1α deacetylation; Sirt1 activation; T2DM-associated FLD.

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