2. Academic Validation
  3. Cytoplasmic SIRT6-mediated ACSL5 deacetylation impedes nonalcoholic fatty liver disease by facilitating hepatic fatty acid oxidation

Cytoplasmic SIRT6-mediated ACSL5 deacetylation impedes nonalcoholic fatty liver disease by facilitating hepatic fatty acid oxidation

  • Mol Cell. 2022 Oct 6;S1097-2765(22)00907-8. doi: 10.1016/j.molcel.2022.09.018.
Tianyun Hou 1,  Yuan Tian 2,  Ziyang Cao 3,  Jun Zhang 4,  Tingting Feng 4,  Wenhui Tao 4,  Hanyong Sun 5,  He Wen 4,  Xiaopeng Lu 4,  Qian Zhu 4,  Meiting Li 3,  Xifeng Lu 4,  Baohua Liu 6,  Ying Zhao 3,  Yang Yang 7,  Wei-Guo Zhu 8
Affiliations

Affiliations

  • 1 Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Shenzhen University International Cancer Center, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen 518055, China; Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK.
  • 2 Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Shenzhen University International Cancer Center, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen 518055, China; Shenzhen Bay Laboratory, Shenzhen University School of Medicine, Shenzhen 518055, China. Electronic address: [email protected].
  • 3 Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
  • 4 Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Shenzhen University International Cancer Center, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen 518055, China.
  • 5 Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
  • 6 Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Shenzhen University International Cancer Center, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen 518055, China; Shenzhen Bay Laboratory, Shenzhen University School of Medicine, Shenzhen 518055, China.
  • 7 Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China. Electronic address: [email protected].
  • 8 Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Shenzhen University International Cancer Center, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen 518055, China; Shenzhen Bay Laboratory, Shenzhen University School of Medicine, Shenzhen 518055, China. Electronic address: [email protected].
PMID: 36208627 DOI: 10.1016/j.molcel.2022.09.018
Abstract

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive hepatic lipid accumulation, which can progress to nonalcoholic steatohepatitis (NASH). Histone deacetylase Sirtuin 6 (SIRT6) regulates NAFLD by regulating metabolism-related gene expression, but an extrachromosomal role for SIRT6 in NAFLD development remains elusive. We investigated whether SIRT6 functions on NAFLD in the cytoplasm. We found that SIRT6 binds saturated fatty acids, especially palmitic acid. This binding leads to its nuclear export, where it deacetylates long-chain acyl-CoA synthase 5 (ACSL5), thereby facilitating fatty acid oxidation. High-fat diet-induced NAFLD is suppressed by ACSL5 hepatic overexpression but is exacerbated by its depletion. As confirmation, overexpression of a deacetylated ACSL5 mimic attenuated NAFLD in SIRT6 liver-specific knockout mice. Moreover, NASH-hepatic tissues from both patients and diet-fed mice exhibited significantly reduced cytoplasmic SIRT6 levels and increased ACSL5 acetylation. The SIRT6/ACSL5 signaling pathway has a critical role in NAFLD progression and might constitute an avenue for therapeutic intervention.

Keywords

ACSL5; NAFLD; NASH; SIRT6; acetylation; deacetylation; fatty acid oxidation; palmitic acid.

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