4.8 Article

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

期刊

MOLECULAR CELL
卷 82, 期 21, 页码 4099-+

出版社

CELL PRESS
DOI: 10.1016/j.molcel.2022.09.018

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资金

  1. National Natural Science Foundation of China [32090030, 81720108027, 81972697, 820029888, 82002986]
  2. National Key Research and Development Program of China [2017YFA0503900]
  3. Science and Technology Program of the Guangdong Province in China [2017B030301016]
  4. Shenzhen Municipal Commission of Science and Technology Innovation [JCYJ20200109114214463]
  5. National Key Ramp
  6. D Program of China [2017YFC0908100]
  7. Clinical Research Plan of Shanghai Shen-kang Hospital Development Center [SHDC2020CR4036]

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SIRT6 binds saturated fatty acids, leading to nuclear export, where it deacetylates ACSL5 and facilitates fatty acid oxidation, thereby suppressing NAFLD progression.
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 develop-ment 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.

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