Sirtuin 3-mediated deacetylation of acyl-CoA synthetase family member 3 by protocatechuic acid attenuates non-alcoholic fatty liver disease

Br J Pharmacol. 2020 Sep;177(18):4166-4180. doi: 10.1111/bph.15159. Epub 2020 Aug 9.

Abstract

Background and purpose: Hepatic fatty acid metabolism disorder, a key pathogenic mechanism underlying non-alcoholic fatty liver disease (NAFLD), is associated with the hyperacetylation of mitochondrial enzymes. Acyl-CoA synthetase family member 3 (ACSF3), which is involved in the regulation of fatty acid metabolism, was predicted to contain lysine acetylation sites related to the mitochondrial deacetylase sirtuin 3 (SIRT3). The purpose of this study was to explore the underlying mechanism by which SIRT3 deacetylates ACSF3 in NAFLD and the protective effect of the natural phenolic compound protocatechuic acid (PCA) against fatty acid metabolism disorder via the SIRT3/ACSF3 pathway.

Experimental approach: The role of protocatechuic acid and its molecular mechanism in NAFLD were detected in rats and SIRT3-knockout mice fed a high-fat diet (HFD) and in AML-12 cells treated with palmitic acid (PA).

Key results: Pharmacological treatment with protocatechuic acid significantly attenuated high-fat diet-induced fatty acid metabolism disorder in NAFLD. Molecular docking assays showed that protocatechuic acid specifically bound SIRT3 as a substrate and increased SIRT3 protein expression. However, the protective role of protocatechuic acid was abolished by SIRT3 knockdown, which increased ACSF3 expression and exacerbated fatty acid metabolism disorder. Mechanistically, SIRT3 was shown to specifically regulate the acetylation and degradation of ACSF3, which govern the capacity of ACSF3 to mediate fatty acid metabolism disorder during NAFLD.

Conclusion and implications: SIRT3-mediated ACSF3 deacetylation is a novel molecular mechanism in NAFLD therapy and protocatechuic acid confers protection against high-fat diet- and palmitic acid-induced hepatic fatty acid metabolism disorder through the SIRT3/ACSF3 pathway.

Keywords: ACSF3; NAFLD; SIRT3; fatty acid metabolism; protocatechuic acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Coenzyme A
  • Diet, High-Fat / adverse effects
  • Hydroxybenzoates* / pharmacology
  • Ligases
  • Liver
  • Mice
  • Molecular Docking Simulation
  • Non-alcoholic Fatty Liver Disease* / drug therapy
  • Rats
  • Sirtuin 3* / drug effects

Substances

  • Hydroxybenzoates
  • protocatechuic acid
  • Sirtuin 3
  • Ligases
  • Coenzyme A