Malonylation of Acetyl-CoA carboxylase 1 promotes hepatic steatosis and is attenuated by ketogenic diet in NAFLD

Cell Rep. 2023 Apr 25;42(4):112319. doi: 10.1016/j.celrep.2023.112319. Epub 2023 Mar 31.

Abstract

Protein post-translational modifications (PTMs) participate in important bioactive regulatory processes and therefore can help elucidate the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here, we investigate the involvement of PTMs in ketogenic diet (KD)-improved fatty liver by multi-omics and reveal a core target of lysine malonylation, acetyl-coenzyme A (CoA) carboxylase 1 (ACC1). ACC1 protein levels and Lys1523 malonylation are significantly decreased by KD. A malonylation-mimic mutant of ACC1 increases its enzyme activity and stability to promote hepatic steatosis, whereas the malonylation-null mutant upregulates the ubiquitination degradation of ACC1. A customized Lys1523ACC1 malonylation antibody confirms the increased malonylation of ACC1 in the NAFLD samples. Overall, the lysine malonylation of ACC1 is attenuated by KD in NAFLD and plays an important role in promoting hepatic steatosis. Malonylation is critical for ACC1 activity and stability, highlighting the anti-malonylation effect of ACC1 as a potential strategy for treating NAFLD.

Keywords: CP: Metabolism; Lysine malonylation; acetyl-CoA carboxylase 1; hepatic steatosis; ketogenic diet; non-alcoholic fatty liver disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyl-CoA Carboxylase / genetics
  • Acetyl-CoA Carboxylase / metabolism
  • Acetyl-CoA Carboxylase / pharmacology
  • Diet, Ketogenic*
  • Humans
  • Liver / metabolism
  • Lysine / metabolism
  • Non-alcoholic Fatty Liver Disease* / metabolism
  • Protein Processing, Post-Translational

Substances

  • Acetyl-CoA Carboxylase
  • Lysine
  • ACACA protein, human