Therapeutic targeting of hepatic ACSL4 ameliorates NASH in mice

Hepatology. 2022 Jan;75(1):140-153. doi: 10.1002/hep.32148. Epub 2021 Nov 27.


Background and aims: Globally, NAFLD is one of the most common liver disorders, with an estimated prevalence rate of more than 30% in men and 15% in women and an even higher prevalence in people with type 2 diabetes mellitus. Optimal pharmacologic therapeutic approaches for NAFLD are an urgent necessity.

Approach and results: In this study, we showed that compared with healthy controls, hepatic ACSL4 levels in patients with NAFLD were found to be elevated. Suppression of ACSL4 expression promoted mitochondrial respiration, thereby enhancing the capacity of hepatocytes to mediate β-oxidation of fatty acids and to minimize lipid accumulation by up-regulating peroxisome proliferator-activated receptor coactivator-1 alpha. Moreover, we found that abemaciclib is a potent and selective ACSL4 inhibitor, and low dose of abemaciclib significantly ameliorated most of the NAFLD symptoms in multiple NAFLD mice models.

Conclusions: Therefore, inhibition of ACSL4 is a potential alternative therapeutic approach for NAFLD.

Publication types

  • Observational Study
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / pharmacology
  • Aminopyridines / therapeutic use*
  • Animals
  • Benzimidazoles / pharmacology
  • Benzimidazoles / therapeutic use*
  • Biopsy
  • Coenzyme A Ligases / analysis
  • Coenzyme A Ligases / antagonists & inhibitors*
  • Coenzyme A Ligases / metabolism
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal
  • Fatty Acids / metabolism
  • Gene Knockdown Techniques
  • Hep G2 Cells
  • Humans
  • Liver / drug effects
  • Liver / enzymology
  • Liver / pathology
  • Mice
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease / drug therapy*
  • Non-alcoholic Fatty Liver Disease / etiology
  • Non-alcoholic Fatty Liver Disease / pathology
  • Oxidation-Reduction / drug effects


  • Aminopyridines
  • Benzimidazoles
  • Fatty Acids
  • abemaciclib
  • Acsl4 protein, mouse
  • Coenzyme A Ligases
  • long-chain-fatty-acid-CoA ligase