Aging exaggerates acute-on-chronic alcohol-induced liver injury in mice and humans by inhibiting neutrophilic sirtuin 1-C/EBPα-miRNA-223 axis

Hepatology. 2022 Mar;75(3):646-660. doi: 10.1002/hep.32152. Epub 2021 Dec 5.


Background and aims: Aging exacerbates liver neutrophil infiltration and alcohol-associated liver disease (ALD) in mice and humans, but the underlying mechanisms remain obscure. This study aimed to examine the effect of aging and alcohol consumption on neutrophilic Sirtuin 1 (SIRT1) and microRNA-223 (miR-223), and their contribution to ALD pathogeneses.

Approach and results: Young and aged myeloid-specific Sirt1 knockout mice were subjected to chronic-plus-binge ethanol feeding. Blood samples from healthy controls and patients with chronic alcohol drinking who presented with acute intoxication were analyzed. Neutrophilic Sirt1 and miR-223 expression were down-regulated in aged mice compared with young mice. Deletion of the Sirt1 gene in myeloid cells including neutrophils exacerbated chronic-plus-binge ethanol-induced liver injury and inflammation and down-regulated neutrophilic miR-223 expression. Immunoprecipitation experiments revealed that SIRT1 promoted C/EBPα deacetylation by directly interacting with C/EBPα, a key transcription factor that controls miR-223 biogenesis, and subsequently elevated miR-223 expression in neutrophils. Importantly, down-regulation of SIRT1 and miR-223 expression was also observed in circulating neutrophils from middle-aged and elderly subjects compared with those from young individuals. Chronic alcohol users with acute intoxication had a reduction in neutrophilic SIRT1 expression in young and middle-aged patients, with a greater reduction in the latter group. The neutrophilic SIRT1 expression correlated with neutrophilic miR-223 and serum alanine transaminase levels in those patients.

Conclusions: Aging increases the susceptibility of alcohol-induced liver injury in mice and humans through the down-regulation of the neutrophilic SIRT1-C/EBPα-miR-223 axis, which could be a therapeutic target for the prevention and/or treatment of ALD.

Publication types

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

MeSH terms

  • Age Factors
  • Aging / physiology*
  • Alcohol Drinking / adverse effects
  • Animals
  • Chemical and Drug Induced Liver Injury, Chronic / etiology
  • Chemical and Drug Induced Liver Injury, Chronic / metabolism
  • Chemical and Drug Induced Liver Injury, Chronic / pathology
  • Down-Regulation
  • Gene Expression Regulation
  • Humans
  • Liver Diseases, Alcoholic* / metabolism
  • Liver Diseases, Alcoholic* / pathology
  • Liver* / metabolism
  • Liver* / pathology
  • Mice
  • Mice, Knockout
  • MicroRNAs* / biosynthesis
  • MicroRNAs* / metabolism
  • Myeloid Cells / metabolism
  • Neutrophil Infiltration / physiology*
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*


  • MIRN223 microRNA, human
  • MIRN223 microRNA, mouse
  • MicroRNAs
  • SIRT1 protein, human
  • Sirt1 protein, mouse
  • Sirtuin 1