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

Abstract

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.

• Authors: Ruixue Ren, Yong He, Dong Ding, Aoyuan Cui, Huarui Bao, Jing Ma, Xin Hou, Yu Li, Dechun Feng, Xiaoling Li, Suthat Liangpunsakul, Bin Gao, Hua Wang
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 75 Issue 3 Pg. 646-660 (03 2022) ISSN: 1527-3350 [Electronic] United States
• PMID: 34510484 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 American Association for the Study of Liver Diseases.

Chemical References

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

Topics

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