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 micro-RNA-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 chronicplus-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

Crosstalk between Oxidative Stress and Inflammatory Liver Injury in the Pathogenesis of Alcoholic Liver Disease

“…Therefore, miR-223 inhibits neutrophil infiltration and protects against alcohol-induced liver injury. Interestingly, the neutrophilic miR-223 expression level was lower in aged mice than in young mice [ 214 ]. Aging stimulates the susceptibility to acute and chronic alcohol-induced liver injury by inhibiting the neutrophilic SIRT1-C/EBPα-miR-223 axis.…”

Hepatocyte-specific deletion of cellular repressor of E1A-stimulated genes 1 exacerbates alcohol-induced liver injury by activating stress kinases

“…Aging as a risk factor has been shown to modify the development and progression of ALD 39 . In our previous study, aging increases the susceptibility of alcohol-induced liver injury by downregulating sirtuin 1 (SIRT1) in hepatocytes and hepatic stellate cells, and the SIRT1-C/EBPα-miR-223 axis in neutrophils 7 , 8 . The ASK1-signalosome network is a major center of stress signals that plays multiple roles in promotion of senescence, aging and diseases of oxidative stress 40 .…”

“…Aging is associated with progressive changes in hepatic structure and function, and also increases the risk of various types of liver diseases, including ALD, non-alcoholic liver disease, liver fibrosis and liver cancer 6 . Our previous studies have shown that aged mice have a high susceptibility to ethanol-induced liver damage, mainly manifested by excessive inflammation and oxidative stress 7 , 8 . In addition, it has been documented that activation of stress kinases plays critical role in the progression of ALD 9 .…”

MiR-223 as a Regulator and Therapeutic Target in Liver Diseases

“…The factors that influence these transcription factors are also involved in miR-223 expression. For example, Sirtuin-1, an NAD + -dependent histone deacetylase, interacts with C/EBPα to induce its deacetylation, thereby inducing miR-223 expression in neutrophils ( 13 ). Meanwhile, macrophage colony-stimulating factor and receptor activator of nuclear factor kappa-B ligand can increase expression of PU.1 ( 14 ).…”

“…A recent study showed that aging increases the susceptibility of alcohol-induced liver injury in both mice and humans via downregulation of the SIRT1-C/EBPα-miR-223 axis in neutrophils ( 13 ). When circulating neutrophils were obtained from both middle-aged and elderly subjects, levels of SIRT1 and miR-223 were found to be lower than in circulating neutrophils obtained from young individuals.…”