Sex Disparity in Alcohol-Induced Inflammation and Oxidative Stress in Macrophage-Specific Histone Deacetylase 4 Knockout Mice

Abstract

ObjectivesWe have previously shown that histone deacetylase 4 (HDAC4), a class IIa histone deacetylase expression was increased in alcohol-induced inflammation of macrophages in vitro. We determined the role of macrophage HDAC4 in the pathogenesis of alcoholic hepatitis (AH).MethodsHuman liver specimens were analyzed for HDAC protein expression. Macrophage-specific Hdac4 knockout mice (Hdac4MKO) were generated by crossing homozygous Hdac4 floxed (Hdac4fl/fl) mice with mice expressing Cre recombinase under the control of the lysozyme M promoter. Male and female Hdac4fl/fl (control) and Hdac4MKO mice were pair-fed Lieber-DeCarli (LD) control diet or LD containing 5% ethanol for ten days with one ethanol binge according to the National Institute on Alcohol Abuse and Alcoholism (NIAAA) model. Serum and tissue samples were collected for analysis.ResultsHuman livers with alcoholic cirrhosis showed significantly higher HDAC4 expression than the normal and non-alcoholic steatohepatitis livers. When mice were fed alcohol, the loss of macrophage Hdac4 decreased serum levels of alcohol, triglycerides, alanine aminotransferase, and malondialdehyde in female mice, but not males. Consistently, female Hdac4MKO mice on the ethanol diet showed a reduction in the expression of genes involved in ethanol metabolism and oxidative stress; however, male Hdac4MKO mice exhibited higher expression of the genes than Hdac4fl/fl control. In both sexes, liver steatosis was not significantly different between Hdac4MKO and Hdac4fl/fl. However, macrophage Hdac4 deficiency attenuated alcohol-induced hepatic inflammation in females, but the opposite effects were seen in male mice.ConclusionsThe deletion of HDAC4 in macrophages attenuates alcohol-induced hepatic oxidative stress and inflammation in female mice, which was aggravated in males. The results indicate sex-specific roles of macrophage Hdac4 in the pathogenesis of AH.Funding SourcesNational Institute of Health R21 1R21AA027310-01A1.