Macrophage Histone Deacetylase 4 Has Sex‐Dependent Dimorphic Effects on the Pathogenesis of Alcohol‐Associated Hepatitis

Background and Aim Epigenetic modifications affect the expression of genes related to inflammation. Our previous in vitro studies demonstrated that histone deacetylase 4 (HDAC4), a class IIa histone deacetylase, promotes alcohol‐induced inflammation in macrophages. Therefore, we explored the role of macrophage HDAC4 in the pathogenesis of alcohol‐associated liver disease (ALD). Methods Human liver samples from healthy individuals, ALD, and metabolic dysfunction‐associated steatohepatitis (MASH) were used to evaluate the expression of histone deacetylases (HDACs). Also, male and female Hdac4 floxed control ( Hdac4 fl/fl ) and macrophage‐specific Hdac4 knockout ( Hdac4 MKO ) mice were pair‐fed either Lieber‐DeCarli (LD) control diet or LD containing 5% ethanol for 10 days, and the latter received a single alcohol binge. Results Human liver samples from ALD, but not MASH, showed a marked induction of HDAC4 expression. Female Hdac4 MKO mice fed ethanol showed less serum alcohol, triglycerides, alanine aminotransferase, and malondialdehyde levels than female Hdac4 fl/fl controls, while males showed an opposite effect. The deletion of Hdac4 in macrophages did not elicit marked changes in liver steatosis, lipogenic gene expression, and NAD + metabolism, regardless of sex. However, female Hdac4 MKO mice fed ethanol displayed less inflammatory gene expression and macrophage infiltration in the liver compared with female control mice, but no significant differences were found in males. Conclusions This study indicates that macrophage HDAC4 plays a sex‐dependent role in the pathogenesis of alcohol‐associated hepatitis, with its deletion attenuating alcohol‐induced hepatic oxidative stress and inflammation in female mice while oxidative stress was aggravated in males.