The loss of histone deacetylase 4 in macrophages exacerbates hepatic and adipose tissue inflammation in male but not in female mice with diet-induced non-alcoholic steatohepatitis

Epigenetic regulation in macrophages plays a crucial role in the inflammatory response of cells. We investigated the role of macrophage histone deacetylase 4 (HDAC4) in diet-induced obesity and non-alcoholic steatohepatitis using macrophage-specific Hdac4 knockout mice (Hdac4^MKO). Hdac4 floxed control (Hdac4^fl/fl) and Hdac4^MKO mice were fed a regular chow diet or an obesogenic high-fat/high-sucrose/high-cholesterol (HF/HS/HC) diet for 12 weeks. The loss of macrophage Hdac4, compared with Hdac4^fl/fl control, aggravated the diet-induced inflammation in the liver and white adipose tissue only in male mice. Splenic monocytes isolated from male mice fed the HF/HS/HC diet showed increased lipopolysaccharide (LPS) sensitivity and decreased Ly6C–/Ly6C+ ratios in male Hdac4^MKO mice, but not in females. Bone marrow-derived macrophages (BMMs) from male Hdac4^MKO mice had a lesser efferocytotic capacity but higher proinflammatory gene expression upon LPS stimulation than male Hdac4^fl/fl mice. However, female Hdac4^MKO BMMs exhibited the opposite responses. The induction of estrogen receptor α (ERα, Esr1) expression by LPS was less in male but more in female Hdac4^MKO BMMs than Hdac4^fl/fl BMMs. Moreover, overexpression of human HDAC4 decreased basal expression of Esr1 and abolished its induction by LPS. Inhibition of ERα increased Hdac4 with induction of inflammatory genes, whereas activation of ERα decreased Hdac4 with reduction of inflammatory genes in male and female Hdac4^fl/fl BMMs treated with LPS. However, regardless of the inhibition or activation of ERα, proinflammatory genes were induced by LPS more in male Hdac4^MKO BMMs than Hdac4^fl/fl cells, whereas cells in females showed opposite responses. In conclusion, this study suggests that the lack of macrophage Hdac4 aggravates hepatic and white adipose inflammation in male mice with diet-induced obesity and non-alcoholic steatohepatitis, and not in female mice. HDAC4 and ERα appear to counteract each other, but ERα may not be a major player in sex-dependent inflammatory responses in macrophages deficient in HDAC4.