Loss of histone deacetylase 4 in hepatocytes perturbs lipid metabolism and insulin signaling in mice with diet-induced obesity

Epigenetic regulations link environmental factors to the development of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). We determined the role of hepatocyte histone deacetylase 4 (HDAC4) in the pathogenesis of MASLD. Male and female hepatocyte-specific <i>Hdac4</i> knockout (<i>Hdac4</i>^HKO) mice and control <i>Hdac4</i> floxed (<i>Hdac4</i>^fl/fl) mice were fed a high-fat, high-sucrose, high-cholesterol diet for 16 wk to induce obesity and MASLD. The loss of hepatic <i>Hdac4</i> increased serum alanine transaminase activity and exacerbated hepatic steatosis with higher liver weights and triglyceride levels than <i>Hdac4</i>^fl/fl mice in males. Hepatic expression of lipogenic genes was significantly higher in male and female <i>Hdac4</i>^HKO mice than in controls. Moreover, primary hepatocytes and the liver of <i>Hdac4</i>^HKO mice exhibited perturbed insulin signaling, characterized by reduced phosphorylated AKT2. Interestingly, hepatocyte <i>Hdac4</i> loss increased inflammatory and fibrogenic genes in gonadal white adipose tissue (gWAT). Serum cytokine array and proteomic analysis demonstrated alterations in several serum factors, which may contribute to crosstalk between the liver and WAT in <i>Hdac4</i>^HKO, leading to obesity-induced metabolic dysfunction in gWAT. In conclusion, hepatocyte <i>Hdac4</i> loss exacerbates hepatic steatosis, accompanied by disturbed insulin signaling and WAT inflammation and fibrosis in obese mice, underscoring its crucial role in liver-WAT crosstalk.<b>NEW & NOTEWORTHY</b> We examined the role of hepatocyte histone deacetylase 4 (HDAC4) in the development of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) using <i>Hdac4</i>-deficient mice with hepatocyte-specific deletion. We found that deleting <i>Hdac4</i> in hepatocytes worsens hepatic steatosis and disrupts insulin signaling in the liver. In addition, this deletion caused inflammation and fibrosis in the white adipose tissue of obese mice, highlighting the role of HDAC4 in the liver-adipose axis.