Loss of Histone Deacetylase 4 in Hepatocytes Perturbs Lipid Metabolism and Insulin Signaling in Diet-Induced Obesity Mice

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 Hdac4 knockout ( Hdac4 HKO ) mice and control Hdac4 floxed ( Hdac4 fl/fl ) mice were fed a high-fat, high-sucrose, high-cholesterol diet for 16 weeks to induce obesity and MASLD. The loss of hepatic Hdac4 increased serum alanine transaminase activity and exacerbated hepatic steatosis with higher liver weights and triglyceride levels than Hdac4 fl/fl mice in males. Hepatic expression of lipogenic genes was significantly higher in male and female Hdac4 HKO mice than in controls. Moreover, primary hepatocytes and the liver of Hdac4 HKO mice exhibited perturbed insulin signaling, characterized by reduced phosphorylated AKT2. Interestingly, hepatocyte Hdac4 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 Hdac4 HKO , leading to obesity-induced metabolic dysfunction in gWAT. In conclusion, hepatocyte Hdac4 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.