Resveratrol affects hepatic gluconeogenesis via histone deacetylase 4

The aim of this study was to determine whether resveratrol (Rev) affects the expression, phosphorylation, and nuclear and cytoplasmic distribution of histone deacetylase 4 (HDAC4), which in turn affects gluconeogenesis in hepatocytes under an insulin-resistant state.

HepG2 cells were treated with 0.25 mmol/L palmitic acid (PA) to establish an insulin resistance model. The cells were divided into five groups: control, PA, PA + Rev 100 µM, PA + Rev 50 µM, and PA + Rev 20 µM. After treatment for 24 hours, mRNA and protein expression levels of gluconeogenesis pathway-related molecules and HDAC4 were examined. Next, HepG2 cells were transfected with siRNA-HDAC4. The cells were divided into control, PA, PA + Rev 20 µM, PA + Rev 20 µM +siRNA-HDAC4 negative control, and PA + Rev 20 µM +siRNA-HDAC4 knockdown groups to determine the expression of gluconeogenesis pathway proteins.

Compared with the control group, the gluconeogenesis pathway-related molecules, glucose-6-phosphatase catalytic subunit (G6PC), phosphoenolpyruvate carboxykinase 1 (PCK1) and forkhead box protein O1 (FOXO1), were increased, and the phosphorylation of FOXO1 decreased after PA treatment. The p-HDAC4 level decreased with the increase in HDAC4 in the nucleus and the decrease in HDAC4 in the cytoplasm in the PA group. Treatment with Rev 20 µM suppressed gluconeogenesis and promoted HDAC4 shuttling into the cytoplasm from the nucleus. However, 100 and Rev 50 µM exerted the opposite effects. Finally, after HDAC4 knockdown, the expression levels of the key gluconeogenesis molecules, G6PC, PCK1, and FOXO1, were increased, and p-FOXO1 was decreased, indicating that gluconeogenesis was enhanced.

A low concentration of Rev inhibited gluconeogenesis under insulin-resistance conditions via translocation of HDAC4 from the nucleus to the cytoplasm.