Supplementary Materials-Histone Deacetylases Inhibitor Chidamide Mitigates Inflammation and Insulin Resistance by Targeting VDR in Skeletal Muscle Cells

Diabetes mellitus (DM) is a metabolic syndrome leading to increased healthy burden worldwide, among which Type 2 diabetes mellitus (T2DM), primarily characterized by insulin resistance in the liver, skeletal muscle and adipose tissues, comprised to the major part of the patients. Therefore, targeting periphery inflammation and insulin resistance serves as an effective therapy in T2DM. Chidamide, a histone deacetylases inhibitor, is well utilized in the treatment of malignant tumors. However, its impact on regulating peripherical insulin resistance in metabolic diseases has not been reported to date. Here we elucidated a novel approach for treating inflammation and insulin resistance by utilizing Chidamide in C2C12 skeletal muscle cells. Chidamide exhibited an exciting treating effect in mitigating inflammation and insulin resistance in PA-induced C2C12 model. Mechanistically, PA induced inflammation and insulin resistance by downregulating the transcription of vitamin D receptor (VDR) and cell surface located GLUT4, therefore impairing glucose uptake. This effect was counteracted by Chidamide through elevating histone acetylation and VDR transcription, thereby enhancing insulin sensitivity and increasing cell surface localization of GLUT4. Our findings highlighted that Chidamide epigenetically regulates VDR expression, thus mitigating inflammation and improving insulin sensitivity of skeletal muscle cells, thereby providing novel insights into enhancing peripherical insulin sensitivity of T2DM.