MON-579 Metabolic Function of Hepatic Chromodomain Helicase DNA Binding Protein 4 (Chd4)

Abstract Disclosure: T. Hung: None. A. Tsay: None. M. Chang: None. C. Xu: None. J. Lin: None. M.A. Pufall: None. J. Wang: None. Chromodomain Helicase DNA Binding Protein 4 (Chd4) is a subunit of the nucleosome remodeling and deacetylase (NuRD) complex, a transcriptional regulatory complex that regulates specific gene transcriptions. Chd4 contains ATPase activity that is required for its nucleosome remodeling activity. Chd4 has been shown to play a role in various physiological processes, but its function in metabolism remains unclear. Hepatic Chd4 expression was reduced using adeno-associated virus-mediated expression of short hairpin RNA (shRNA) in chow diet-fed male C57BL6/J mice, and the effects on glucose and lipid homeostasis were investigated. We found that Chd4 knockdown had lower fasting glucose levels and improved glucose tolerance. This is likely due to reduced hepatic glycogen levels in hepatic Chd4 knockdown mice. Mechanistically, hepatic Chd4 knockdown had reduced glycogen synthase (GS) activity, but glycogen phosphorylase (GP) activity was unaffected. Interestingly, hepatic Chd4 knockdown reduced the phosphorylation of serine 9 of glycogen synthase kinase 3 β (Gsk3β) in the liver, which increased Gsk3β activity to suppress GS activity. In addition, we observed hepatic Chd4 knockdown mice exhibited lowered circulating triglyceride levels while hepatic triglyceride levels were unchanged. In conclusion, our studies demonstrated that hepatic Chd4 plays a critical role in regulating glucose and lipid homeostasis. As Chd4 is a transcriptional coregulator, the next step is to identify Chd4 direct target genes that contribute to these metabolic phenotypes. Presentation: Monday, July 14, 2025