ZHX3 interacts with CEBPB to repress hepatic gluconeogenic gene expression and uric acid secretion

<i>ZHX3</i>, which encodes for a transcriptional repressor, is associated with fasting blood glucose (FBG) levels and increased type 2 diabetes (T2D) risk but its role in cell types involved in glucose metabolism is not well understood. Here, we show that the deletion of <i>ZHX3</i> in the human pancreatic β-cell line EndoC-βH1 did not impair glucose-stimulated insulin secretion (GSIS) nor perturb its transcriptome. On the other hand, we found that ZHX3 represses the expression of gluconeogenic genes <i>PCK1</i> and <i>G6PC1</i> in the human hepatoma line HepG2. Transcriptomic analysis of <i>ZHX3</i>-deficient HepG2 cells revealed that the uric acid transporter gene <i>SLC17A1</i> was up-regulated, which consequentially led to increased uric acid secretion. High levels of uric acid could then impair GSIS in EndoC-βH1 cells. Subsequently, in-depth co-immunoprecipitation followed by mass spectrometry analysis of ZHX3 in HepG2 cells identified transcription factor CEBPB as its binding partner, required to repress the transcription of <i>PCK1</i>, <i>G6PC1</i>, and partially <i>SLC17A1</i> in HepG2 cells. Overall, our study uncovered the role of ZHX3 in regulating glucose metabolism in hepatocytes, thereby influencing FBG levels and their association with T2D risk.