Dataset Information

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

ABSTRACT: ZHX3, 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 ZHX3 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 PCK1 and G6PC1 in the human hepatoma line HepG2. Transcriptomic analysis of ZHX3-deficient HepG2 cells revealed that the uric acid transporter gene SLC17A1 was upregulated, 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 PCK1, G6PC1 and partially SLC17A1 in HepG2 cells. Overall, our study uncovered the role of ZHX3 in regulating glucose metabolism in hepatocytes, thereby influencing FBG levels and its association with T2D risk.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hepatocyte, Cell Culture

DISEASE(S): Type 2 Diabetes Mellitus

SUBMITTER: Suat Peng Neo

LAB HEAD: Jayantha Gunaratne

PROVIDER: PXD046714 | Pride | 2026-04-27

REPOSITORIES: Pride

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			Action	DRS
	G902L3L6_proteinGroups_Pride_upload.xlsx	Xlsx
	G913_proteinGroups_Pride_Upload.xlsx	Xlsx
	TBP_QE_P6_220224_08_G902L3_A01.raw	Raw
	TBP_QE_P6_220224_09_G902L3_A02.raw	Raw
	TBP_QE_P6_220224_10_G902L3_A03.raw	Raw

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

Tan Wei Xuan WX Lim Lillian Yuxian LY Afsha Nesha N Chan Gloria Mei En GME Ching Carmen C Oguz Gokce G Neo Suat Peng SP Mohamed Ali Safiah S Ramasamy Adaikalavan A Gunaratne Jayantha J Hunziker Walter W Khoo Chin Meng CM Teo Adrian Kee Keong AKK

PNAS nexus 20241220 2

<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 ...[more]

PMID: 39990763

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Project description:Arsenic is a pervasive environmental toxin that is ranked as the number one investigative priority by the Agency for Toxic Substance and Disease Registry. Chronic exposure to arsenic has been associated with type 2 diabetes (T2D). However, the underlying mechanisms remain largely unknown. We have recently demonstrated that arsenic treatment of INS-1 832/13 pancreatic beta-cells impairs glucose stimulated insulin secretion (GSIS), a hallmark of T2D. We have also shown that arsenic alters the microRNA (miRNA) profile in beta-cells more dramatically than other metals. miRNAs have a well-established regulatory role in both normal beta-cell function and T2D pathogenesis. We hypothesized that there are miRNA master regulators that mediate arsenic-associated GSIS defects. To test this hypothesis, we first treated INS-1 832/13 beta-cells with either 1 μM of inorganic arsenic (iAsIII) or 0.5 μM of monomethylarsenite (MAsIII) and confirmed that GSIS is significantly reduced. We then performed multi-omic analysis using chromatin run-on sequencing (ChRO-seq), RNA-sequencing (RNA-seq), and small RNA-seq in order to define arsenic-associated chromatin and transcriptional activity, gene expression, and miRNA profiles, respectively. Integrating across these data sets we first showed that genes downregulated by iAsIII treatment are enriched in insulin secretion, T2D, and maturity onset diabetes of the young (MODY) pathways, whereas genes downregulated by MAsIII treatment are enriched in cell cycle and include genes that encode the critical beta cell maintenance factors Neurod1 and Rfx6. Secondly, we also identified those genes that are subject primarily to post-transcriptional regulation in response to arsenicals. Finally, we demonstrated that miR-29a is the top candidate master regulator of these genes. Our study is the first multi-omic analysis of beta cells after exposure to arsenicals, and the results strongly suggest that arsenicals lead to aberrant miR-29 expression and activity in beta-cells, which in turn leads to the repression of critical genes for beta-cell function, ultimately predisposing to diabetes.