Hepatitis B X-interacting protein promotes the formation of the insulin gene–transcribing protein complex Pdx-1/Neurod1 in animal pancreatic β-cells

Abstract

The activation of insulin gene transcription depends on multiple nuclear proteins, including the transcription factors PDX-1 and NEUROD1, which form a transcriptional complex. We recently reported that hepatitis B X-interacting protein (HBXIP, also termed LAMTOR5) can modulate glucose metabolism reprogramming in cancer cells. However, the physiological role of HBXIP in the modulation of glucose metabolism in normal tissues is poorly understood. Here, we report that Hbxip is an essential regulator of the effect of the Pdx-1/Neurod1 complex on insulin gene transcription in murine pancreatic β-cells and We found that pancreatic β-cell-specific Hbxip-knockout mice displayed higher fasting blood glucose levels and impaired glucose tolerance. Furthermore, Hbxip was involved in the regulation of insulin in the pancreas islets and increased insulin gene expression in rat pancreatic β-cells. Mechanistically, Hbxip stimulated insulin enhancer activity by interacting with Pdx-1 and recruiting Neurod1 to Pdx-1. Functionally, we provide evidence that Hbxip is required for Pdx-1/Neurod1-mediated insulin expression in rat pancreatic β-cells. Collectively, these results indicate that Hbxip is involved in the transcription of insulin by increasing the levels of the Pdx-1/Neurod1 complex in animal pancreatic β-cells. Our finding provides the insight into the mechanism by which Hbxip stimulates the transcription of the insulin gene.

EGF suppresses the expression of miR-124a in pancreatic β cell lines via ETS2 activation through the MEK and PI3K signaling pathways

“…5B-5D and Fig. 6), which are known to not only control beta cell development but also maintain mature beta cell function [18,[47][48][49][76][77][78][79]. NEUROD1, which has been reported to modulate insulin expression, has been confirmed to be regulated by miR-124a (Fig.…”

Hbxip (Lamtor5) is essential for embryogenesis and regulates embryonic stem cell differentiation through activating mTORC1

“…To study the function of Hbxip in normal development, we knocked out Hbxip in previous generated Hbxip floxed mice (Figure 1A) (Li et al, 2018). Heterozygous Hbxip KO ( Hbxip +/- ) mice were obtained through mating between Hbxip floxed mice and EIIa-cre mice.…”

“…However, the role of HBXIP in normal development remains poorly understood. Only a recent work reported that due to the pivotal role of Hbxip in activating the transcription of insulin by elevating the level of Pdx-1/Neurod1 complex, pancreatic β-cell-specific Hbxip knockout (KO) mice display higher fasting blood glucose levels and impaired glucose tolerance (Li et al, 2018).…”

Research progress on oncoprotein hepatitis B X‑interacting protein (Review)

“…HBXIP knockout mice have impaired glucose tolerance and reduced insulin production ( 22 ). Furthermore, HBXIP is highly expressed in pancreatic islets, acting as a coactivator of pancreatic and duodenal homeobox transcription factor and forming a complex with neurogenic differentiation 1 to upregulate insulin transcription genes and promote insulin secretion ( 22 ). Furthermore, the DNA damage response is an intrinsic signaling network in cells that recognizes and repairs DNA damage ( 27 ).…”

“…The carcinogenic mechanism of HBXIP in most tumors has been established, but its role in normal cells has been less well studied. At present, the role of HBXIP in maintaining normal glucose tolerance phenotype and normal embryonic tissue development in mice has been preliminarily studied ( 22 , 23 ). Likewise, HBXIP is involved in DNA damage repair ( 21 ).…”