JunD Regulates Pancreatic β-Cells Function by Altering Lipid Accumulation

Abstract

The impairment of pancreatic β-cells function is partly caused by lipotoxicity, which aggravates the development of type 2 diabetes mellitus. Activator Protein 1 member JunD modulates apoptosis and oxidative stress. Recently, it has been found that JunD regulates lipid metabolism in hepatocytes and cardiomyocytes. Here, we studied the role of JunD in pancreatic β-cells. The lipotoxic effects of palmitic acid on INS-1 cells were measured, and JunD small-interfering RNA was used to assess the effect of JunD in regulating lipid metabolism and insulin secretion. The results showed that palmitic acid stimulation induced the overexpression of JunD, impaired glucose-stimulated insulin secretion, and increased intracellular lipid accumulation of β-cells. Moreover, the gene expression involved in lipid metabolism (Scd1, Fabp4, Fas, Cd36, Lpl, and Plin5) was upregulated, while gene expression involved in the pancreatic β-cells function (such as Pdx1, Nkx6.1, Glut2, and Irs-2) was decreased. Gene silencing of JunD reversed the lipotoxic effects induced by PA on β-cells. These results suggested that JunD regulated the function of pancreatic β-cells by altering lipid accumulation.

Predicting the Key Regulators of Cell Identity in Human Adult Pancreas

“…This could explain the absence of well-established pancreas TFs such as MAFA (Olbrot et al 2002), MNX1 (Flanagan et al 2014), NEUROG3 (Krentz et al 2017), FOXA2 (Lee et al 2019) and NKX2-2 (Mastracci et al 2011) in this analysis. Nevertheless, in support of the validity of our findings, ATAC-seq, the literature and immunohistochemistry of human pancreas sections corroborate several pySCENIC predictions reported here such as BHLHE41, JUND and HEYL (Gomez et al 2015; Good et al 2019; K. Wang et al 2021).…”

“…EGR1 (but not EGR4) has been shown to transcriptionally regulate GCG (Leung-Theung-Long et al 2005) as well as the PDX1 promoter in beta cells (Eto, Kaur, and Thomas 2007). STAT4 and JUND have been described respectively in pancreatic tissue in general and in beta cells but not in alpha cells (Yu and Kim 2012; Good et al 2019; K. Wang et al 2021) (Figure 3B,C) .…”

“…To examine the effect of perturbation of candidate TFs in the human adult pancreas, we selected two TFs for targeting with siRNAs in hiPSC-derived islet cells, an in vitro pancreatic islet model (Balboa et al 2022). JUND was identified as a regulator of oxidative stress and lipotoxicity in beta cells (K. Wang et al 2021; Good et al 2019) but its potential role in alpha cells remains unknown. BHLHE41 was of interest due to its role in circadian rhythm regulation (Hamaguchi et al 2004) but its putative impact on cell identity in the human pancreas has not yet been investigated.…”

Improving stem cell-derived pancreatic islets using single-cell multiome-inferred regulomes

“…RXRA was predicted to cooperate with the bile acid receptor NR1H4 in SC-β-cell and SC-EC gene regulation ( Figure 2J ), identifying a possible mechanism for the role of bile acids in insulin secretion (Vettorazzi et al, 2016). Of interest is also the SC-β-cell-specific interaction between BACH2 and JUND ( Figure 2K ), which have both been reported to contribute to β-cell dysfunction in type 2 diabetes (Good et al, 2019; Son et al, 2021; Wang et al, 2021). In summary, our GRN provides a resource for interrogating gene regulatory mechanisms in SC-islet cell types and their precursors.…”

TFvelo: gene regulation inspired RNA velocity estimation

“…Especially, JUND are assigned with high weights on the models of multiple target genes, and also tend to form clockwise curve (Supplementary Figure 2c). Early studies have reported that JUND modulates cell differentiation, proliferation, and apoptosis [30], further confirming the regulation mechanisms of JUND in pancreatic cells [31,32].…”