Palmitate increases Nur77 expression by modulating ZBP89 and Sp1 binding to the Nur77 proximal promoter in pancreatic β‐cells

Abstract

Nur77 is a stress sensor in pancreatic β-cells, which negatively regulates glucose-stimulated insulin secretion. We recently showed that a lipotoxic shock caused by exposure of β-cells to the saturated fatty acid palmitate strongly increases Nur77 expression. Here, using dual luciferase reporter assays and Nur77 promoter deletion constructs, we identified a regulatory cassette between -1534 and -1512 bp upstream from the translational start site mediating Nur77 promoter activation in response to palmitate exposure. Chromatin immunoprecipitation, transient transfection and siRNA-mediated knockdown assays revealed that palmitate induced Nur77 promoter activation involves Sp1 recruitment and ZBP89 release from the gene promoter.

SP and KLF Transcription Factors in Digestive Physiology and Diseases

“…In pancreatic cancer cells, SP1, SP3, and SP4 regulate expression of genes involved in cell proliferation, differentiation, and migration 158 . SP1 also activates genes during the stress response 159-161 . In normal pancreas, SP1 maintains basal expression of pancreas-specific transcription factor 1 A (PTF1A) in acinar cells and vesicular glucose transporter 2 and pyruvate carboxylase in β cells 154, 156, 157 .…”

“…SP1 binding to the PDX1 promoter increases its activation by forkhead box A2 (FOXA2, also called HNF3B); whereas binding of SP3 to the same region reduces transactivation by HNF3B 155 . SP1 also mediates the response of β cells to lipotoxicity and acinar cells to chronic alcohol exposure 159-161 .…”

The Roles of Nuclear Receptor NR4A1 in Cancer Cell Proliferation and Skeletal Muscle Differentiation

“…In addition to the proteins discussed here, other transcription factors such as Sp1, NF-kB, and CREB have all been shown to bind the promoter of NR4A1 to modulate its expression [137,445,446]. Other binding partners also include NFAT, GATA4, SRC-2, and c-JUN [77,[447][448][449]].…”

“…Studies from our lab have demonstrated that knockdown of the transcription factor ZNF148 rapidly induces differentiation in LHCN cells, suggesting that ZNF148 plays an inhibitory role during myogenesis. One study has shown that ZNF148 can suppress the expression of NR4A1 by directly binding to its promoter [446]. To determine the functional significance of this inhibitory mechanism, ZNF148 was knocked down via siRNA in LHCN cells which resulted in the rapid formation of myotubes by Day 2 (A-D) HSMM were transfected with 10 nm NT and siNR4A1 prior to differentiation for 5 days.…”

“…Several previous reports suggest that miR-124 might also regulate NR4A1 indirectly. In pancreatic beta-cells, Sp1 binds to the promoter of NR4A1 and increases NR4A1 levels [480]. Interestingly, during neuronal differentiation of mesenchymal stem cells, miR-124 targets Sp1 mRNA and decreases Sp1 expression [481].…”