LDB1-mediated transcriptional complexes are sensitive to islet stress

Excess nutrients and proinflammatory cytokines impart stresses on pancreatic islet β-cells that, if unchecked, can lead to cellular dysfunction and/or death. Among these stress-induced effects is loss of key β-cell transcriptional regulator mRNA and protein levels required for β-cell function. Previ...

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Bibliographic Details
Published in:Islets 2022-12, Vol.14 (1), p.58-68
Main Authors: Liu, Yanping, Kepple, Jessica D., Shalev, Anath, Hunter, Chad S.
Format: Article
Language:English
Subjects:
Animals
co-regulator
cytokine
Cytokines
diabetes
DNA-Binding Proteins
glucose
Glucose - pharmacology
islet
LIM Domain Proteins - genetics
LIM Domain Proteins - metabolism
LIM-Homeodomain Proteins - genetics
LIM-Homeodomain Proteins - metabolism
Mice
palmitate
Palmitates
pancreas
RNA, Messenger - metabolism
Transcription factor
Transcription Factors - genetics
Transcription Factors - metabolism
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Summary:Excess nutrients and proinflammatory cytokines impart stresses on pancreatic islet β-cells that, if unchecked, can lead to cellular dysfunction and/or death. Among these stress-induced effects is loss of key β-cell transcriptional regulator mRNA and protein levels required for β-cell function. Previously, our lab and others reported that LIM-domain complexes comprised the LDB1 transcriptional co-regulator and Islet-1 (ISL1) transcription factor are required for islet β-cell development, maturation, and function. The LDB1:ISL1 complex directly occupies and regulates key β-cell genes, including MafA, Pdx1, and Slc2a2, to maintain β-cell identity and function. Given the importance of LDB1:ISL1 complexes, we hypothesized that LDB1 and/or ISL1 levels, like other transcriptional regulators, are sensitive to β-cell nutrient and cytokine stresses, likely contributing to β-cell (dys)function under various stimuli. We tested this by treating β-cell lines or primary mouse islets with elevating glucose concentrations, palmitate, or a cytokine cocktail of IL-1β, TNFα, and IFNγ. We indeed observed that LDB1 mRNA and/or protein levels were reduced upon palmitate and cytokine (cocktail or singly) incubation. Conversely, acute high glucose treatment of β-cells did not impair LDB1 or ISL1 levels, but increased LDB1:ISL1 interactions. These observations suggest that LDB1:ISL1 complex formation is sensitive to β-cell stresses and that targeting and/or stabilizing this complex may rescue lost β-cell gene expression to preserve cellular function.
ISSN:1938-2014
1938-2022
DOI:10.1080/19382014.2021.2016028