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Open Access 04-11-2023 | Cytokines | Article

Apolipoprotein L genes are novel mediators of inflammation in beta cells

Authors: Miriam Paz-Barba, Amadeo Muñoz Garcia, Twan J. J. de Winter, Natascha de Graaf, Maarten van Agen, Elisa van der Sar, Ferdy Lambregtse, Lizanne Daleman, Arno van der Slik, Arnaud Zaldumbide, Eelco J. P. de Koning, Françoise Carlotti

Published in: Diabetologia | Issue 1/2024

Abstract

Aims/hypothesis

Inflammation induces beta cell dysfunction and demise but underlying molecular mechanisms remain unclear. The apolipoprotein L (APOL) family of genes has been associated with innate immunity and apoptosis in non-pancreatic cell types, but also with metabolic syndrome and type 2 diabetes mellitus. Here, we hypothesised that APOL genes play a role in inflammation-induced beta cell damage.

Methods

We used single-cell transcriptomics datasets of primary human pancreatic islet cells to study the expression of APOL genes upon specific stress conditions. Validation of the findings was carried out in EndoC-βH1 cells and primary human islets. Finally, we performed loss- and gain-of-function experiments to investigate the role of APOL genes in beta cells.

Results

APOL genes are expressed in primary human beta cells and APOL1, 2 and 6 are strongly upregulated upon inflammation via the Janus kinase (JAK)−signal transducer and activator of transcription (STAT) pathway. APOL1 overexpression increases endoplasmic reticulum stress while APOL1 knockdown prevents cytokine-induced beta cell death and interferon-associated response. Furthermore, we found that APOL genes are upregulated in beta cells from donors with type 2 diabetes compared with donors without diabetes mellitus.

Conclusions/interpretation

APOLs are novel regulators of islet inflammation and may contribute to beta cell damage during the development of diabetes.

Data availability

scRNAseq data generated by our laboratory and used in this study are available in the Gene Expression Omnibus (GEO; www.ncbi.nlm.nih.gov/geo/), accession number GSE218316.

Graphical Abstract

Available only for authorised users

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Title: Apolipoprotein L genes are novel mediators of inflammation in beta cells
Authors: Miriam Paz-Barba
Amadeo Muñoz Garcia
Twan J. J. de Winter
Natascha de Graaf
Maarten van Agen
Elisa van der Sar
Ferdy Lambregtse
Lizanne Daleman
Arno van der Slik
Arnaud Zaldumbide
Eelco J. P. de Koning
Françoise Carlotti
Publication date: 04-11-2023
Publisher: Springer Berlin Heidelberg
Keywords: Cytokines
Type 2 Diabetes
Published in: Diabetologia / Issue 1/2024
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-023-06033-z

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