2. Academic Validation
  3. Apolipoprotein L genes are novel mediators of inflammation in beta cells

Apolipoprotein L genes are novel mediators of inflammation in beta cells

  • Diabetologia. 2023 Nov 4. doi: 10.1007/s00125-023-06033-z.
Miriam Paz-Barba 1,  Amadeo Muñoz Garcia 1,  Twan J J de Winter 1,  Natascha de Graaf 1,  Maarten van Agen 1,  Elisa van der Sar 1,  Ferdy Lambregtse 1,  Lizanne Daleman 1,  Arno van der Slik 2,  Arnaud Zaldumbide 2,  Eelco J P de Koning 1,  Françoise Carlotti 3
Affiliations

Affiliations

  • 1 Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands.
  • 2 Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands.
  • 3 Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands. f.carlotti@lumc.nl.
PMID: 37924378 DOI: 10.1007/s00125-023-06033-z
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.

Keywords

Apolipoprotein L; Beta cells; Human islets; Inflammation.

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