BCL-XL Overexpression Protects Pancreatic β-Cells against Cytokine- and Palmitate-Induced Apoptosis

• Published in: International journal of molecular sciences Vol. 24; no. 6; p. 5657
• Main Authors: Perez-Serna, Atenea A., Dos Santos, Reinaldo S., Ripoll, Cristina, Nadal, Angel, Eizirik, Decio L., Marroqui, Laura
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 16.03.2023; MDPI
• Subjects: Analysis; Animals; Apoptosis; Apoptosis - genetics; Cell cycle; Cell Line; Cytokines; Cytokines - metabolism; Dextrose; Diabetes; Glucose; Humans; Infections; Insulin; Insulin-Secreting Cells - metabolism; Metabolism; Neuroendocrine tumors; Palmitates - metabolism; Palmitates - pharmacology; Physiological aspects; Proteins; Rats; Type 2 diabetes; Spain; pancreatic β-cells; Ca2+ signaling; palmitate; BCL-XL; apoptosis; cytokines; insulin secretion
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24065657

Diabetes is a chronic disease that affects glucose metabolism, either by autoimmune-driven β-cell loss or by the progressive loss of β-cell function, due to continued metabolic stresses. Although both α- and β-cells are exposed to the same stressors, such as proinflammatory cytokines and saturated free fatty acids (e.g., palmitate), only α-cells survive. We previously reported that the abundant expression of BCL-XL, an anti-apoptotic member of the BCL-2 family of proteins, is part of the α-cell defense mechanism against palmitate-induced cell death. Here, we investigated whether BCL-XL overexpression could protect β-cells against the apoptosis induced by proinflammatory and metabolic insults. For this purpose, BCL-XL was overexpressed in two β-cell lines—namely, rat insulinoma-derived INS-1E and human insulin-producing EndoC-βH1 cells—using adenoviral vectors. We observed that the BCL-XL overexpression in INS-1E cells was slightly reduced in intracellular Ca2+ responses and glucose-stimulated insulin secretion, whereas these effects were not observed in the human EndoC-βH1 cells. In INS-1E cells, BCL-XL overexpression partially decreased cytokine- and palmitate-induced β-cell apoptosis (around 40% protection). On the other hand, the overexpression of BCL-XL markedly protected EndoC-βH1 cells against the apoptosis triggered by these insults (>80% protection). Analysis of the expression of endoplasmic reticulum (ER) stress markers suggests that resistance to the cytokine and palmitate conferred by BCL-XL overexpression might be, at least in part, due to the alleviation of ER stress. Altogether, our data indicate that BCL-XL plays a dual role in β-cells, participating both in cellular processes related to β-cell physiology and in fostering survival against pro-apoptotic insults.