Non-esterified fatty acid palmitate facilitates oxidative endoplasmic reticulum stress and apoptosis of ß-cells by upregulating ERO-1α expression.
Redox Biol
; 73: 103170, 2024 Jul.
Article
in En
| MEDLINE
| ID: mdl-38692092
ABSTRACT
Adipose tissue-derived non-esterified saturated long-chain fatty acid palmitate (PA) decisively contributes to ß-cell demise in type 2 diabetes mellitus in part through the excessive generation of hydrogen peroxide (H2O2). The endoplasmic reticulum (ER) as the primary site of oxidative protein folding could represent a significant source of H2O2. Both ER-oxidoreductin-1 (ERO-1) isoenzymes, ERO-1α and ERO-1ß, catalyse oxidative protein folding within the ER, generating equimolar amounts of H2O2 for every disulphide bond formed. However, whether ERO-1-derived H2O2 constitutes a potential source of cytotoxic luminal H2O2 under lipotoxic conditions is still unknown. Here, we demonstrate that both ERO-1 isoforms are expressed in pancreatic ß-cells, but interestingly, PA only significantly induces ERO-1α. Its specific deletion significantly attenuates PA-mediated oxidative ER stress and subsequent ß-cell death by decreasing PA-mediated ER-luminal and mitochondrial H2O2 accumulation, by counteracting the dysregulation of ER Ca2+ homeostasis, and by mitigating the reduction of mitochondrial membrane potential and lowered ATP content. Moreover, ablation of ERO-1α alleviated PA-induced hyperoxidation of the ER redox milieu. Importantly, ablation of ERO-1α did not affect the insulin secretory capacity, the unfolded protein response, or ER redox homeostasis under steady-state conditions. The involvement of ERO-1α-derived H2O2 in PA-mediated ß-cell lipotoxicity was corroborated by the overexpression of a redox-active ERO-1α underscoring the proapoptotic activity of ERO-1α in pancreatic ß-cells. Overall, our findings highlight the critical role of ERO-1α-derived H2O2 in lipotoxic ER stress and ß-cell failure.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Palmitates
/
Apoptosis
/
Insulin-Secreting Cells
/
Endoplasmic Reticulum Stress
/
Hydrogen Peroxide
Limits:
Animals
/
Humans
Language:
En
Journal:
Redox Biol
Year:
2024
Document type:
Article
Affiliation country:
Alemania