Defective lipid droplet biogenesis exacerbates oleic acid-induced cellular homeostasis disruption and ferroptosis in mouse cardiac endothelial cells
Abstract Endothelial dysfunction is a hallmark of various metabolic disorders and plays a pivotal role in the progression of cardiovascular diseases, including coronary microvascular dysfunction and myocardial ischemia. Lipid droplets (LDs) have emerged as key regulators of fatty acid metabolism in...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-08-01
|
| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02669-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849333721220513792 |
|---|---|
| author | Yun-Ting Wang Alexandra K. Moura Rui Zuo Zhengchao Wang Kiana Roudbari Jenny Z. Hu Mi Wang Pin-Lan Li Yang Zhang Xiang Li |
| author_facet | Yun-Ting Wang Alexandra K. Moura Rui Zuo Zhengchao Wang Kiana Roudbari Jenny Z. Hu Mi Wang Pin-Lan Li Yang Zhang Xiang Li |
| author_sort | Yun-Ting Wang |
| collection | DOAJ |
| description | Abstract Endothelial dysfunction is a hallmark of various metabolic disorders and plays a pivotal role in the progression of cardiovascular diseases, including coronary microvascular dysfunction and myocardial ischemia. Lipid droplets (LDs) have emerged as key regulators of fatty acid metabolism in endothelial cells (ECs), but their functional role in lipotoxicity-induced EC damage in the context of coronary microvascular dysfunction remains unclear. Here, we examined the contribution of LD biogenesis to oleic acid-induced lipotoxic effects in mouse cardiac ECs (MCECs). Our findings reveal that oleic acid markedly increases LD biogenesis in MCECs via a diacylglycerol O-acyltransferase 1 (DGAT1)-dependent pathway. This process is accompanied by substantial disruptions in cellular homeostasis, including elevated endoplasmic reticulum (ER) stress, impaired mitochondrial respiration, reduced ATP production, and heightened hypoxic responses. Furthermore, oleic acid-induced lipotoxicity is primarily mediated by ferroptosis−a form of lipid peroxide-dependent, caspase-independent cell death. Notably, pharmacological inhibition or genetic knockdown of DGAT1, which diminishes LD biogenesis, exacerbates oleic acid-induced cellular stress, mitochondrial dysfunction, and ferroptosis in MCECs. These results suggest that LD biogenesis plays a protective role in mitigating lipotoxicity, preserving mitochondrial function, and preventing lipid peroxide accumulation and ferroptosis, thereby safeguarding cardiac microvascular endothelial function in the context of metabolic disorders. |
| format | Article |
| id | doaj-art-d90a42f300164be1ab827c6076f4dbba |
| institution | Kabale University |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-d90a42f300164be1ab827c6076f4dbba2025-08-20T03:45:45ZengNature Publishing GroupCell Death Discovery2058-77162025-08-0111111710.1038/s41420-025-02669-5Defective lipid droplet biogenesis exacerbates oleic acid-induced cellular homeostasis disruption and ferroptosis in mouse cardiac endothelial cellsYun-Ting Wang0Alexandra K. Moura1Rui Zuo2Zhengchao Wang3Kiana Roudbari4Jenny Z. Hu5Mi Wang6Pin-Lan Li7Yang Zhang8Xiang Li9Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of HoustonDepartment of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of HoustonDepartment of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of HoustonDepartment of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of HoustonDepartment of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of HoustonDepartment of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of HoustonDepartment of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of HoustonDepartment of Pharmacology and Toxicology, Virginia Commonwealth University, School of MedicineDepartment of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of HoustonDepartment of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of HoustonAbstract Endothelial dysfunction is a hallmark of various metabolic disorders and plays a pivotal role in the progression of cardiovascular diseases, including coronary microvascular dysfunction and myocardial ischemia. Lipid droplets (LDs) have emerged as key regulators of fatty acid metabolism in endothelial cells (ECs), but their functional role in lipotoxicity-induced EC damage in the context of coronary microvascular dysfunction remains unclear. Here, we examined the contribution of LD biogenesis to oleic acid-induced lipotoxic effects in mouse cardiac ECs (MCECs). Our findings reveal that oleic acid markedly increases LD biogenesis in MCECs via a diacylglycerol O-acyltransferase 1 (DGAT1)-dependent pathway. This process is accompanied by substantial disruptions in cellular homeostasis, including elevated endoplasmic reticulum (ER) stress, impaired mitochondrial respiration, reduced ATP production, and heightened hypoxic responses. Furthermore, oleic acid-induced lipotoxicity is primarily mediated by ferroptosis−a form of lipid peroxide-dependent, caspase-independent cell death. Notably, pharmacological inhibition or genetic knockdown of DGAT1, which diminishes LD biogenesis, exacerbates oleic acid-induced cellular stress, mitochondrial dysfunction, and ferroptosis in MCECs. These results suggest that LD biogenesis plays a protective role in mitigating lipotoxicity, preserving mitochondrial function, and preventing lipid peroxide accumulation and ferroptosis, thereby safeguarding cardiac microvascular endothelial function in the context of metabolic disorders.https://doi.org/10.1038/s41420-025-02669-5 |
| spellingShingle | Yun-Ting Wang Alexandra K. Moura Rui Zuo Zhengchao Wang Kiana Roudbari Jenny Z. Hu Mi Wang Pin-Lan Li Yang Zhang Xiang Li Defective lipid droplet biogenesis exacerbates oleic acid-induced cellular homeostasis disruption and ferroptosis in mouse cardiac endothelial cells Cell Death Discovery |
| title | Defective lipid droplet biogenesis exacerbates oleic acid-induced cellular homeostasis disruption and ferroptosis in mouse cardiac endothelial cells |
| title_full | Defective lipid droplet biogenesis exacerbates oleic acid-induced cellular homeostasis disruption and ferroptosis in mouse cardiac endothelial cells |
| title_fullStr | Defective lipid droplet biogenesis exacerbates oleic acid-induced cellular homeostasis disruption and ferroptosis in mouse cardiac endothelial cells |
| title_full_unstemmed | Defective lipid droplet biogenesis exacerbates oleic acid-induced cellular homeostasis disruption and ferroptosis in mouse cardiac endothelial cells |
| title_short | Defective lipid droplet biogenesis exacerbates oleic acid-induced cellular homeostasis disruption and ferroptosis in mouse cardiac endothelial cells |
| title_sort | defective lipid droplet biogenesis exacerbates oleic acid induced cellular homeostasis disruption and ferroptosis in mouse cardiac endothelial cells |
| url | https://doi.org/10.1038/s41420-025-02669-5 |
| work_keys_str_mv | AT yuntingwang defectivelipiddropletbiogenesisexacerbatesoleicacidinducedcellularhomeostasisdisruptionandferroptosisinmousecardiacendothelialcells AT alexandrakmoura defectivelipiddropletbiogenesisexacerbatesoleicacidinducedcellularhomeostasisdisruptionandferroptosisinmousecardiacendothelialcells AT ruizuo defectivelipiddropletbiogenesisexacerbatesoleicacidinducedcellularhomeostasisdisruptionandferroptosisinmousecardiacendothelialcells AT zhengchaowang defectivelipiddropletbiogenesisexacerbatesoleicacidinducedcellularhomeostasisdisruptionandferroptosisinmousecardiacendothelialcells AT kianaroudbari defectivelipiddropletbiogenesisexacerbatesoleicacidinducedcellularhomeostasisdisruptionandferroptosisinmousecardiacendothelialcells AT jennyzhu defectivelipiddropletbiogenesisexacerbatesoleicacidinducedcellularhomeostasisdisruptionandferroptosisinmousecardiacendothelialcells AT miwang defectivelipiddropletbiogenesisexacerbatesoleicacidinducedcellularhomeostasisdisruptionandferroptosisinmousecardiacendothelialcells AT pinlanli defectivelipiddropletbiogenesisexacerbatesoleicacidinducedcellularhomeostasisdisruptionandferroptosisinmousecardiacendothelialcells AT yangzhang defectivelipiddropletbiogenesisexacerbatesoleicacidinducedcellularhomeostasisdisruptionandferroptosisinmousecardiacendothelialcells AT xiangli defectivelipiddropletbiogenesisexacerbatesoleicacidinducedcellularhomeostasisdisruptionandferroptosisinmousecardiacendothelialcells |