2. Academic Validation
  3. Palmitic acid induces β-cell ferroptosis by activating ceramide signaling pathway

Palmitic acid induces β-cell ferroptosis by activating ceramide signaling pathway

  • Exp Cell Res. 2024 Jun 19;440(2):114134. doi: 10.1016/j.yexcr.2024.114134.
Maojun Guo 1,  Xiaolong Huang 1,  Junhan Zhang 1,  Ying Huang 1,  Ying Tang 1,  Honghua Wen 1,  Yanan Xu 2,  Shaokun Zhang 3,  Xiao Wei 4,  Shuoshuo Sun 5,  Qun Zhu 6
Affiliations

Affiliations

  • 1 Department of Endocrinology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210011, China.
  • 2 Department of Endocrinology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210011, China; Department of Endocrinology, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, 222002, China.
  • 3 Department of Endocrinology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210011, China; Department of Infectious Diseases, Taizhou Second People's Hospital, Taizhou, Jiangsu, 225500, China.
  • 4 Department of Endocrinology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210028, China.
  • 5 The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
  • 6 Department of Endocrinology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210011, China. Electronic address: zhuqun@njmu.edu.cn.
PMID: 38901790 DOI: 10.1016/j.yexcr.2024.114134
Abstract

Individuals with type 2 diabetes mellitus frequently display heightened levels of palmitic acid (PA) in their serum, which may lead to β-cell damage. The involvement of Ferroptosis, a form of oxidative cell death in lipotoxic β-cell injury remains uncertain. Here, we have shown that PA induces intracellular lipid peroxidation, increases intracellular Fe2+ content and decreases intracellular Glutathione Peroxidase 4 (GPX4) expression. Furthermore, PA causes distinct changes in pancreatic islets and INS-1 cells, such as mitochondrial atrophy and increased membrane density. Furthermore, the presence of the Ferroptosis inhibitor has a significant mitigating effect on PA-induced β-cell damage. Mechanistically, PA increased ceramide content and c-Jun N-terminal kinase (JNK) phosphorylation. The ceramide synthase inhibitor effectively attenuated PA-induced β-cell damage and GPX4/Fe2+ abnormalities, while inhibiting JNK phosphorylation. Additionally, the JNK Inhibitor SP600125 improved PA-induced cell damage. In conclusion, by promoting ceramide synthesis, PA inhibited GPX4 expression and increased intracellular Fe2+ to induce β-cell Ferroptosis. Moreover, JNK may be a downstream mechanism of ceramide-triggered lipotoxic Ferroptosis in β-cells.

Keywords

Ceramide; Ferroptosis; Palmitic acid; c-Jun N-terminal kinase; β-cell.

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