Silibinin alleviates ferroptosis of rat islet β cell INS-1 induced by the treatment with palmitic acid and high glucose through enhancing PINK1/parkin-mediated mitophagy

Type 2 diabetes (T2DM) is induced by the abundance of glucose and lipids, which causes glucolipotoxicity to the pancreatic β-cells. Silibinin is a natural flavonoid possessing the regulatory activity on insulin production and therapeutic activity in diabetic mice; however, its effect on glucolipotox...

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Published in:Archives of biochemistry and biophysics 2023-07, Vol.743, p.109644-109644, Article 109644
Main Authors: Du, Qingqing, Wu, Xiaoyun, Ma, Kai, Liu, Weiwei, Liu, Panwen, Hayashi, Toshihiko, Mizuno, Kazunori, Hattori, Shunji, Fujisaki, Hitomi, Ikejima, Takashi
Format: Article
Language:English
Subjects:
Animals
Diabetes Mellitus, Experimental
Diabetes Mellitus, Type 2
Ferroptosis
Glucose - pharmacology
Glycolipid toxicity
Mice
Mitophagy
Palmitic Acid - pharmacology
Protein Kinases - genetics
Rats
Reactive Oxygen Species - metabolism
Silibinin
Silybin - pharmacology
Type 2 diabetes mellitus
Ubiquitin-Protein Ligases - metabolism
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Summary:Type 2 diabetes (T2DM) is induced by the abundance of glucose and lipids, which causes glucolipotoxicity to the pancreatic β-cells. Silibinin is a natural flavonoid possessing the regulatory activity on insulin production and therapeutic activity in diabetic mice; however, its effect on glucolipotoxicity is not fully explained. This in vitro study investigates the effects of silibinin on palmitic acid (PA) and high glucose (HG)-induced cell loss and ferroptosis of rat insulinoma INS-1 cells. In the cells treated with PA and HG, expressions of glucose transporter 4 (Glut4) and carnitine acyltransferase I (CPT1) for β-oxidation of fatty acids are reduced. Mitochondria are the metabolic organelles for glucose and fatty acids. The mitochondrial membrane potential (MMP) and ATP production were decreased, while the ROS level was elevated in the cells treated with PA and HG, indicating an induction of mitochondrial disorder. Cell loss was partially rescued by ferroptosis inhibition, suggesting an involvement of ferroptosis in the cells treated with PA and HG. More importantly, the increases in total iron, lipid ROS, MDA and COX-2, and the decrease in ferroptosis inhibitory molecules GSH, GPX4 and FSP1 appeared in the cells treated with PA and HG, confirming the occurrence of ferroptosis. Moreover, PINK1/parkin-mediated mitophagy, a vital process for selective elimination of damaged mitochondria, was blocked. Interestingly, silibinin rescued the mitochondria, restricted the ferroptosis and restored the mitophagy. By using the pharmacological stimulator and inhibitor of mitophagy, and si-RNA transfection to silence PINK1 expression, silibinin's protective effect against ferroptosis caused by PA and HG treatment was found to depend on mitophagy. Collectively, our current study reveals the new mechanisms for the protection of silibinin against the injury of INS-1 cells treated with PA and HG, elucidates the participation of ferroptosis in glucolipotoxicity, highlighting the involvement of mitophagy in defense against ferroptotic cell death. [Display omitted] •Silibinin improves the mitochondrial function in INS-1 cells treated with palmitic acid and high glucose.•Silibinin alleviates the reduction of PINK1/parkin-mediated mitophagy in INS-1 cells treated with palmitic acid and high glucose.•Silibinin attenuates ferroptosis in INS-1 cells treated with palmitic acid and high glucose.•Silibinin-induced mitophagy negatively regulates ferroptosis in INS-1 cells treated wi
ISSN:0003-9861
1096-0384
DOI:10.1016/j.abb.2023.109644