1. Academic Validation
  2. The protective role of the MKP-5-JNK/P38 pathway in glucolipotoxicity-induced islet β-cell dysfunction and apoptosis

The protective role of the MKP-5-JNK/P38 pathway in glucolipotoxicity-induced islet β-cell dysfunction and apoptosis

  • Exp Cell Res. 2019 Sep 1;382(1):111467. doi: 10.1016/j.yexcr.2019.06.012.
Zhuoyao Song 1 Jie Ma 1 Yuanhua Lu 1 Chao Zhou 1 Tongjian Zhao 1 Xilei Ai 1 Xuechen Wei 1 Jian Lin 1 Wei Wang 1 Weiqun Yan 1 Ping Jiao 2
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Jilin University, Changchun, China.
  • 2 School of Pharmaceutical Sciences, Jilin University, Changchun, China. Electronic address: [email protected].
Abstract

Hyperglycemia and hyperlipidemia (glycolipotoxicity)-triggered islet β-cell dysfunction is known to drive the progression of obesity-related type 2 diabetes, however the underlying mechanisms have not been clearly elucidated. The current study aimed to investigate the role of mitogen-activated protein kinase Phosphatase 5 (MKP-5) in islet cells under glucolipotoxic conditions. Using gene overexpression and knockdown approaches, we demonstrated that MKP-5 could alleviate glucolipotoxicity-induced Apoptosis via the endoplasmic reticulum (ER) stress and mitochondrial Apoptosis pathways owing to the altered regulation of Caspase family members and ER stress-related molecules in MIN6 and primary islet cells. Overexpression of MKP-5 reversed the glucose and palmitic acid (GP)-induced impairment of Insulin secretion as well as the abnormal decreases in the expression of islet functional genes, thereby maintaining the normal Insulin secretory functionality, whereas the absence of MKP-5 aggravated islet cell dysfunction. In parallel, the production of ROS and increased inflammation-associated genes in response to GP were also reduced upon MKP-5 overexpression. Further, inhibition of JNK or p38 MAPK pathways resisted to glucolipotoxicity observed in MKP-5 knockdown MIN6 cells. These findings indicate that MKP-5 is an important mediator for glucolipotoxicity-induced islet cell dysfunction and Apoptosis, with JNK and P38 as the critical downstream pathways.

Keywords

Apoptosis; Dysfunction; Glucoliptoxicity; Islet β-cell; MKP-5.

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