Abstract
Under adverse conditions, such as sustained or chronic hyperglycemia or hyperlipidemia, ROS (reactive oxygen species) or/and ER-stress (endoplasmic reticulum stress) will be induced in pancreatic β cells. ROS or ER-stress damages β-cells even leads to apoptosis. Previously we found ROS or ER-stress resulted in JNK activation in β cells and overexpressing NR4A1 in MIN6 cells reduced JNK activation via modulating cbl-b expression and subsequent degrading the upstream JNK kinase (MKK4). To search other possible mechanisms, we found the mRNA level and protein level of MKP7 (a phosphatase for phospho-JNK) were dramatic reduced in pancreatic β cells in the islets from NR4A1 KO mice compared with that from wild type mice. To confirm what we found in animals, we applied pancreatic β cells (MIN6 cells) and found that the expression of MKP7 was increased in NR4A1-overexpression MIN6 cells. We further found that knocking down the expression of MKP7 increased the p-JNK level in pancreatic β cells upon treatment with TG or H2O2. After that, we figured out that NR4A1 did enhance the transactivation of the MKP7 promoter by physical association with two putative binding sites. In sum, NR4A1 attenuates JNK phosphorylation incurred by ER-stress or ROS partially via enhancing MKP7 expression, potentially decreases pancreatic β cell apoptosis induced by ROS or ER-stress. Our finding provides a clue for diabetes prevention.
Highlights
In the past two decades, an increasing number of researchers were involved in research on the etiology of type 2 diabetes mellitus
MKP7 was dramatically reduced in pancreatic islets from NR4A1 KO mice compared with that from WT mice fed with a normal diet (Fig. 1A)
Western blotting results exhibited that the protein level of MKP7 was significantly reduced in the islets from NR4A1 KO mice compared with that from WT mice fed with normal diet (Fig. 1B)
Summary
In the past two decades, an increasing number of researchers were involved in research on the etiology of type 2 diabetes mellitus. It is popularly accepted that some adverse conditions, such as sustained or chronic hyperglycemia and/or hyperlipidemia, result in type 2 diabetes[1]. NR4A1 is a multi-stress response factor, and it has the role of tackling some stresses in response[3,4,5,6]. It contains a ligand-binding domain, its natural ligand has not been found[7]. The role of NR4A1 in apoptosis is still controversial. Sometimes it is anti-apoptotic and sometimes pro-apoptotic, depending on its localization.
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