MKP-5 Relieves Lipotoxicity-Induced Islet β-Cell Dysfunction and Apoptosis via Regulation of Autophagy
| Autor: | Tongjian Zhao, Yafei Tian, Ping Jiao, Lu-Lu Li, Wenjing Teng, Wei Wang, Jie Ma, Yongjun Ma, Weiqun Yan |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Male Palmitic Acid Apoptosis p38 Mitogen-Activated Protein Kinases lcsh:Chemistry Mice 0302 clinical medicine Transduction Genetic lcsh:QH301-705.5 Spectroscopy Mitogen-Activated Protein Kinase 1 geography.geographical_feature_category Mitogen-Activated Protein Kinase 3 Chemistry Kinase General Medicine lipotoxicity Islet Computer Science Applications Cell biology Lipotoxicity 030220 oncology & carcinogenesis Dual-Specificity Phosphatases Signal Transduction autophagy p38 mitogen-activated protein kinases Genetic Vectors Primary Cell Culture Diet High-Fat Catalysis Article Adenoviridae Inorganic Chemistry 03 medical and health sciences Islets of Langerhans Animals Obesity Physical and Theoretical Chemistry Protein kinase A Molecular Biology Protein Kinase Inhibitors geography Adenine Organic Chemistry Autophagy JNK Mitogen-Activated Protein Kinases Lipid Metabolism Mice Inbred C57BL 030104 developmental biology lcsh:Biology (General) lcsh:QD1-999 Gene Expression Regulation islet cells MKP-5 |
| Zdroj: | International Journal of Molecular Sciences International Journal of Molecular Sciences, Vol 21, Iss 7161, p 7161 (2020) Volume 21 Issue 19 |
| ISSN: | 1422-0067 |
| Popis: | Mitogen-activated protein kinase phosphatase-5 (MKP-5) is a regulator of extracellular signaling that is known to regulate lipid metabolism. In this study, we found that obesity caused by a high-fat diet (HFD) decreased the expression of MKP-5 in the pancreas and primary islet cells derived from mice. Then, we further investigated the role of MKP-5 in the protection of islet cells from lipotoxicity by modulating MKP-5 expression. As a critical inducer of lipotoxicity, palmitic acid (PA) was used to treat islet &beta cells. We found that MKP-5 overexpression restored PA-mediated autophagy inhibition in Rin-m5f cells and protected these cells from PA-induced apoptosis and dysfunction. Consistently, a lack of MKP-5 aggravated the adverse effects of lipotoxicity. Islet cells from HFD-fed mice were infected using recombinant adenovirus expressing MKP-5 (Ad-MKP-5), and we found that Ad-MKP-5 was able to alleviate HFD-induced apoptotic protein activation and relieve the HFD-mediated inhibition of functional proteins. Notably, HFD-mediated impairments in autophagic flux were restored by Ad-MKP-5 transduction. Furthermore, the autophagy inhibitor 3-methyladenine (3-MA) was used to treat Rin-m5f cells, confirming that the MKP-5 overexpression suppressed apoptosis, dysfunction, inflammatory response, and oxidative stress induced by PA via improving autophagic signaling. Lastly, employing c-Jun amino-terminal kinas (JNK), P38, or extracellular-regulated kinase (ERK) inhibitors, we established that the JNK and P38 MAPK pathways were involved in the MKP-5-mediated apoptosis, dysfunction, and autophagic inhibition observed in islet &beta cells in response to lipotoxicity. |
| Databáze: | OpenAIRE |
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