Intracellular Insulin and Impaired Autophagy in a Zebrafish model and a Cell Model of Type 2 diabetes
Autor: | Bo Chen, Jing-Pu Zhang, Xiang-Hui Meng |
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Jazyk: | angličtina |
Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Autophagosome Preproinsulin defective autophagy preproinsulin medicine.medical_treatment ATG5 Blotting Western Autophagy-Related Proteins Type 2 diabetes Real-Time Polymerase Chain Reaction Applied Microbiology and Biotechnology 03 medical and health sciences Insulin resistance subcellular localization medicine Autophagy Animals Humans Immunoprecipitation Insulin Protein Precursors Molecular Biology Ecology Evolution Behavior and Systematics Zebrafish Glucose Transporter Type 2 Chemistry Glucose transporter insulin-targeting tissues Cell Biology Hep G2 Cells medicine.disease animal models Cell biology 030104 developmental biology Diabetes Mellitus Type 2 type 2 diabetes Developmental Biology Research Paper |
Zdroj: | International Journal of Biological Sciences |
ISSN: | 1449-2288 |
Popis: | Type 2 diabetes mellitus is characterized by insulin resistance. However, the complete molecular mechanism remains unclear. In this study, zebrafish were fed a long-term high-fat diet to induce type 2 diabetes, which resulted in a higher body weight, body mass index, more lipid vacuoles in liver, increased insulin transcription level in liver, brain and muscle, and high fasting blood glucose in the high-fat diet zebrafish. Oppositely, the transcription levels of insulin substrate-2 and glucose transporter 2 were significantly decreased, indicating insulin signaling pathway and glucose transport impaired in the insulin-targeting tissues. Transcription of the autophagy-related genes, ATG3, ATG4B, ATG5, ATG7, ATG12, and FOXO3, were decreased but autophagy inhibitor gene m-TOR increased, and autophagy-flux was inhibited in liver of the high-fat diet zebrafish. Main of these changes were confirmed in palmitic acid-treated HepG2 cells. Further, in co-immunoprecipitation and subcellular co-localization experiments, the conjunction of preproinsulin with cargo-recognition protein p62 increased, but conjuncts of autophagosome with p62-cargo, lysosomes with p62-cargo, and autolysosomes decreased apparently. Interestingly, lysosomes, autolysosomes and conjuncts of p62-insulin localized at the periphery of palmitic acid-treated cells, the margination of lysosomes may mediate deactivation of proteases activity. These findings suggest that intracellular high-lipid may trigger defective autophagy, defective downstream signaling of insulin and accumulated intracellular preproinsulin, leading to dysregulation of cell homeostasis mechanism, which may be one of reasons involved in insulin-resistance in type 2 diabetes. |
Databáze: | OpenAIRE |
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