RNA-binding protein DDX1 is responsible for fatty acid-mediated repression of insulin translation
| Autor: | Dongwan Cheng, Wen Zhong, Tao Xu, Junjie Hou, Qiang Hao, Maoge Zhou, Zhaokui Cai, Hongyang Liu, Zonghong Li, Xihao Hu, Yifa Zhou, Yuanchao Xue, Pingyong Xu |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty medicine.medical_treatment Palmitates Mice Obese Fatty Acids Nonesterified Biology Carbohydrate metabolism DEAD-box RNA Helicases Islets of Langerhans Mice 03 medical and health sciences 0302 clinical medicine Eukaryotic translation Insulin resistance Insulin-Secreting Cells Internal medicine RNA and RNA-protein complexes Genetics medicine Protein biosynthesis Animals Insulin RNA Messenger Phosphorylation RNA Small Interfering EIF4B Gene knockdown Fatty Acids RNA-Binding Proteins Translation (biology) Oligonucleotides Antisense medicine.disease Rats Mice Inbred C57BL Glucose 030104 developmental biology Endocrinology Gene Knockdown Techniques Protein Biosynthesis 030220 oncology & carcinogenesis Protein Binding Signal Transduction |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| DOI: | 10.1093/nar/gky867 |
| Popis: | The molecular mechanism in pancreatic β cells underlying hyperlipidemia and insulin insufficiency remains unclear. Here, we find that the fatty acid-induced decrease in insulin levels occurs due to a decrease in insulin translation. Since regulation at the translational level is generally mediated through RNA-binding proteins, using RNA antisense purification coupled with mass spectrometry, we identify a novel insulin mRNA-binding protein, namely, DDX1, that is sensitive to palmitate treatment. Notably, the knockdown or overexpression of DDX1 affects insulin translation, and the knockdown of DDX1 eliminates the palmitate-induced repression of insulin translation. Molecular mechanism studies show that palmitate treatment causes DDX1 phosphorylation at S295 and dissociates DDX1 from insulin mRNA, thereby leading to the suppression of insulin translation. In addition, DDX1 may interact with the translation initiation factors eIF3A and eIF4B to regulate translation. In high-fat diet mice, the inhibition of insulin translation happens at an early prediabetic stage before the elevation of glucose levels. We speculate that the DDX1-mediated repression of insulin translation worsens the situation of insulin resistance and contributes to the elevation of blood glucose levels in obese animals. |
| Databáze: | OpenAIRE |
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