RNA-binding protein DDX1 is responsible for fatty acid-mediated repression of insulin translation.

Abstract

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.

• Authors: Zonghong Li, Maoge Zhou, Zhaokui Cai, Hongyang Liu, Wen Zhong, Qiang Hao, Dongwan Cheng, Xihao Hu, Junjie Hou, Pingyong Xu, Yuanchao Xue, Yifa Zhou, Tao Xu
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 46 Issue 22 Pg. 12052-12066 (12 14 2018) ISSN: 1362-4962 [Electronic] England
• PMID: 30295850 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fatty Acids
• Fatty Acids, Nonesterified
• Insulin
• Oligonucleotides, Antisense
• Palmitates
• RNA, Messenger
• RNA, Small Interfering
• RNA-Binding Proteins
• DDX1 protein, mouse
• Ddx1 protein, rat
• DEAD-box RNA Helicases
• Glucose

Topics

• Animals
• DEAD-box RNA Helicases (metabolism)
• Fatty Acids (metabolism)
• Fatty Acids, Nonesterified (metabolism)
• Gene Knockdown Techniques
• Glucose (metabolism)
• Insulin (metabolism)
• Insulin-Secreting Cells (metabolism)
• Islets of Langerhans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Obese
• Oligonucleotides, Antisense (genetics)
• Palmitates (metabolism)
• Phosphorylation
• Protein Binding
• Protein Biosynthesis
• RNA, Messenger (metabolism)
• RNA, Small Interfering (genetics)
• RNA-Binding Proteins (metabolism)
• Rats
• Signal Transduction