Rpl13a small nucleolar RNAs regulate systemic glucose metabolism
Jiyeon Lee, Alexis N. Harris, Christopher L. Holley, Jana Mahadevan, Kelly D. Pyles, Zeno Lavagnino, David E. Scherrer, Hideji Fujiwara, Rohini Sidhu, Jessie Zhang, Stanley Ching-Cheng Huang, David W. Piston, Maria S. Remedi, Fumihiko Urano, Daniel S. Ory, Jean E. Schaffer
Jiyeon Lee, Alexis N. Harris, Christopher L. Holley, Jana Mahadevan, Kelly D. Pyles, Zeno Lavagnino, David E. Scherrer, Hideji Fujiwara, Rohini Sidhu, Jessie Zhang, Stanley Ching-Cheng Huang, David W. Piston, Maria S. Remedi, Fumihiko Urano, Daniel S. Ory, Jean E. Schaffer
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Research Article Endocrinology Metabolism

Rpl13a small nucleolar RNAs regulate systemic glucose metabolism

Abstract

Small nucleolar RNAs (snoRNAs) are non-coding RNAs that form ribonucleoproteins to guide covalent modifications of ribosomal and small nuclear RNAs in the nucleus. Recent studies have also uncovered additional non-canonical roles for snoRNAs. However, the physiological contributions of these small RNAs are largely unknown. Here, we selectively deleted four snoRNAs encoded within the introns of the ribosomal protein L13a (Rpl13a) locus in a mouse model. Loss of Rpl13a snoRNAs altered mitochondrial metabolism and lowered reactive oxygen species tone, leading to increased glucose-stimulated insulin secretion from pancreatic islets and enhanced systemic glucose tolerance. Islets from mice lacking Rpl13a snoRNAs demonstrated blunted oxidative stress responses. Furthermore, these mice were protected against diabetogenic stimuli that cause oxidative stress damage to islets. Our study illuminates a previously unrecognized role for snoRNAs in metabolic regulation.

Authors

Jiyeon Lee, Alexis N. Harris, Christopher L. Holley, Jana Mahadevan, Kelly D. Pyles, Zeno Lavagnino, David E. Scherrer, Hideji Fujiwara, Rohini Sidhu, Jessie Zhang, Stanley Ching-Cheng Huang, David W. Piston, Maria S. Remedi, Fumihiko Urano, Daniel S. Ory, Jean E. Schaffer

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Figure 2

Rpl13a-snoless mice demonstrate lower ROS tone.

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Rpl13a-snoless mice demonstrate lower ROS tone. (A) RT-qPCR-quantified ...
(A) RT-qPCR-quantified expression of Rpl13a snoRNAs and mRNA (relative to Rplp0) in WT and Rpl13a-snoless (–/–) fibroblasts. Mean + SEM for n = 3 independent experiments. (B) Representative Western blot of RPL13a protein in embryos (n = 4 mice/genotype). (C) MitoSOX staining of embryonic fibroblasts. Mean fluorescence of 104 cells/sample (+SEM) for n = 4 independent experiments. (D) DCF staining of embryonic fibroblasts under basal growth conditions and following exposure to 100 μM H2O2 for 10 minutes. n = 3 independent experiments. *P < 0.005 for –/– vs. WT determined by unpaired t test. rel, relative.