Excess lipid accumulation in non-adipose tissues is associated with cellular dysfunction and cell death that is linked to the pathogenesis of complications of diabetes and obesity. Using a genetic screen, we have shown that small nucleolar RNAs (snoRNAs) embedded within introns of the ribosomal protein L13a (rpL13a) gene act in mammalian cells through non-canonical mechanisms to serve as critical mediators in the propagation of oxidative stress and cell death in response to lipotoxicity. This study will extend our findings by elucidating the mechanism of action of rpL13a snoRNAs, by characterizing genes that relate to their biogenesis and downstream actions, and by examining their contributions to the pathogenesis of cardiac lipotoxicity in a mouse model. The results of these studies will provide new insights into the lipotoxic response to excess lipid accumulation in cardiovascular complications of metabolic diseases.

Public Health Relevance

Diabetes is associated with serious cardiovascular complications including heart failure. Scientific evidence suggests that blood fat levels play a major role in this complication. The studies proposed in this application will characterize how excess fat leads to dysfunction and death of cells. We will also extend our findings to genetically modified mouse models of diabetic cardiovascular complications to understand how these mechanisms affect heart muscle function. Given the prevalence of heart failure in diabetic patients and its associated morbidity and mortality, further understanding of this disease process will facilitate the development of new treatments and preventative strategies.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-EMNR-P (02))
Program Officer
Pawlyk, Aaron
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
Zip Code
Caputa, G; Zhao, S; Criado, A E G et al. (2016) RNASET2 is required for ROS propagation during oxidative stress-mediated cell death. Cell Death Differ 23:347-57
Caputa, George; Schaffer, Jean E (2016) RNA Regulation of Lipotoxicity and Metabolic Stress. Diabetes 65:1816-23
Lee, Jiyeon; Harris, Alexis N; Holley, Christopher L et al. (2016) Rpl13a small nucleolar RNAs regulate systemic glucose metabolism. J Clin Invest 126:4616-4625
Holley, Christopher L; Li, Melissa W; Scruggs, Benjamin S et al. (2015) Cytosolic accumulation of small nucleolar RNAs (snoRNAs) is dynamically regulated by NADPH oxidase. J Biol Chem 290:11741-8
Jinn, Sarah; Brandis, Katrina A; Ren, Aileen et al. (2015) snoRNA U17 regulates cellular cholesterol trafficking. Cell Metab 21:855-67
Schilling, Joel D; Machkovech, Heather M; He, Li et al. (2013) Palmitate and lipopolysaccharide trigger synergistic ceramide production in primary macrophages. J Biol Chem 288:2923-32
Schilling, Joel D; Machkovech, Heather M; He, Li et al. (2013) TLR4 activation under lipotoxic conditions leads to synergistic macrophage cell death through a TRIF-dependent pathway. J Immunol 190:1285-96
Brandis, Katrina A; Gale, Sarah; Jinn, Sarah et al. (2013) Box C/D small nucleolar RNA (snoRNA) U60 regulates intracellular cholesterol trafficking. J Biol Chem 288:35703-13
Li, Xin; Gonzalez, Oscar; Shen, Xia et al. (2013) Endothelial acyl-CoA synthetase 1 is not required for inflammatory and apoptotic effects of a saturated fatty acid-rich environment. Arterioscler Thromb Vasc Biol 33:232-40
Crawford, Peter A; Schaffer, Jean E (2013) Metabolic stress in the myocardium: adaptations of gene expression. J Mol Cell Cardiol 55:130-8

Showing the most recent 10 out of 16 publications