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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
4R01DK064989-12
Application #
9040149
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Teff, Karen L
Project Start
2003-09-01
Project End
2018-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
12
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Tsushima, Kensuke; Bugger, Heiko; Wende, Adam R et al. (2018) Mitochondrial Reactive Oxygen Species in Lipotoxic Hearts Induce Post-Translational Modifications of AKAP121, DRP1, and OPA1 That Promote Mitochondrial Fission. Circ Res 122:58-73
Rimer, Jamie M; Lee, Jiyeon; Holley, Christopher L et al. (2018) Long-range function of secreted small nucleolar RNAs that direct 2'-O-methylation. J Biol Chem 293:13284-13296
Goldberg, Ira J; Reue, Karen; Abumrad, Nada A et al. (2018) Deciphering the Role of Lipid Droplets in Cardiovascular Disease: A Report From the 2017 National Heart, Lung, and Blood Institute Workshop. Circulation 138:305-315
Li, Melissa W; Sletten, Arthur C; Lee, Jiyeon et al. (2017) Nuclear export factor 3 regulates localization of small nucleolar RNAs. J Biol Chem 292:20228-20239
Caputa, George; Schaffer, Jean E (2016) RNA Regulation of Lipotoxicity and Metabolic Stress. Diabetes 65:1816-23
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
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

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