Although excess lipid accumulation in non-adipose tissues is initially well tolerated, this metabolic excess ultimately causes cell dysfunction and cell death that is linked to the pathogenesis of complications of diabetes and obesity. Using a genetic screen, we discovered that RNASET2, a T2 endoribonuclease, is a critical mediator of oxidative stress damage and cell death in response to lipotoxicity. This study will elucidate the mechanism of action of RNASET2, by identifying the RNAs that this enzyme degrades, by elucidating the pathways through which RNA substrates are delivered to RNASET2, and by examining the contributions of RNASET2 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 complications that arise from deposition of excess fats in tissues such as the heart. The studies proposed in this application will characterize how excess fat leads to dysfunction and death of cells. We will extend our findings to models of diabetic heart disease to understand how this process affects heart muscle function. Given the prevalence, morbidity, and mortality of heart failure in patients with diabetes, 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 #
5R01DK064989-15
Application #
9647443
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Teff, Karen L
Project Start
2003-09-01
Project End
2022-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
15
Fiscal Year
2019
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
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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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