Excess lipid accumulation in non-adipose tissues is associated with cellular dysfunction and cell death that may contribute to the pathogenesis of insulin resistance, non-alcoholic steatohepatitis, and cardiomyopathy in diabetes and obesity. Mechanisms involved in these pathophysiological responses have been studied in cultured cells by supplementation of growth media with high concentrations of free fatty acids. The saturated fatty acid, palmitate, leads to apoptosis in cultured cells by a mechanism involving oxidative and endoplasmic reticulum stress. This proposal will test the hypothesis that cells with gene disruptions that prevent lipotoxic cell death may have defects in fatty acid import, in fatty acid channeling, in lipid-induced oxidative stress, or in the response to perturbations of endoplasmic reticulum structure and function. Our first two aims will employ biochemical and genetic approaches in cultured cells to identify molecular targets and signaling pathways in the lipotoxic response. In our third aim, we will translate our findings to mouse models relevant to diabetic cardiovascular disease, in which lipid accumulation in cardiomyocytes is associated with heart failure. The results of these studies will provide new insights into the lipotoxic response to excess lipid accumulation in non-adipose tissues in diabetes and obesity.

Public Health Relevance

Heart failure is a serious medical complication of obesity and diabetes that is linked to alterations in fat metabolism in the heart. The studies proposed in this application will characterize how excess fat leads to dysfunction and death of cells and extend these findings to genetically modified mouse models of diabetes and obesity to understand how these mechanisms affect heart muscle function. Given the prevalence of heart failure in diabetic and obese 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 #
3R01DK064989-07S1
Application #
8289804
Study Section
Special Emphasis Panel (ZRG1-EMNR-B (03))
Program Officer
Laughlin, Maren R
Project Start
2003-09-01
Project End
2013-03-31
Budget Start
2011-07-01
Budget End
2012-03-31
Support Year
7
Fiscal Year
2011
Total Cost
$43,700
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

Showing the most recent 10 out of 23 publications