: Diabetics are at increased risk of heart disease from several factors including geometric and functional changes that occur independently of other risk factor; this is termed 'diabetic cardiomyopathy'. Mechanisms of this disease are not completely understood, but data increasingly support the notion that aberrant lipid metabolism contributes to this disease process. Among these metabolic changes are perturbations in sphingolipid synthesis; others and we have shown that blocking sphingolipid synthesis ameliorates many facets of diabetic cardiomyopathy. Sphingolipid metabolism comprises numerous enzymes, pathways, and products; teasing apart specific sphingolipids that mediate a specific process has proven challenging. Moreover, mechanisms by which these processes occur have been difficult to determine. We recently published that a specific enzyme of sphingolipid synthesis, Ceramide Synthase 5 (CerS5), mediated lipid- induced cardiomyocyte hypertrophy and autophagy. In a high saturated-fat feeding model in mice, which caused insulin resistance and obesity, sphingolipid biosynthesis was perturbed in heart. We observed sphingolipid-dependent cell hypertrophy, autophagy, and most importantly, cardiac dysfunction. New preliminary data implicate sphingolipids in mitochondrial damage and mitophagy, and also shed light on molecular mechanisms by which CerS5 causes autophagy. We have observed 1-nuclear accumulation of CerS5 and its product C14-ceramide, 2-CerS5-dependent accumulation of p53 in the nucleus, and 3- sphingolipid-dependent loss of mitochondrial reserve, and increase in mitophagy. Here we propose to dissect mechanisms for DbCM based on these initial findings, and using a combination of strategies including in vivo determinations o diastolic dysfunction in mice lacking CerS5, components of the mitophagy pathway, components of the macroautophagy pathway. As evidenced by our recent publications (Russo et al. 2012, J. Clin. Invest.; Russo et al 2013, J. Biol. Chem.), we are highly suited to address these questions that lie at the interface of sphingolipid biochemistry and cardiology. To facilitat this highly translational work we have enlisted cardiology and metabolism experts to complement our expertise in sphingolipid biochemistry, signaling, and analysis. These studies will reveal roles of these cell processes in diabetic cardiomyopathy, address the controversy surrounding the nature of autophagy in cardiac injury, specifically whether it is adaptive or deleterious, provide insights into sphingolipid-dependent mitochondrial dysfunction, which is especially important in the diabetic context, and finally reveal cell, biochemical, and molecular mechanisms of sphingolipid-dependent lipotoxicity in the heart.

Public Health Relevance

Diabetics have a higher risk of heart failure than healthy individuals, and this is attributable to multiple factors including changes in heart geometry and function that occur independently of other risk factors. Mechanisms for this are thought to include toxic effects of lipid oversupply to cardiomyocytes, and the sphingolipid ceramide has been implicated by numerous groups to be involved in these processes. We have recently discovered that a distinct ceramide biosynthesis pathway mediates cardiomyocyte hypertrophy and autophagy, and this proposal will further our mechanistic understanding of this process, with the ultimate goal of identifying molecular pathways that might be targeted to improve cardiac function in diabetics.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL117233-05
Application #
9634368
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Buxton, Denis B
Project Start
2014-08-18
Project End
2019-05-31
Budget Start
2018-02-05
Budget End
2018-05-31
Support Year
5
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Montefusco, David J; Allegood, Jeremy C; Spiegel, Sarah et al. (2018) Non-alcoholic fatty liver disease: Insights from sphingolipidomics. Biochem Biophys Res Commun 504:608-616
Law, Brittany A; Liao, Xianghai; Moore, Kelsey S et al. (2018) Lipotoxic very-long-chain ceramides cause mitochondrial dysfunction, oxidative stress, and cell death in cardiomyocytes. FASEB J 32:1403-1416
Xiong, Y; Russell, D L; McDonald, L T et al. (2017) Hematopoietic Stem Cell-derived Adipocytes Promote Tumor Growth and Cancer Cell Migration. Int J Cancer Res Mol Mech 3:
Jadhav, Shyamalagauri; Russo, Sarah; Cowart, L Ashley et al. (2017) Inositol Depletion Induced by Acute Treatment of the Bipolar Disorder Drug Valproate Increases Levels of Phytosphingosine. J Biol Chem 292:4953-4959
Sutter, Alton G; Palanisamy, Arun P; Lench, Julie H et al. (2016) Dietary Saturated Fat Promotes Development of Hepatic Inflammation Through Toll-Like Receptor 4 in Mice. J Cell Biochem 117:1613-21
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Jadhav, Shyamalagauri; Russo, Sarah; Cottier, Stéphanie et al. (2016) Valproate Induces the Unfolded Protein Response by Increasing Ceramide Levels. J Biol Chem 291:22253-22261
Rachidi, Saleh; Sun, Shaoli; Wu, Bill X et al. (2015) Endoplasmic reticulum heat shock protein gp96 maintains liver homeostasis and promotes hepatocellular carcinogenesis. J Hepatol 62:879-88
Khakhina, Svetlana; Johnson, Soraya S; Manoharlal, Raman et al. (2015) Control of Plasma Membrane Permeability by ABC Transporters. Eukaryot Cell 14:442-53
Geng, Tuoyu; Sutter, Alton; Harland, Michael D et al. (2015) SphK1 mediates hepatic inflammation in a mouse model of NASH induced by high saturated fat feeding and initiates proinflammatory signaling in hepatocytes. J Lipid Res 56:2359-71

Showing the most recent 10 out of 13 publications