Department of biochemistry and Molecular biology
L. Ashley Cowart, PhD
Biochemistry and Molecular Biology
2005 Research Health Scientist, Ralph H. Johnson VA Medical Center
2001-2005 Postdoctoral Fellowship, Dr. Yusuf Hannun, Biochemistry, MUSC
2001 Ph.D., Biochemistry, Vanderbilt University
1995 B.S., Biology, Furman University
Office: 512-D Basic Sciences Building
Lab: 513 Basic Sciences Building
Our laboratory studies how plasma lipids affect tissue sphingolipid metabolism. This is important because obesity and diabetes increase plasma lipid concentrations, and this increase has been demonstrated to change sphingolipid profiles in tissues including adipose, liver, skeletal muscle, and heart. In fact, elevation of plasma lipids probably contributes to pathologies observed in these tissues from diabetic patients. We hypothesize that aberrant sphingolipid synthesis promotes tissue pathologies including inflammation, muscle wasting, and cardiac hypertrophy. To address this hypothesis we use a combination of tissue culture and rodent models. Placing rodents on a high-fat diet increases plasma fatty acids and dramatically impacts tissue sphingolipids. These changes precipitate major changes in gene regulation and signaling pathways. We have dissected some of these changes using microarrays, and with collaborators in the department of Biostatistics, Bioinformatics, and Epidemiology, we also are actively developing novel bioinformatics strategies for co-analysis of gene expression data from microarrays and sphingolipid levels from lipidomics analysis. These strategies have allowed us to find “needles” in the “haystack” of lipid-mediated cell signaling.
Recent Publications | Additional Publications
Khakhina S, Johnson SS, Manoharlal R, Russo SB, Blugeon C, Lemoine S, Sunshine AB, Dunham MJ, Cowart LA, Devaux F, Moye-Rowley WS. Control of plasma membrane permeability by ABC transporters. Eukaryot Cell. 2015 May;14(5):442-53. PMID: 25724885
Jaishy B, Zhang Q, Chung HS, Riehle C, Soto J, Jenkins S, Abel P, Cowart LA, Van Eyk JE, Abel ED. Lipid-induced NOX2 activation inhibits autophagic flux by impairing lysosomal enzyme activity. J Lipid Res. 2015 Mar;56(3):546-61. doi: PMID: 25529920
Rachidi S, Sun S, Wu BX, Jones E, Drake RR, Ogretmen B, Cowart LA, Clarke CJ, Hannun YA, Chiosis G, Liu B, Li Z. Endoplasmic reticulum heat shock protein gp96 maintains liver homeostasis and promotes hepatocellular carcinogenesis. J Hepatol. 2015 Apr;62(4):879-88. PMID: 25463537
Jin J, Zhang X, Lu Z, Perry DM, Li Y, Russo SB, Cowart LA, Hannun YA, Huang Y. Acid sphingomyelinase plays a key role in palmitic acid-amplified inflammatory signaling triggered by lipopolysaccharide at low concentrations in macrophages. Am J Physiol Endocrinol Metab. 2013 Oct 1;305(7):E853-67. PMID: 23921144
Geng T, Hu W, Broadwater MH, Snider JM, Bielawski J, Russo SB, Schwacke JH, Ross J, Cowart LA. Fatty acids differentially regulate insulin resistance through endoplasm reticulum stress-mediated induction of tribbles homologue 3: a potential link between dietary fat composition and the pathophysiological outcomes of obesity. Diabetologia. 2013 Sep;56(9):2078-87. doi: 10.1007/s00125-013-2973-2. Epub 2013 Jul 3.
Ross JS, Hu W, Rosen B, Snider AJ, Obeid LM, Cowart LA. Sphingosine kinase 1 is regulated by peroxisome proliferator-activated receptor α in response to free fatty acids and is essential for skeletal muscle interleukin-6 production and signaling in diet-induced obesity. J Biol Chem. 2013 Aug 2;288(31):22193-206. doi: 10.1074/jbc.M113.477786. Epub 2013 Jun 13.
Russo SB, Ross JS, Cowart LA. Sphingolipids in obesity, type 2 diabetes, and metabolic disease. Handb Exp Pharmacol. 2013;(216):373-401. doi: 10.1007/978-3-7091-1511-4-19. Review.
Russo SB, Tidhar R, Futerman AH, Cowart LA. Myristate-derived d16:0 sphingolipids constitute a cardiac sphingolipid pool with distinct synthetic routes and functional properties. J Biol Chem. 2013 May 10;288(19):13397-409. doi: 10.1074/jbc.M112.428185. Epub 2013 Mar 25.
Russo SB, Baicu CF, Van Laer A, Geng T, Kasiganesan H, Zile MR, Cowart LA. Ceramide synthase 5 mediates lipid-induced autophagy and hypertrophy in cardiomyocytes. J Clin Invest. 2012 Nov 1;122(11):3919-30.
Montefusco DJ, Newcomb B, Gandy JL, Brice SE, Matmati N, Cowart LA, Hannun YA. Sphingoid bases and the serine catabolic enzyme CHA1 define a novel feedforward/feedback mechanism in the response to serine availability. J Biol Chem. 2012 287(12):9280-9. Epub 2012 Jan 25. PMID: 22277656.
Brice SE, Cowart LA. Sphingolipid metabolism and analysis in metabolic disease. Adv Exp Med Biol. 2011 721:1-17. Review. PMID: 21910079c
Hu W, Ross J, Geng T, Brice SE, Cowart LA. Differential regulation of dihydroceramide desaturase by palmitate versus monounsaturated fatty acids: implications for insulin resistance. J Biol Chem. 2011 286(19):16596-605. Epub 2011 Mar 15. PMID: 2145453
Johnson SS, Hanson PK, Manoharlal R, Brice SE, Cowart LA, Moye-Rowley WS. Regulation of yeast nutrient permease endocytosis by ATP-binding cassette transporters and a seven-transmembrane protein, RSB1. J Biol Chem. 2010 285(46):35792-802. Epub 2010 Sep 8. PMID: 20826817.
Cowart LA, Gandy JL, Tholanikunnel B, Hannun YA. Sphingolipids mediate formation of mRNA processing bodies during the heat-stress response of Saccharomyces cerevisiae. Biochem J. 2010 431(1):31-8. PMID: 20629639.
Cowart LA. A novel role for sphingolipid metabolism in oxidant-mediated skeletal muscle fatigue. Focus on "Sphingomyelinase stimulates oxidant signaling to weaken skeletal muscle and promote fatigue". Am J Physiol Cell Physiol. 2010 299(3):C549-51. Epub 2010 Jun 23. PMID: 2057399
Richards AJ, Muller B, Shotwell M, Cowart LA, Rohrer B, Lu X. Assessing the functional coherence of gene sets with metrics based on the Gene Ontology graph. Bioinformatics. 2010 26(12):i79-87. PMID: 20529941.
Cowart LA, Shotwell M, Worley ML, Richards AJ, Montefusco DJ, Hannun YA, Lu X. Revealing a signaling role of phytosphingosine-1-phosphate in yeast. Mol Syst Biol. 2010 6:349. Epub 2010 Feb 16. PMID: 20160710.
Hu W, Bielawski J, Samad F, Merrill AH Jr, Cowart LA. Palmitate increases sphingosine-1-phosphate in C2C12 myotubes via upregulation of sphingosine kinase message and activity. J Lipid Res. 2009 50(9):1852-62. Epub 2009 Apr 15. PMID: 19369694.
Kitagaki H, Cowart LA, Matmati N, Montefusco D, Gandy J, de Avalos SV, Novgorodov SA, Zheng J, Obeid LM, Hannun YA. ISC1-dependent metabolic adaptation reveals an indispensable role for mitochondria in induction of nuclear genes during the diauxic shift in Saccharomyces cerevisiae. J Biol Chem. 2009 284(16):10818-30. Epub 2009 Jan 29. PMID: 19179331.
Brice SE, Alford CW, Cowart LA. Modulation of sphingolipid metabolism by the phosphatidylinositol-4-phosphate phosphatase Sac1p through regulation of phosphatidylinositol in Saccharomyces cerevisiae. J Biol Chem. 2009 284(12):7588-96. Epub 2009 Jan 12. PMID: 19139096.