Obesity-associated steatotic liver exhibits aberrant or altered sphingolipid composition and preferentially accumulates ceramide species containing long chain fatty acids — Oak Academic Publishing
Research ArticleOpen AccessGoogle Scholar indexed
Obesity-associated steatotic liver exhibits aberrant or altered sphingolipid composition and preferentially accumulates ceramide species containing long chain fatty acids
Department of Biology, University of Waterloo, Waterloo, Canada
,
Department of Biological Sciences, University of Windsor, Windsor, Canada
1 Department of Biology, University of Waterloo, Waterloo, Canada
2 Department of Biological Sciences, University of Windsor, Windsor, Canada
The sphingolipid (SL) signaling pathways are induced by reactive oxygen species and proin-flammatory molecules, which are shown to be upregulated in the obese state. The present work was conducted to determine if an altered SL pathway exists, and contributes to the pathogenesis of hepatic steatosis associated with obesity. Steatotic and non-steatotic livers were procured from Zucker Obese female rats and their lean counterparts in this pre-clinical study, and assessed for enzymes involved in degradation as well as in phos-phorylation of proapoptotic SLs. The expression of enzymes [sphingo-myelinase (SMase), ceramidase, and sphingosine kinase-1 (SK1)] and apoptotic proteins (Bax and Bcl-2) was quantified by ELISA and by Western Blot. Sphingomyelin (SM), ceramide, cera mide-1 phosphate (C1P), sphingosine (SPH), and sphingosine-1-phosphate (S1P) levels were quantified by high-performance liquid chroma-tography (HPLC)-tandem mass spectroscopy (MS). Obese steatotic livers exhibited significantly upregulated ceramidase and down-regulated SK1 and C1P levels (P < 0.05), as well as significantly lower levels of SM and higher levels of ceramide species containing long chain fatty acids, compared to their lean counterparts. These findings demonstrate that obese liver harbours SLs that favour a proapoptotic environment. Moreover, accumulation of ceramides containing long chain fatty acids could be involved in the pathogenesis of hepatic steatosis.
Kolesnick, R. (2002) The therapeutic potential of modulating the ceramide/sphingomyelin pathway. Journal of Clinical In-vestigation, 110, 3-8. doi:10.1172/JCI200216127
Merrill Jr., A.H. (2002) De novo sphingolipid biosynthesis: A necessary, but dangerous, pathway. Journal of Bio- logical Chemistry, 277, 25843-25846. doi:10.1074/jbc.R200009200
Ogretmen, B. and Hannun, Y.A. (2004) Biologically active sphingolipids in cancer pa-thogenesis and treatment. Nature Reviews Cancer, 4, 604-616. doi:10.1038/nrc1411
Marchesini, N. and Hannun, Y.A. (2004) Acid and neu- tral sphingomyelinases: roles and me-chanisms of regu- lation. Biochemistry and Cell Biology, 82, 27-44. doi:10.1139/o03-091
Levade, T. and Jaffrezou, J.P. (1999) Signalling sphingo-myelinases: which, where, how and why? Biochimica et Biophysica Actaolecular and Cell Biology of Lipids, 1438, 1-17. doi:10.1016/S1388-1981(99)00038-4
Perry, D.K. and Hannun, Y.A. (1998) The role of ceramide in cell signaling. Biochimica et Biophysica Acta—Mole- cular and Cell Biology of Lipids, 1436, 233-243. doi:10.1016/S0005-2760(98)00145-3
Xu, R., Jin, J., Hu, W., Sun, W., Bielawski, J., Szulc, Z., Taha, T., Obeid, L.M. and Mao, C. (2006) Golgi alkaline ceramidase regulates cell proliferation and survival by controlling levels of sphingosine and S1P. Journal of the Federation of American Societies of Experimental Biology, 20, 1813-1825. doi:10.1096/fj.05-5689com
Formiguera, X. and Canton, A. (2004) Obesity: Epidemiology and clinical aspects. Best Practice and Research Clinical Gastroenterology, 18, 1125-1146. doi:10.1016/S1521-6918(04)00091-5
Samad, F., Hester, K.D., Yang, G., Hannun, Y.A. and Bielawski, J. (2006) Altered adipose and plasma sphingo- lipid metabolism in obesity: a potential mechanism for cardiovascular and metabolic risk. Diabetes, 55, 2579- 2587. doi:10.2337/db06-0330
Pi-Sunyer, F.X. (2002) The obes-ity epidemic: Pathophy- siology and consequences of obesity. Obesity Research, 10, 97S-104S. doi:10.1038/oby.2002.202
Kushner, R.F. (2002) Medical management of obesity. Seminars in Gastrointestinal Disease, 13, 123-132.
Lee, Y.H. and Pratley, R.E. (2005) The evolving role of inflammation in obesity and the metabolic syndrome. Current Diabetes Reports, 5, 70-75. doi:10.1007/s11892-005-0071-7
Zucker, T.F. and Zucker, L.M. (1962) Hereditary obesity in the rat associated with high serum fat and cholesterol. Proceedings of the Society for Experimental Biology and Medicine Society for Experimental Biology and Medicine, 110, 165-171.
Bray, G.A. (1977) The Zucker-fatty rat: A review. Fede- ration Proceedings, 36, 148-153.
McCaleb, M.L. and Sredy, J. (1992) Metabolic abnorma- lities of the hyperglycemic obese Zucker rat. Meta-bolism, 41, 522-525. doi:10.1016/0026-0495(92)90212-S
Raju, J., Bajaj, G., Chrusch, J. and Bird, R.P. (2006) Obese state leads to elevated levels of TGF-β and COX isoforms in platelets of Zucker rats. Molecular and Cel- lular Biochemistry, 284, 19-24. doi:10.1007/s11010-005-9008-3
Raju, J. and Bird, R.P. (2006) Alleviation of hepatic stea- tosis accompanied by mod-ulation of plasma and liver TNF-α levels by Trigonella foenum graecum (Fenugreek) seeds in Zucker obese (fa/fa) rats. Inter-national Journal of Obesity, 30, 1298-1307. doi:10.1038/sj.ijo.0803254
Jain, S.S. and Bird, R.P. (2010) Elevated expression of tumor necrosis factor-α signaling mole-cules in colonic tumors of Zucker obese (fa/fa) rats. Interna-tional Journal of Cancer, 127, 2042-2050. doi:10.1002/ijc.25232
Jain, S.S., AshokKumar, M. and Bird, R.P. (2011) Dif- ferential expression of TNF-α signaling molecules and ERK1 in distal and proximal colonic tumors associated with obesity. Tumor Biology, 32, 1005-1012. doi:10.1007/s13277-011-0202-5
Bielawski, J., Szulc, Z.M., Hannun, Y.A. and Bielawska, A. (2006) Simultaneous quantitative analysis of bioactive sphingolipids by high-performance liquid chromatographytandem mass spec-trometry. Methods, 39, 82-91. doi:10.1016/j.ymeth.2006.05.004
Chanussot, F., Ulmer, M., Ratanasavanh, R., Max, J.P., and Debry, G. (1984) Influ-ence of diet composition on obesity, hyperlipemia and liver steatosis in Zucker fa/fa rats pair-fed with Zucker Fa/rats. In-ternational Journal of Obesity, 8, 259-270.
Angulo, P. (2002) Nonalcoholic fatty liver disease. New England Journal of Medicine, 346, 1221-1231. doi:10.1056/NEJMra011775
Wellen, K.E. and Thompson, C.B. (2010) Cellular meta- bolic stress: Considering how cells respond to nutrient excess. Molecular Cell, 40, 323-332. doi:10.1016/j.molcel.2010.10.004
Chitturi, S. and Farrell, G.C. (2001) Etiopathogenesis of nonalcoholic steatohepatitis. Seminars in Liver Disease, 21, 27-41. doi:10.1055/s-2001-12927
Woodcock, J. (2006) Sphingo-sine and ceramide signaling in apoptosis. International Union of Biochemistry and Molecular Biology Life, 58, 462-466. doi:10.1080/15216540600871118
Ogretmen, B. (2006) Sphingolipids in cancer: Regulation of pathogenesis and therapy. Federation of European Biochemical Societies Letters, 580, 5467-5476. doi:10.1016/j.febslet.2006.08.052
Yetukuri, L., Katajamaa, M., Medina-Gomez, G., Seppa- nen-Laakso, T., Vidal-Puig, A. and Oresic, M. (2007) Bio- informatics strategies for lipidomics analysis: Characteri- zation of obesity related hepatic steatosis. BMC Systems Biology, 1, 12. doi:10.1186/1752-0509-1-12
Suzuki, E., Handa, K., To-ledo, M.S. and Hakomori, S. (2004) Sphingosine-dependent apoptosis: A unified con- cept based on multiple mechanisms operating in concert. Proceedings of the National Academy of Sciences of the United States of America, 101, 14788-14793. doi:10.1073/pnas.0406536101
Strelow, A., Bernardo, K., dam-Klages, S., Linke, T., Sandhoff, K., Kronke, M. and Adam, D. (2000) Overex- pression of acid ceramidase protects from tumor necrosis factor-induced cell death. Journal of Experi-mental Medi- cine, 192, 601-612. doi:10.1084/jem.192.5.601
Fyrst, H. and Saba, J.D. (2008) Sphingosine-1-phosphate lyase in development and disease: Sphingolipid metabo- lism takes flight. Biochimica et Biophysica Acta—Mole- cular and Cell Biology of Lipids, 1781, 448-458. doi:10.1016/j.bbalip.2008.05.005
Olivera, A., Edsall, L., Poulton, S., Kazlauskas, A. and Spiegel, S. (1999) Plate-let-derived growth factor-induced activation of sphingosine kinase requires phosphorylation of the PDGF receptor tyrosine residue responsible for binding of PLCγ. Journal of the Federation of American Societies for Experimental Biology, 13, 1593-1600. http://www.fasebj.org/content/13/12/1593.full
Olivera, A., Kohama, T., Edsall, L., Nava, V., Cuvillier, O., Poulton, S. and Spiegel, S. (1999) Sphingosine kinase expression increases intracellular sphingosine-1-phosphate and promotes cell growth and survival. Journal of Cell Biology, 147, 545-558. doi:10.1083/jcb.147.3.545
Xin, M. and Deng, X. (2006) Protein phosphatase 2A enhances the proapoptotic function of Bax through dephosphorylation. Journal of Biological Chemistry, 281, 18859- 18867. doi:10.1074/jbc.M512543200
Ruvolo, P.P. (2003) Intra-cellular signal transduction pathways activated by ceramide and its metabolites. Pharmacological Research, 47, 383-392. doi:10.1016/S1043-6618(03)00050-1
Gross, A., Jockel, J., Wei, M.C. and Korsmeyer, S.J. (1998) Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis. Euro- pean Molecular Biology Organization (EMBO) Journal, 17, 3878-3885. doi:10.1093/emboj/17.14.3878
Canbay, A., Gieseler, R.K., Gores, G.J. and Gerken, G. (2005) The relationship between apoptosis and non-alcoholic fatty liver disease: An evolutionary cornerstone turned pathogenic. Zeitschrift für Gastroenterologie, 43, 211-217. doi:10.1055/s-2004-813744.