Identification of Genes that Regulate Multiple Cellular Processes/Responses in the Context of Lipotoxicity to Hepatoma Cells

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dc.contributor.author Srivastava, Shireesh en_US
dc.contributor.author Li, Zheng en_US
dc.contributor.author Yang, Xuerui en_US
dc.contributor.author Yedwabnick, Matthew en_US
dc.contributor.author Shaw, Stephen en_US
dc.contributor.author Chan, Christina en_US
dc.date.accessioned 2011-12-29T22:56:30Z
dc.date.available 2011-12-29T22:56:30Z
dc.date.copyright 2007 en_US
dc.date.issued 2007-10-9 en_US
dc.identifier.citation Srivastava, Shireesh, Zheng Li, Xuerui Yang, Matthew Yedwabnick, Stephen Shaw, Christina Chan. "Identification of genes that regulate multiple cellular processes/responses in the context of lipotoxicity to hepatoma cells." BMC Genomics 8:364. (2007) en_US
dc.identifier.issn 1471-2164 en_US
dc.identifier.uri http://hdl.handle.net/2144/2623
dc.description.abstract BACKGROUND: In order to devise efficient treatments for complex, multi-factorial diseases, it is important to identify the genes which regulate multiple cellular processes. Exposure to elevated levels of free fatty acids (FFAs) and tumor necrosis factor alpha (TNF-α) alters multiple cellular processes, causing lipotoxicity. Intracellular lipid accumulation has been shown to reduce the lipotoxicity of saturated FFA. We hypothesized that the genes which simultaneously regulate lipid accumulation as well as cytotoxicity may provide better targets to counter lipotoxicity of saturated FFA. RESULTS: As a model system to test this hypothesis, human hepatoblastoma cells (HepG2) were exposed to elevated physiological levels of FFAs and TNF-α. Triglyceride (TG) accumulation, toxicity and the genomic responses to the treatments were measured. Here, we present a framework to identify such genes in the context of lipotoxicity. The aim of the current study is to identify the genes that could be altered to treat or ameliorate the cellular responses affected by a complex disease rather than to identify the causal genes. Genes that regulate the TG accumulation, cytotoxicity or both were identified by a modified genetic algorithm partial least squares (GA/PLS) analysis. The analyses identified NADH dehydrogenase and mitogen activated protein kinases (MAPKs) as important regulators of both cytotoxicity and lipid accumulation in response to FFA and TNF-α exposure. In agreement with the predictions, inhibiting NADH dehydrogenase and c-Jun N-terminal kinase (JNK) reduced cytotoxicity significantly and increased intracellular TG accumulation. Inhibiting another MAPK pathway, the extracellular signal regulated kinase (ERK), on the other hand, improved the cytotoxicity without changing TG accumulation. Much greater reduction in the toxicity was observed upon inhibiting the NADH dehydrogenase and MAPK (which were identified by the dual-response analysis), than for the stearoyl-CoA desaturase (SCD) activation (which was identified for the TG-alone analysis). CONCLUSION: These results demonstrate the applicability of GA/PLS in identifying the genes that regulate multiple cellular responses of interest and that genes regulating multiple cellular responses may be better candidates for countering complex diseases. en_US
dc.description.sponsorship National Institute of Health (IR01GM079688-01, IR21CA126136-01); National Science Foundation (BES 0331297, 0425821); Environmental Protection Agency (RD83184701); Whitaker Foundation; Michigan State University Foundation; Center for Systems Biology en_US
dc.language.iso en en_US
dc.publisher BioMed Central en_US
dc.rights Copyright 2007 Srivastava et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution 2.0 License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. en_US
dc.rights.uri http://creativecommons.org/licenses/by/2.0 en_US
dc.title Identification of Genes that Regulate Multiple Cellular Processes/Responses in the Context of Lipotoxicity to Hepatoma Cells en_US
dc.type article en_US
dc.identifier.doi 10.1186/1471-2164-8-364 en_US
dc.identifier.pubmedid 17925029 en_US
dc.identifier.pmcid 2110894 en_US

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