Identification of genes that regulate multiple cellular processes/ responses in the context of lipotoxicity to hepatoma cells

Shireesh Srivastava, Zheng Li, Xuerui Yang, Matthew Yedwabnick, Stephen Shaw, Christina Chan

    Research output: Research - peer-reviewArticle

    • 9 Citations

    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.

    LanguageEnglish (US)
    Article number364
    JournalBMC Genomics
    Volume8
    DOIs
    StatePublished - Oct 9 2007

    Profile

    Hepatocellular Carcinoma
    Genes
    Nonesterified Fatty Acids
    Triglycerides
    Tumor Necrosis Factor-alpha
    NADH Dehydrogenase
    Mitogen-Activated Protein Kinases
    Lipids
    Least-Squares Analysis
    Fatty Acids
    Stearoyl-CoA Desaturase
    Hepatoblastoma
    JNK Mitogen-Activated Protein Kinases
    Lipoma
    Extracellular Signal-Regulated MAP Kinases
    Hep G2 Cells

    ASJC Scopus subject areas

    • Medicine(all)

    Cite this

    Identification of genes that regulate multiple cellular processes/ responses in the context of lipotoxicity to hepatoma cells. / Srivastava, Shireesh; Li, Zheng; Yang, Xuerui; Yedwabnick, Matthew; Shaw, Stephen; Chan, Christina.

    In: BMC Genomics, Vol. 8, 364, 09.10.2007.

    Research output: Research - peer-reviewArticle

    Srivastava, Shireesh ; Li, Zheng ; Yang, Xuerui ; Yedwabnick, Matthew ; Shaw, Stephen ; Chan, Christina. / Identification of genes that regulate multiple cellular processes/ responses in the context of lipotoxicity to hepatoma cells. In: BMC Genomics. 2007 ; Vol. 8.
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    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.",
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    AU - Shaw,Stephen

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