A hierarchical approach employing metabolic and gene expression profiles to identify the pathways that confer cytotoxicity in HepG2 cells

Zheng Li, Shireesh Srivastava, Xuerui Yang, Sheenu Mittal, Paul Norton, James Resau, Brian Haab, Christina Chan

    Research output: Contribution to journalArticle

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    Abstract

    Background: Free fatty acids (FFA) and tumor necrosis factor alpha (TNF-α) have been implicated in the pathogenesis of many obesity-related metabolic disorders. When human hepatoblastoma cells (HepG2) were exposed to different types of FFA and TNF-α, saturated fatty acid was found to be cytotoxic and its toxicity was exacerbated by TNF-α. In order to identify the processes associated with the toxicity of saturated FFA and TNF-α, the metabolic and gene expression profiles were measured to characterize the cellular states. A computational model was developed to integrate these disparate data to reveal the underlying pathways and mechanisms involved in saturated fatty acid toxicity. Results: A hierarchical framework consisting of three stages was developed to identify the processes and genes that regulate the toxicity. First, discriminant analysis identified that fatty acid oxidation and intracellular triglyceride accumulation were the most relevant in differentiating the cytotoxic phenotype. Second, gene set enrichment analysis (GSEA) was applied to the cDNA microarray data to identify the transcriptionally altered pathways and processes. Finally, the genes and gene sets that regulate the metabolic responses identified in step 1 were identified by integrating the expression of the enriched gene sets and the metabolic profiles with a multi-block partial least squares (MBPLS) regression model. Conclusion: The hierarchical approach suggested potential mechanisms involved in mediating the cytotoxic and cytoprotective pathways, as well as identified novel targets, such as NADH dehydrogenases, aldehyde dehydrogenases 1A1 (ALDH1A1) and endothelial membrane protein 3 (EMP3) as modulator of the toxic phenotypes. These predictions, as well as, some specific targets that were suggested by the analysis were experimentally validated.

    Original languageEnglish (US)
    Article number21
    JournalBMC Systems Biology
    Volume1
    DOIs
    StatePublished - May 11 2007

    Profile

    Hep G2 Cells
    Transcriptome
    Tumor Necrosis Factor-alpha
    Fatty acids
    Genes
    Tumor necrosis factor
    Gene
    Fatty Acids
    Toxicity
    Pathway
    Nonesterified Fatty Acids
    Phenotype
    Saturated fatty acids
    Gene expression
    Gene expression profile
    Target
    Cell
    Hepatoblastoma
    NADH Dehydrogenase
    Aldehyde Dehydrogenase

    ASJC Scopus subject areas

    • Molecular Biology
    • Structural Biology
    • Applied Mathematics
    • Modeling and Simulation
    • Computer Science Applications

    Cite this

    A hierarchical approach employing metabolic and gene expression profiles to identify the pathways that confer cytotoxicity in HepG2 cells. / Li, Zheng; Srivastava, Shireesh; Yang, Xuerui; Mittal, Sheenu; Norton, Paul; Resau, James; Haab, Brian; Chan, Christina.

    In: BMC Systems Biology, Vol. 1, 21, 11.05.2007.

    Research output: Contribution to journalArticle

    Li, Zheng; Srivastava, Shireesh; Yang, Xuerui; Mittal, Sheenu; Norton, Paul; Resau, James; Haab, Brian; Chan, Christina / A hierarchical approach employing metabolic and gene expression profiles to identify the pathways that confer cytotoxicity in HepG2 cells.

    In: BMC Systems Biology, Vol. 1, 21, 11.05.2007.

    Research output: Contribution to journalArticle

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