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.

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

Profile

Cytotoxicity
Gene Expression Profile
Tumor Necrosis Factor
Hep G2 Cells
Fatty Acids
Transcriptome
Gene expression
Pathway
Fatty acids
Tumor Necrosis Factor-alpha
Genes
Toxicity
Nonesterified Fatty Acids
Gene
Saturated fatty acids
Cell
Phenotype
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. 2007 ; Vol. 1.
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