Using dynamic gene module map analysis to identify targets that modulate free fatty acid induced cytotoxicity

Zheng Li, Shireesh Srivastava, Robert Findlan, Christina Chan

    Research output: Research - peer-reviewArticle

    • 10 Citations

    Abstract

    The objective of this study was to identify pathways that regulate the cytotoxicity induced by free fatty acids (FFAs) in human hepatoblastoma cells (HepG2/C3A). Gene expression profiles of HepG2/C3A cells were obtained at three time points, after 24, 48, and 72 h of exposure to different types of FFA. Saturated fatty acid (palmitate) was found to be cytotoxic. The pathways activated by the different FFAs at the different time points were identified using global gene module map analysis. Unsaturated FFAs exerted transcriptional regulation mainly within the first 24 h, whereas saturated FFA, palmitate, regulated energy production pathways, such as the electron transport chain (ETC) and tricarboxylic acid cycle, within the first 24 h. In the next 24 h, palmitate up-regulated 36 cell death relevant pathways and down-regulated several protective pathways, such as the pentose phosphate pathway and glutathione-related pathways. In the final 24 h, the FFAs did not induce significant transcriptional regulation. We hypothesized that palmitate induced cytotoxicity by first perturbing metabolic pathways in the initial 24 h, resulting in changes to factors, such as metabolites or signaling molecules, which subsequently triggered cell death relevant pathways in the next 24 h. The uptake and release of 27 metabolites were measured to further elucidate the metabolic changes in the first 24 h. It was determined that ketone bodies such as β-hydroxybutyrate and acetoacetate were important in separating the toxic from the nontoxic phenotypes. A regression model was used to identify the genes relevant to these metabolites. Some of the genes identified to be important were experimentally validated. It was found that ETC genes such as NADH dehydrogenase and succinate dehydrogenase were involved in palmitate induced cytotoxicity.

    LanguageEnglish (US)
    Pages29-37
    Number of pages9
    JournalBiotechnology Progress
    Volume24
    Issue number1
    DOIs
    StatePublished - Jan 2008

    Profile

    free fatty acids
    cytotoxicity
    gene regulatory networks
    Gene Regulatory Networks
    Nonesterified Fatty Acids
    palmitates
    Palmitates
    metabolites
    genes
    Genes
    electron transport chain
    cell death
    cells
    Hep G2 Cells
    Electron Transport
    Cell Death
    Fatty Acids
    3-hydroxybutyric acid
    ketone bodies
    NADH dehydrogenase

    ASJC Scopus subject areas

    • Food Science
    • Biotechnology
    • Microbiology

    Cite this

    Using dynamic gene module map analysis to identify targets that modulate free fatty acid induced cytotoxicity. / Li, Zheng; Srivastava, Shireesh; Findlan, Robert; Chan, Christina.

    In: Biotechnology Progress, Vol. 24, No. 1, 01.2008, p. 29-37.

    Research output: Research - peer-reviewArticle

    @article{b442584479204c61a51764f037cba6c2,
    title = "Using dynamic gene module map analysis to identify targets that modulate free fatty acid induced cytotoxicity",
    abstract = "The objective of this study was to identify pathways that regulate the cytotoxicity induced by free fatty acids (FFAs) in human hepatoblastoma cells (HepG2/C3A). Gene expression profiles of HepG2/C3A cells were obtained at three time points, after 24, 48, and 72 h of exposure to different types of FFA. Saturated fatty acid (palmitate) was found to be cytotoxic. The pathways activated by the different FFAs at the different time points were identified using global gene module map analysis. Unsaturated FFAs exerted transcriptional regulation mainly within the first 24 h, whereas saturated FFA, palmitate, regulated energy production pathways, such as the electron transport chain (ETC) and tricarboxylic acid cycle, within the first 24 h. In the next 24 h, palmitate up-regulated 36 cell death relevant pathways and down-regulated several protective pathways, such as the pentose phosphate pathway and glutathione-related pathways. In the final 24 h, the FFAs did not induce significant transcriptional regulation. We hypothesized that palmitate induced cytotoxicity by first perturbing metabolic pathways in the initial 24 h, resulting in changes to factors, such as metabolites or signaling molecules, which subsequently triggered cell death relevant pathways in the next 24 h. The uptake and release of 27 metabolites were measured to further elucidate the metabolic changes in the first 24 h. It was determined that ketone bodies such as β-hydroxybutyrate and acetoacetate were important in separating the toxic from the nontoxic phenotypes. A regression model was used to identify the genes relevant to these metabolites. Some of the genes identified to be important were experimentally validated. It was found that ETC genes such as NADH dehydrogenase and succinate dehydrogenase were involved in palmitate induced cytotoxicity.",
    author = "Zheng Li and Shireesh Srivastava and Robert Findlan and Christina Chan",
    year = "2008",
    month = "1",
    doi = "10.1021/bp070120b",
    volume = "24",
    pages = "29--37",
    journal = "Biotechnology Progress",
    issn = "8756-7938",
    publisher = "John Wiley and Sons Ltd",
    number = "1",

    }

    TY - JOUR

    T1 - Using dynamic gene module map analysis to identify targets that modulate free fatty acid induced cytotoxicity

    AU - Li,Zheng

    AU - Srivastava,Shireesh

    AU - Findlan,Robert

    AU - Chan,Christina

    PY - 2008/1

    Y1 - 2008/1

    N2 - The objective of this study was to identify pathways that regulate the cytotoxicity induced by free fatty acids (FFAs) in human hepatoblastoma cells (HepG2/C3A). Gene expression profiles of HepG2/C3A cells were obtained at three time points, after 24, 48, and 72 h of exposure to different types of FFA. Saturated fatty acid (palmitate) was found to be cytotoxic. The pathways activated by the different FFAs at the different time points were identified using global gene module map analysis. Unsaturated FFAs exerted transcriptional regulation mainly within the first 24 h, whereas saturated FFA, palmitate, regulated energy production pathways, such as the electron transport chain (ETC) and tricarboxylic acid cycle, within the first 24 h. In the next 24 h, palmitate up-regulated 36 cell death relevant pathways and down-regulated several protective pathways, such as the pentose phosphate pathway and glutathione-related pathways. In the final 24 h, the FFAs did not induce significant transcriptional regulation. We hypothesized that palmitate induced cytotoxicity by first perturbing metabolic pathways in the initial 24 h, resulting in changes to factors, such as metabolites or signaling molecules, which subsequently triggered cell death relevant pathways in the next 24 h. The uptake and release of 27 metabolites were measured to further elucidate the metabolic changes in the first 24 h. It was determined that ketone bodies such as β-hydroxybutyrate and acetoacetate were important in separating the toxic from the nontoxic phenotypes. A regression model was used to identify the genes relevant to these metabolites. Some of the genes identified to be important were experimentally validated. It was found that ETC genes such as NADH dehydrogenase and succinate dehydrogenase were involved in palmitate induced cytotoxicity.

    AB - The objective of this study was to identify pathways that regulate the cytotoxicity induced by free fatty acids (FFAs) in human hepatoblastoma cells (HepG2/C3A). Gene expression profiles of HepG2/C3A cells were obtained at three time points, after 24, 48, and 72 h of exposure to different types of FFA. Saturated fatty acid (palmitate) was found to be cytotoxic. The pathways activated by the different FFAs at the different time points were identified using global gene module map analysis. Unsaturated FFAs exerted transcriptional regulation mainly within the first 24 h, whereas saturated FFA, palmitate, regulated energy production pathways, such as the electron transport chain (ETC) and tricarboxylic acid cycle, within the first 24 h. In the next 24 h, palmitate up-regulated 36 cell death relevant pathways and down-regulated several protective pathways, such as the pentose phosphate pathway and glutathione-related pathways. In the final 24 h, the FFAs did not induce significant transcriptional regulation. We hypothesized that palmitate induced cytotoxicity by first perturbing metabolic pathways in the initial 24 h, resulting in changes to factors, such as metabolites or signaling molecules, which subsequently triggered cell death relevant pathways in the next 24 h. The uptake and release of 27 metabolites were measured to further elucidate the metabolic changes in the first 24 h. It was determined that ketone bodies such as β-hydroxybutyrate and acetoacetate were important in separating the toxic from the nontoxic phenotypes. A regression model was used to identify the genes relevant to these metabolites. Some of the genes identified to be important were experimentally validated. It was found that ETC genes such as NADH dehydrogenase and succinate dehydrogenase were involved in palmitate induced cytotoxicity.

    UR - http://www.scopus.com/inward/record.url?scp=38949218422&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=38949218422&partnerID=8YFLogxK

    U2 - 10.1021/bp070120b

    DO - 10.1021/bp070120b

    M3 - Article

    VL - 24

    SP - 29

    EP - 37

    JO - Biotechnology Progress

    T2 - Biotechnology Progress

    JF - Biotechnology Progress

    SN - 8756-7938

    IS - 1

    ER -