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: Contribution to journalArticle

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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

Gene Regulatory Networks
Nonesterified Fatty Acids
Palmitates
palmitates
free fatty acids
cytotoxicity
Hep G2 Cells
electron transport chain
metabolites
Electron Transport
cell death
Cell Death
Fatty Acids
3-hydroxybutyric acid
Genes
Hepatoblastoma
NADH Dehydrogenase
ketone bodies
Pentose Phosphate Pathway
Ketone Bodies

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: Contribution to journalArticle

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