Knowledge-based integration of metabolic and genetic information to identify targets of fatty acid toxicity

Shireesh Srivastava, Christina Chan

Research output: ResearchConference contribution

Abstract

Cells respond to alterations in the environment by changing the levels and activities of proteins. Many metabolic disorders are mediated through alterations in the levels of serum FFA and TNF-&alpha. Due to a significant increase in the incidences of obesity-related disorders it has become essential to identify the correct cellular targets to manipulate in order to protect cells from the deleterious effects of FFAs and TNF-&alpha. Hepatocytes are the first cells which metabolize fatty acids. Excess FFA levels alter the glucose and lipid metabolism of hepatocytes and are associated with liver disorders such as nonalcoholic steatohepatitis (NASH). We studied the genetic and metabolic responses of human hepatoma cell line (HepG2 cells) to identify the mechanism of toxicity of fatty acids. Saturated fatty acid, palmitate, was found to be cytotoxic. Application of metabolic flux analysis (MFA) to identify the changes in metabolic response upon exposure to palmitate revealed increased flux through fatty acid oxidation and diacylglycerol, indicating involvement of reactive oxygen species and protein kinase C (PKC). Pharmaceutical inhibition of these pathways significantly reduced the cytotoxicity of palmitate. Application of cDNA microarrays to identify the genetic response to exposure of the fatty acid revealed significant alteration in the redox-related genes and also in the levels of genes related to ion channels. Inhibition of K-ATP ion channels significantly reduced the toxicity of the fatty acid. Therefore, through knowledge-based integration of metabolic and genetic information, we were able to identify the pathways altered by exposure to FF As. Genetic and metabolic information can complement each other to identify multiple targets to control the cell's response to pathogenic insults.

LanguageEnglish (US)
Title of host publicationAIChE Annual Meeting, Conference Proceedings
Pages8606
Number of pages1
StatePublished - 2005
Externally publishedYes
Event05AIChE: 2005 AIChE Annual Meeting and Fall Showcase - Cincinnati, OH, United States
Duration: Oct 30 2005Nov 4 2005

Other

Other05AIChE: 2005 AIChE Annual Meeting and Fall Showcase
CountryUnited States
CityCincinnati, OH
Period10/30/0511/4/05

Profile

Fatty acids
Toxicity
Genes
Fluxes
Proteins
Ions
Hepatocytes
Saturated fatty acids
Enzyme inhibition
Adenosinetriphosphate
Cytotoxicity
Microarrays
Liver
Drug products
Glucose
Cells
Oxidation
Oxygen
Lipid Metabolism
Oxidation-Reduction

ASJC Scopus subject areas

  • Engineering(all)

Cite this

Srivastava, S., & Chan, C. (2005). Knowledge-based integration of metabolic and genetic information to identify targets of fatty acid toxicity. In AIChE Annual Meeting, Conference Proceedings (pp. 8606)

Knowledge-based integration of metabolic and genetic information to identify targets of fatty acid toxicity. / Srivastava, Shireesh; Chan, Christina.

AIChE Annual Meeting, Conference Proceedings. 2005. p. 8606.

Research output: ResearchConference contribution

Srivastava, S & Chan, C 2005, Knowledge-based integration of metabolic and genetic information to identify targets of fatty acid toxicity. in AIChE Annual Meeting, Conference Proceedings. pp. 8606, 05AIChE: 2005 AIChE Annual Meeting and Fall Showcase, Cincinnati, OH, United States, 10/30/05.
Srivastava S, Chan C. Knowledge-based integration of metabolic and genetic information to identify targets of fatty acid toxicity. In AIChE Annual Meeting, Conference Proceedings. 2005. p. 8606.
Srivastava, Shireesh ; Chan, Christina. / Knowledge-based integration of metabolic and genetic information to identify targets of fatty acid toxicity. AIChE Annual Meeting, Conference Proceedings. 2005. pp. 8606
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