Reactive lipid electrophiles are hypothesized to be critical mediators of toxicities and disease processes associated with oxidative stress.  We employed alkynyl analogs of the prototypical lipid electrophiles 4-hydroxynonenal (aHNE) and 4-oxononenal (aONE) as probes for global inventory of protein adducts in RKO human colon carcinoma cells and THP-1 human macrophage cells.  Comparison of protein adduct inventories with global protein inventories revealed that adduction was selective.  Moreover, distinct chemistry of the electrophiles led to different protein targeting, as only half of the aHNE targets were also targets for aONE.  Acquisition of mRNA transcript profiles and shotgun proteomic expression profiles, together with targeted knockdown of transcriptional regulators revealed candidate mediators of electrophile effects on gene and protein expression.  Despite similar toxic potencies in both cell types, aHNE and aONE exerted distinctly different effects on gene and protein expression.  Network analyses of the datasets identify candidate triggers for pathway and transcriptional effects.

Lipid electrophiles:  From protein adducts to systems responses

244th National Meeting (2012)

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