Perfluorooctanoic acid affects the activity of the hepatocyte nuclear factor 4 alpha (HNF4α)

► PFOA alters the proteome of HepG2 cells. ► PFOA affects signalling pathways which are associated with lipid metabolism and cancer. ► PFOA inhibits the activity of the nuclear receptor HNF4α. ► PFOA decreases the intracellular amount of HNF4α. Perfluorooctanoic acid (PFOA) is an industrial chemical that is a global contaminant of water, soil and foodstuff. Numerous animal studies have revealed that PFOA has embryotoxic and hepatotoxic effects in rodents. On the molecular level, the adverse effects of PFOA have been correlated with the PFOA-mediated activation of peroxisome proliferator-activated receptor alpha (PPARα), however, the toxicological relevance of this mode of action for humans is under debate. In this study, a proteomic approach was chosen to screen for molecular targets affected by PFOA in human liver cells. Treatment of the human liver cell line HepG2 with 25μM PFOA resulted in 51 deregulated proteins in a two-dimensional gel experiment, and 36 of these proteins were identified by mass spectrometry. Network analysis revealed that these proteins are primarily involved in lipid metabolism and cancer. The hepatocyte nuclear factor 4α (HNF4α), but not PPARα, was the key regulator of the network. Indeed, subsequent western blot analysis revealed that the amount of HNF4α as well as of its target HNF1α was downregulated in PFOA-treated HepG2 cells. Moreover, PFOA was shown to inhibit HNF4α-dependent gene transcription. Thus, this study provides first experimental evidence that HNF4α is negatively affected by PFOA.