The role of hepatocyte nuclear factor 4-alpha in perfluorooctanoic acid- and perfluorooctanesulfonic acid-induced hepatocellular dysfunction

• Published in: Toxicology and applied pharmacology 2016-08, Vol.304, p.18-29
• Main Authors: Beggs, Kevin M., McGreal, Steven R., McCarthy, Alex, Gunewardena, Sumedha, Lampe, Jed N., Lau, Christoper, Apte, Udayan
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ALANINES; ALCOHOL DEHYDROGENASE; ALCOHOLS; Alkanesulfonic Acids - toxicity; AMINOTRANSFERASES; Animals; APOPTOSIS; Caprylates - toxicity; CARCINOGENESIS; CELL PROLIFERATION; Cell Proliferation - drug effects; CONCENTRATION RATIO; CYTOCHROMES; DMSO; Dose-Response Relationship, Drug; Down-Regulation; Fluorocarbons - toxicity; Gene Expression - drug effects; GENES; Hepatocyte Nuclear Factor 4 - biosynthesis; Hepatocyte Nuclear Factor 4 - drug effects; Hepatocyte nuclear factor 4-alpha; Hepatocytes - drug effects; Human hepatocyte; Humans; LIPIDS; LIVER; LIVER CELLS; Male; MESSENGER-RNA; METABOLISM; Mice; NEOPLASMS; OCCUPATIONAL EXPOSURE; Perfluorooctanesulfonic acid; Perfluorooctanoic acid; PHOSPHATES; Real-Time Polymerase Chain Reaction; RECEPTORS; RNA, Messenger - metabolism; RODENTS; Sequence Analysis, RNA; STEM CELLS; TRANSCRIPTION FACTORS; TYROSINE; Up-Regulation - drug effects
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2016.05.001

Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), chemicals present in a multitude of consumer products, are persistent organic pollutants. Both compounds induce hepatotoxic effects in rodents, including steatosis, hepatomegaly and liver cancer. The mechanisms of PFOA- and PFOS-induced hepatic dysfunction are not completely understood. We present evidence that PFOA and PFOS induce their hepatic effects via targeting hepatocyte nuclear factor 4-alpha (HNF4α). Human hepatocytes treated with PFOA and PFOS at a concentration relevant to occupational exposure caused a decrease in HNF4α protein without affecting HNF4α mRNA or causing cell death. RNA sequencing analysis combined with Ingenuity Pathway Analysis of global gene expression changes in human hepatocytes treated with PFOA or PFOS indicated alterations in the expression of genes involved in lipid metabolism and tumorigenesis, several of which are regulated by HNF4α. Further investigation of specific HNF4α target gene expression revealed that PFOA and PFOS could promote cellular dedifferentiation and increase cell proliferation by down regulating positive targets (differentiation genes such as CYP7A1) and inducing negative targets of HNF4α (pro-mitogenic genes such as CCND1). Furthermore, in silico docking simulations indicated that PFOA and PFOS could directly interact with HNF4α in a similar manner to endogenous fatty acids. Collectively, these results highlight HNF4α degradation as novel mechanism of PFOA and PFOS-mediated steatosis and tumorigenesis in human livers. •PFOA and PFOS cause decreased HNF4α protein expression in human hepatocytes.•PFOA and PFOS promote changes associated with lipid metabolism and carcinogenesis.•PFOA and PFOS induced changes in gene expression associated with cellular dedifferentiation.•PFOA and PFOS induce expression of Nanog, a transcription factor involved in stem cell development.