title: The role of hepatocyte nuclear factor 4-alpha in perfluorooctanoic acid- and perfluorooctanesulfonic acid-induced hepatocellular dysfunction.
abstract: 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.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, 4052 HLSIC, Kansas City, KS 66160, United States. Electronic address: kbeggs2@kumc.edu.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Beggs
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, 4052 HLSIC, Kansas City, KS 66160, United States. Electronic address: smcgreal@kumc.edu.
authors.forename: Steven R
authors.initials: SR
authors.lastname: McGreal
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, 4052 HLSIC, Kansas City, KS 66160, United States.
authors.forename: Alex
authors.initials: A
authors.lastname: McCarthy
authors.affiliation: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Blvd, 2027 HLSIC, Kansas City, KS 66160, United States. Electronic address: sgunewardena@kumc.edu.
authors.forename: Sumedha
authors.initials: S
authors.lastname: Gunewardena
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, 4052 HLSIC, Kansas City, KS 66160, United States. Electronic address: jlampe@kumc.edu.
authors.forename: Jed N
authors.initials: JN
authors.lastname: Lampe
authors.affiliation: Developmental Toxicology Branch, Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC 27711, United States. Electronic address: lau.christopher@epa.gov.
authors.forename: Christoper
authors.initials: C
authors.lastname: Lau
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, 4052 HLSIC, Kansas City, KS 66160, United States. Electronic address: uapte@kumc.edu.
authors.forename: Udayan
authors.initials: U
authors.lastname: Apte
mesh_terms: D017738:Alkanesulfonic Acids / Q000633:toxicity*; D000818:Animals; D002210:Caprylates / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005466:Fluorocarbons / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects*; D051557:Hepatocyte Nuclear Factor 4 / Q000096:biosynthesis* / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D017738:Alkanesulfonic Acids; D002210:Caprylates; D005466:Fluorocarbons; D051557:Hepatocyte Nuclear Factor 4; D012333:RNA, Messenger; C023036:perfluorooctanoic acid; C076994:perfluorooctane sulfonic acid
keywords: Hepatocyte nuclear factor 4-alpha; Human hepatocyte; Liver; Perfluorooctanesulfonic acid; Perfluorooctanoic acid