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

Autor: Kevin M. Beggs, Jed N. Lampe, Sumedha Gunewardena, Steven R. McGreal, Christoper Lau, Alex McCarthy, Udayan Apte
Rok vydání: 2016
Předmět:
Male
0301 basic medicine
Perfluorooctanesulfonic acid
Down-Regulation
Gene Expression
Peroxisome proliferator-activated receptor
010501 environmental sciences
Biology
Real-Time Polymerase Chain Reaction
Toxicology
01 natural sciences
Article
Mice
03 medical and health sciences
chemistry.chemical_compound
Gene expression
medicine
Animals
Humans
RNA
Messenger
Cell Proliferation
0105 earth and related environmental sciences
Pharmacology
chemistry.chemical_classification
Fluorocarbons
Dose-Response Relationship
Drug
Sequence Analysis
RNA
medicine.disease
Up-Regulation
Cell biology
Hepatocyte nuclear factors
030104 developmental biology
Alkanesulfonic Acids
Hepatocyte Nuclear Factor 4
Hepatocyte nuclear factor 4
chemistry
Biochemistry
Hepatocyte nuclear factor 4 alpha
Hepatocytes
Perfluorooctanoic acid
Caprylates
Steatosis
Zdroj: Toxicology and Applied Pharmacology. 304:18-29
ISSN: 0041-008X
Popis: 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.
Databáze: OpenAIRE
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