Perfluorononanoic Acid (PFNA) Suppresses Autophagy and Activates Nrf2 Signaling

Abstract

Perfluorinated compounds (PFCs), a group of persistent environmental pollutants, are frequently detected in human blood. Epidemiological and animal studies show that there are positive associations between higher blood levels of PFCs and greater risk of liver disorders, thyroid disorders, reproductive toxicity, and immunotoxicity. Nuclear factor erythroid 2‐related factor (Nrf) 2, a transcription factor that can be activated by oxidative stress, electrophiles, and accumulated p62 protein after autophagy repression, plays important anti‐inflammatory, anti‐oxidative and cytoprotective roles. We previously reported that PFCs increased the expressions of several Nrf2 target genes in mouse liver. However, the underlying mechanism by which PFCs activate Nrf2 signaling remains largely unknown. The present study was designed to determine whether PFNA activates Nrf2 signaling; and if so, the underlying mechanism. PFNA increased mRNA expressions of Nrf2‐target genes, including Heme oxygenase (Ho/HO) 1 and NAD(P)H: quinone oxidoreductase (Nqo/NQO) 1, as well as nuclear levels of Nrf2/NRF2 protein in both mouse liver and cultured human Hep3B hepatoma cells. To our surprise, PFNA did not produce apparent oxidative stress in both mouse liver and cultured human Hep3B hepatoma cells. We next determined the impact of PFNA on autophagy progression. In both mouse liver and cultured human Hep3B hepatoma cells, PFNA decreased the conversion of microtubule‐associated protein 1 light chain 3 beta (LC3B)‐I into LC3B‐II, and increased cytosolic levels of p62 protein, indicating that PFNA repressed autophagic flux. In addition, PFNA decreased nuclear levels of transcription factor EB (TFEB) protein, an upstream signaling molecule of autophagy. Morphologically, PFNA caused liver injury in both wide‐type and Nrf2‐null mouse liver, evidenced by hepatocyte necrosis and hemorrhage. In consistency with histology study, PFNA (0.1mmole/kg) increased serum AST and ALT levels in both wide‐type mice and Nrf2‐null mice. In addition, PFNA produced clear inflammation foci in Nrf2‐null mouse liver, but not in wide‐type mouse liver. Furthermore, PFNA induced mRNA expressions of pro‐inflammatory cytokines, including IL‐1β, IL‐6, and TNF‐α only in Nrf2‐null mouse liver, but not in wide‐type mouse liver. In conclusion, PFNA activates Nrf2 signaling, primarily mediated by accumulated p62 protein after autophagy repression, which significantly attenuated PFNA‐induced inflammation.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.