Per‐ and polyfluoroalkyl substances activate UPR pathway, induce steatosis and fibrosis in liver cells

Abstract

Per-and polyfluoroalkyl substances (PFAS), which include perfluorooctanoic acid (PFOA), heptafluorobutyric acid (HFBA), and perfluorotetradecanoic acid (PFTA), are commonly occurring organic pollutants. Exposure to PFAS affects the immune system, thyroid and kidney function, lipid metabolism, and insulin signaling and is also involved in the development of fatty liver disease and cancer. The molecular mechanisms by which PFAS cause fatty liver disease are not understood in detail. In the current study, we investigated the effect of low physiologically relevant concentrations of PFOA, HFBA, and PFTA on cell survival, steatosis, and fibrogenic signaling in liver cell models. Exposure of PFOA and HFBA (10 to 1000 nM) specifically promoted cell survival in HepaRG and HepG2 cells. PFAS increased the expression of TNFα and IL6 inflammatory markers, increased endogenous reactive oxygen species (ROS) production, and activated unfolded protein response (UPR). Furthermore, PFAS enhanced cell steatosis and fibrosis in HepaRG and HepG2 cells which were accompanied by upregulation of steatosis (SCD1, ACC, SRBP1, and FASN), and fibrosis (TIMP2, p21, TGFβ) biomarkers expression, respectively. RNA-seq data suggested that chronic exposures to PFOA modulated the expression of fatty acid/lipid metabolic genes that

Cadmium modulates steatosis, fibrosis, and oncogenic signaling in liver cancer cells by activating notch and AKT/mTOR pathways

“…Western blotting was performed as described previously 48 . HepaRG, HepG2, and SK‐Hep1 (1 × 10 5 ) were grown in 6‐well plates for 18 h. Cells were treated with 5 and 10 nM Cd or CCl 4 plus Cd for an additional 24 to 72 h as indicated.…”

“…Western blotting was performed as described previously. 48 HepaRG, HepG2, and SK-Hep1 (1 Â 10 5 ) were grown in 6-well plates for 18 h. as described previously. 49 All experiments were repeated two to three times.…”

Exosome‐derived miR‐142‐5p from liver stem cells improves the progression of liver fibrosis by regulating macrophage polarization through CTSB

“…4 Although great progress has been made in exploring the pathogenesis of liver fibrosis in recent years, finding effective anti-hepatic fibrosis methods and effective early damage markers is still an urgent need for the treatment of liver fibrosis. 5,6 LF is usually caused by chronic or acute injury, which could eventually lead to liver cirrhosis or hepatocellular carcinoma. 5 Therefore, in-depth discussions on the mechanism and treatment of LF have gradually attracted people's attention.…”

“…Liver fibrosis (LF) is an important structural basis for the pathogenesis of various chronic liver diseases (including viral hepatitis, alcoholic and cholestatic liver diseases) 4 . Although great progress has been made in exploring the pathogenesis of liver fibrosis in recent years, finding effective anti‐hepatic fibrosis methods and effective early damage markers is still an urgent need for the treatment of liver fibrosis 5,6 . LF is usually caused by chronic or acute injury, which could eventually lead to liver cirrhosis or hepatocellular carcinoma 5 .…”

GenX Disturbs the Indicators of Hepatic Lipid Metabolism Even at Environmental Concentration in Drinking Water via PPARα Signaling Pathways

“…26 It has been suggested that PFAS may affect lipid metabolism by interfering with the expression of genes involved in lipid synthesis and catabolism. 27 Other studies have suggested that PFAS may affect lipid metabolism by interfering with insulin signaling pathways and liver function, among other pathways. 28 Fatty acids are essential for lipid metabolism and contribute significantly to lipid metabolism.…”