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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\u2009nM) specifically promoted cell survival in HepaRG and HepG2 cells. PFAS increased the expression of TNF\u03b1 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, TGF\u03b2) biomarkers expression, respectively. RNA\u2010seq data suggested that chronic exposures to PFOA modulated the expression of fatty acid\/lipid metabolic genes that are involved in the development of NFALD and fatty liver disease. Collectively our data suggest that acute\/chronic physiologically relevant concentrations of PFAS enhance liver cell steatosis and fibrosis by the activation of the UPR pathway and by modulation of NFALD\u2010related gene expression.<\/jats:p>","DOI":"10.1002\/tox.23680","type":"journal-article","created":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T12:34:19Z","timestamp":1666010059000},"page":"225-242","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":79,"title":["Per\u2010 and polyfluoroalkyl substances activate\n                    <scp>UPR<\/scp>\n                    pathway, induce steatosis and fibrosis in liver cells"],"prefix":"10.1002","volume":"38","author":[{"given":"Qi","family":"Qi","sequence":"first","affiliation":[{"name":"Julius L. 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