Per- and polyfluoroalkyl substances (PFASs) are omnipresent in the environment, food chain, and humans. Epidemiological studies have shown a positive association between serum levels of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), and increased serum cholesterol and, in some cases, also triglyceride levels. However, causality has been questioned, as animal studies, as well as a human trial, showed a decrease in serum cholesterol and no effects or a decrease in plasma triglycerides. To obtain more insight into the effects of PFASs on these processes, the present study investigated the effects of PFOA, PFOS, and perfluorononanoic acid (PFNA) on intracellular triglyceride and cholesterol levels in human HepaRG liver cells. DNA microarray analyses were performed to provide insight into underlying mechanisms. All PFASs induced an increase in cellular triglyceride levels, but had no effect on cholesterol levels. Gene set enrichment analysis (GSEA) of the microarray data indicated that gene sets related to cholesterol biosynthesis were repressed by PFOA, PFOS, and PFNA. Other gene sets commonly affected by all PFAS were related to PERK/ATF4 signaling (induced), tRNA amino-acylation (induced), amino acid transport (induced), and glycolysis/gluconeogenesis (repressed). Moreover, numerous target genes of peroxisome proliferator-activated receptor α (PPARα) were found to be upregulated. Altogether, the present study shows that PFOA, PFOS, and PFNA increase triglyceride levels and inhibit cholesterogenic gene expression in HepaRG cells. In addition, the present study indicates that PFASs induce endoplasmic reticulum stress, which may be an important mechanism underlying some of the toxic effects of these chemicals.

全氟烷基物质和多氟烷基物质 (PFAS) 在环境、食物链和人类中无处不在。流行病学研究表明，全氟辛酸 (PFOA) 和全氟辛烷磺酸 (PFOS) 的血清水平与血清​​胆固醇升高（在某些情况下还与甘油三酯水平升高）呈正相关。然而，因果关系受到质疑，因为动物研究和人体试验显示血清胆固醇降低，但血浆甘油三酯没有影响或降低。为了更深入地了解 PFAS 对这些过程的影响，本研究调查了 PFOA、PFOS 和全氟壬酸 (PFNA) 对人 HepaRG 肝细胞细胞内甘油三酯和胆固醇水平的影响。进行 DNA 微阵列分析以深入了解潜在机制。所有 PFAS 都会导致细胞甘油三酯水平升高，但对胆固醇水平没有影响。微阵列数据的基因集富集分析 (GSEA) 表明，与胆固醇生物合成相关的基因集受到 PFOA、PFOS 和 PFNA 的抑制。通常受所有 PFAS 影响的其他基因组与 PERK/ATF4 信号传导（诱导）、tRNA 氨酰化（诱导）、氨基酸转运（诱导）和糖酵解/糖异生（抑制）相关。此外，发现过氧化物酶体增殖物激活受体α（PPARα）的许多靶基因上调。总之，本研究表明，PFOA、PFOS 和 PFNA 会增加 HepaRG 细胞中的甘油三酯水平并抑制胆固醇生成基因的表达。此外，本研究表明，PFAS 会诱导内质网应激，这可能是这些化学物质某些毒性作用的重要机制。