Perfluorooctanesulfonic Acid (PFOS) Thwarts the Beneficial Effects of Calorie Restriction and Metformin

Abstract

Calorie restriction (CR), dietary modification, and exercise is the recommended therapy to reverse obesity and nonalcoholic fatty liver disease. In the liver, calorie restriction shifts hepatic metabolism from lipid storage to lipid utilization pathways, such as AMP-activated kinase (AMPK). Perfluorooctanesulfonic acid (PFOS), a fluorosurfactant previously used in stain repellents and anti-stick materials, can increase hepatic lipids in mice following relatively low dose exposures. To test the hypothesis that PFOS administration interferes with CR adult male C57BL/6N mice were fed ad libitum or a 25% reduced calorie diet concomitant with either vehicle (water) or 100 μg PFOS/kg/day via oral gavage for 6 weeks. CR alone improved hepatic lipids and glucose tolerance. PFOS did not significantly alter CR-induced weight loss, white adipose tissue mass, or liver weight over 6 weeks. However, PFOS increased hepatic triglyceride accumulation, in both mice fed ad libitum and subjected to CR. This was associated with decreased phosphorylated AMPK expression in liver. Glucagon (100 nM) treatment induced glucose production in hepatocytes, which was further upregulated with PFOS (2.5 μM) co-treatment. Next, to explore whether the observed changes were related to AMPK signaling, HepG2 cells were treated with metformin or AICAR alone or in combination with PFOS (25 μM). PFOS interfered with glucose lowering effects of Metformin, and AICAR treatment partially impaired PFOS-induced increase in glucose production. In 3T3-L1 adipocytes, metformin was less effective with PFOS co-treatment. Overall, PFOS administration disrupted hepatic lipid and glucose homeostasis and interfered with beneficial glucose lowering effects of calorie restriction and Metformin.

Perfluorooctane sulfonate promotes hepatic lipid accumulation and steatosis in high‐fat diet mice through AMP‐activated protein kinase/acetyl‐CoA carboxylase (AMPK/ACC) pathway

“…Therefore, we believe that PFOS-induced inactivation of AMPK may contribute heavily to the accumulation of fat in the liver. In line with our data that PFOS may attenuate the activity of AMPK, a recent report also showed that PFOS can hinder the hypoglycemic effect of metformin (an AMPK agonist) (Salter et al, 2021). In our experiments, we also observed that PFOS can reduce the phosphorylation of AMPK.…”

“…Recent animal studies have shown that AMPK may alleviate lipid accumulation in the liver to prevent the development of liver steatosis in high‐fat diet (HFD)‐fed mice (Qiang et al, 2016). Another study has shown that increased liver TG accumulation is associated with decreased level of phosphorylated AMPK (p‐AMPK) following PFOS exposure (Salter et al, 2021). However, the molecular mechanisms underlying the role of AMPK in PFOS‐initiated liver lipid accumulation remain unclear.…”

Adverse Effects of Perfluorooctane Sulfonate on the Liver and Relevant Mechanisms

“…This figure is still close to or even exceeds the PFOS HBM-I value of 5 ng PFOS/mL blood plasma established by the German Human Biomonitoring Committee [ 17 ]. For human epidemiological studies and experimental animal studies, exposure to PFOS has been shown to have a variety of health effects on the body, such as hepatotoxicity, infertility, altered thyroid function, decreased immunity, neurotoxicity, developmental toxicity, reproductive toxicity, nephrotoxicity, cardiotoxicity, insulin resistance, and carcinogenic effects [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. Data published by the European Food Safety Agency (EFSA) in 2012 showed that the estimated daily dietary intake of PFOS for adults was 5.2–10 ng/kg body weight (bw) [ 26 ].…”

“…Moreover, PFOS can induce hepatic steatosis in mice [ 61 ]; the mechanism may be that PFOS can cause changes in lipid regulatory genes in the liver, thereby promoting the development of steatosis [ 62 ]. A study showed that PFOS administration increases liver weight and expression of genes involved in fatty acid oxidation and transport in rodents [ 20 ]. In particular, 10 and/or 5 mg/kg PFOS significantly increases the gene expression levels of fatty acid translocase (FAT/CD36) and lipoprotein lipase (Lpl), and reduces serum levels of very low density lipoproteins, and reduced rates of mitochondrial β-oxidation are also identified [ 63 ].…”

Perfluorooctane sulfonic acid induces liver lipid accumulation through AMPK/ACC signaling

“…Recent animal studies have shown that AMPK may alleviate lipid accumulation in the liver to prevent the development of liver steatosis in high fat diet (HFD)-fed mice (Qiang et al 2016). Another study has shown that increased liver triglyceride (TG) accumulation by PFOS exposure is associated with decreased level of phosphorylated AMPK (Salter et al 2021). However, the molecular mechanisms underlying the role of AMPK in PFOS-initiated liver lipid accumulation remain unclear.…”