Salter Deanna M, Wei Wei, Nahar Pragati P, Marques Emily, Slitt Angela L
Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, USA.
Toxicol Sci. 2021 Jul 16;182(1):82-95. doi: 10.1093/toxsci/kfab043.
A combination of calorie restriction (CR), dietary modification, and exercise is the recommended therapy to reverse obesity and nonalcoholic fatty liver disease. In the liver, CR shifts hepatic metabolism from lipid storage to lipid utilization pathways, such as AMP-activated protein 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 CR and metformin.
限制热量摄入（CR）、饮食调整和运动相结合是推荐用于逆转肥胖和非酒精性脂肪性肝病的治疗方法。在肝脏中，CR可使肝脏代谢从脂质储存转变为脂质利用途径，如AMP激活的蛋白激酶（AMPK）。全氟辛烷磺酸（PFOS）是一种先前用于防污剂和防粘材料的含氟表面活性剂，在相对低剂量暴露后可增加小鼠肝脏脂质。为了验证PFOS给药会干扰CR这一假设，对成年雄性C57BL/6N小鼠进行自由采食或给予热量减少25%的饮食，同时通过口服灌胃给予载体（水）或100μg PFOS/kg/天，持续6周。单独的CR改善了肝脏脂质和葡萄糖耐量。在6周内，PFOS并未显著改变CR诱导的体重减轻、白色脂肪组织质量或肝脏重量。然而，PFOS增加了自由采食和接受CR处理的小鼠肝脏甘油三酯的积累。这与肝脏中磷酸化AMPK表达的降低有关。胰高血糖素（100 nM）处理诱导肝细胞产生葡萄糖，与PFOS（2.5μM）共同处理可进一步上调葡萄糖生成。接下来，为了探究观察到的变化是否与AMPK信号传导有关，将HepG2细胞单独用二甲双胍或AICAR处理，或与PFOS（25μM）联合处理。PFOS干扰了二甲双胍的降糖作用，AICAR处理部分削弱了PFOS诱导的葡萄糖生成增加。在3T3-L1脂肪细胞中，与PFOS共同处理时二甲双胍的效果较差。总体而言，PFOS给药破坏了肝脏脂质和葡萄糖稳态，并干扰了CR和二甲双胍有益的降糖作用。
