Wen_2019_Toxicology_416_15

Hepatic carboxylesterases (Ces) catalyze the metabolism of drugs, environmental toxicants, and endogenous lipids and are known to be regulated by multiple nuclear receptors. Perfluorooctanoic acid (PFOA) is a synthetic fluorochemical that has been associated with dyslipidemia in exposed populations. In liver, PFOA can activate nuclear receptors such as PPARalpha, and alter the metabolism and excretion of chemicals. Here, we sought to test the ability of PFOA to modulate Ces expression and activity in the presence and absence of the PPARalpha receptor. For this purpose, male C57BL/6 NCrl mice were administered PFOA (1 or 3 mg/kg, po, 7 days) and livers collected for assessment of Ces expression and activity. PFOA increased Ces1 and 2 protein and activity. Notably, PFOA increased Ces1d, 1e, 1f, 1 g, 2c, and 2e mRNAs between 1.5- and 2.5-fold, while it decreased Ces1c and 2b. Activation of PPARalpha by PFOA was confirmed by up-regulation of Cyp4a14 mRNA. In a separate study of PFOA-treated wild-type (WT) and PPARalpha-null mice, induction of Ces 1e and 1f mRNA and in turn, Ces1 protein, was PPARalpha-dependent. Interestingly, in PPARalpha-null mice, Ces1c, 1d, 1 g, 2a, 2b, and 2e mRNAs and Ces2 protein were up-regulated by PFOA which contributed to sustained up-regulation of Ces activity, although to a lower extent than observed in WT mice. Activation of the CAR and PXR receptors likely accounted for up-regulation of select Ces1 and 2 subtypes in PPARalpha-null mice. In conclusion, the environmental contaminant PFOA modulates the expression and function of hepatic Ces enzymes, in part through PPARalpha.