Citation:

Wen, X., A. Baker, C. Klaassen, C. Corton, J. Richardson, AND L. Aleksunes. Hepatic carboxylesterases are differentially regulated in PPARα-null mice treated with perfluorooctanoic acid. TOXICOLOGY. Elsevier Science Ltd, New York, NY, 416:15-22, (2019). https://doi.org/10.1016/j.tox.2019.01.014

Impact/Purpose:

Perfluorooctanoic acid (PFOA) is a synthetic fluorochemical that has been associated with hypercholesterolemia and hyperuricemia in exposed populations. In liver, PFOA can activate nuclear receptors including the peroxisome proliferator-activated receptor alpha (PPARalpha) and the constitutive androstane receptor (CAR) and alter the metabolism and excretion of xenobiotics. Hepatic carboxylesterases (Ces) catalyze the metabolism of drugs, environmental toxicants and carcinogens. Previous studies demonstrated that PPARalpha and CAR regulate the expression and function of Ces. Here, we sought to determine whether activation of PPARalpha and CAR by PFOA could regulate the expression of hepatic Ces.

Description:

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 PPARα, 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 PPARα 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 PPARα by PFOA was confirmed by up-regulation of Cyp4a14 mRNA. In a separate study of PFOA-treated wild-type (WT) and PPARα-null mice, induction of Ces 1e and 1f mRNA and in turn, Ces1 protein, was PPARα-dependent. Interestingly, in PPARα-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 PPARα-null mice. In conclusion, the environmental contaminant PFOA modulates the expression and function of hepatic Ces enzymes, in part through PPARα.

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