Peroxisome proliferator-activated receptor alpha (PPARalpha)-mediated regulation of multidrug resistance 2 (Mdr2) expression and function in mice

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Abstract
Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor that controls expression of genes involved in lipid metabolism and is activated by fatty acids and hypolipidaemic fibrates. Fibrates induce the hepatic expression of murine multidrug resistance 2 (Mdr2), encoding the canalicular phospholipid translocator. The physiological role of PPARα in regulation of Mdr2 and other genes involved in bile formation is unknown. We found no differences in hepatic expression of the ATP binding cassette transporter genes Mdr2, Bsep (bile salt export pump), Mdr1a/1b, Abca1 and Abcg5/Abcg8 (implicated in cholesterol transport), the bile salt-uptake systems Ntcp (Na+-taurocholate co-transporting polypeptide gene) and Oatp1 (organic anion-transporting polypeptide 1 gene) or in bile formation between wild-type and Pparα(-/-) mice. Upon treatment of wild-type mice with ciprofibrate (0.05%, w/w, in diet for 2 weeks), the expression of Mdr2 (+3-fold), Mdr1a (+6-fold) and Mdr1b (+11-fold) mRNAs was clearly induced, while that of Oatp1 (-5-fold) was reduced. Mdr2 protein levels were increased, whereas Bsep, Ntcp and Oatp1 were drastically decreased. Exposure of cultured wild-type mouse hepatocytes to PPARα agonists specifically induced Mdr2 mRNA levels and did not affect expression of Mdr1a/1b. Altered transporter expression in fibrate-treated wild-type mice was associated with a 400% increase in bile flow: secretion of phospholipids and cholesterol was increased only during high-bile-salt infusions. No fibrate effects were observed in Pparα(-/-) mice. In conclusion, our results show that basal bile formation is not affected by PPARα deficiency in mice. The induction of Mdr2 mRNA and Mdr2 protein levels by fibrates is mediated by PPARα, while the induction of Mdr1a/1b in vivo probably reflects a secondary phenomenon related to chronic PPARα activation.

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