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

Abstract

Peroxisome proliferator-activated receptor alpha (PPARalpha) 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 PPARalpha 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 Ppar alpha((-/-)) 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 PPARalpha 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 approximately 400% increase in bile flow: secretion of phospholipids and cholesterol was increased only during high-bile-salt infusions. No fibrate effects were observed in Ppar alpha((-/-)) mice. In conclusion, our results show that basal bile formation is not affected by PPARalpha deficiency in mice. The induction of Mdr2 mRNA and Mdr2 protein levels by fibrates is mediated by PPARalpha, while the induction of Mdr1a / 1b in vivo probably reflects a secondary phenomenon related to chronic PPARalpha activation.

PPAR-α effects on the heart and other vascular tissues

“…Some studies suggest both PPAR-␣ and PPAR-␥ activate ABCA1 expression indirectly by enhancing the transcription of LXR-␣, the promoter of which contains a PPRE (13,16,49,90). A recent study, however, found no change in liver ABCA1 mRNA levels in PPAR-␣ knockout mice (48). While additional studies are required, these findings lend further support for the use of synthetic PPAR as well as LXR or RXR agonists in the prevention or treatment of atherosclerosis.…”

Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation in Mdr2 +/− mice

“…[35][36][37] However, these compounds may induce other hepatic injury and have considerable side effects. 38 In conclusion, our data indicate that toxic bile composition, because of a high biliary bile salt/phospholipid ratio, acts synergistically to ischemia/reperfusion injury in the origin of bile duct injury after OLT. Bile salts aggravate the cold ischemia/reperfusion injury of the bile ducts, initiating an inflammatory cell invasion, cholestasis, and bile duct proliferation.…”

CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice†

“…PPAR-␣ agonists were recently shown to stimulate Mdr2 overexpression, 44 suggesting that this finding could rather be related to the PPAR-␣-activating capacity of atorvastatin. 22 Because an imbalance in the biliary phospholipid and bile acid ratio in Mdr2 knockout mice leads to a cholestatic phenotype resembling primary sclerosing cholangitis, 15,17 it is attractive to speculate that induction of Mdr2 and biliary phospholipid secretion by statins might protect bile ducts against toxic bile acids.…”