FIBRATES INDUCE MDR2 GENE-EXPRESSION AND BILIARY PHOSPHOLIPID SECRETION IN THE MOUSE

Disruption of the murine mdr2 gene leads to the complete absence of bi liary phospholipids. We tested the hypothesis that the increase in bil iary phospholipid output induced by fibrates is mediated via induction of the hepatic mdr2 gene and its encoded product, the P-glycoprotein canalicular flippase. Increased levels of mdr2 mRNA were observed in t he liver of mice treated with different fibrates: ciprofibrate, 660+/- 155% (as compared with control group); clofibrate, 611+/-77 %; bezafib rate, 410+/-47 %; fenofibrate, 310+/-52 %; gemfibrozil, 190+/-25 % (P < 0.05 compared with control group). Induction of expression of the md r gene family was specific to the mdr2 gene. Two- to three-fold increa ses in P-glycoprotein immunodetection were evident on the canalicular plasma-membrane domain of clofibrate- and ciprofibrate-treated mice. B iliary phospholipid output increased from 4.2+/-1.2 nmol/min per g of liver in the control group to 8.5+/-0.6, 7.1+/-2.9 and 5.8+/-2.5 in ci profibrate-, clofibrate- and bezafibrate-treated mice respectively (P < 0.05 compared with control group). Moreover, a significant correlati on between biliary phospholipid output and the relative levels of mdr2 mRNA was found (r = 0.86; P < 0.05). In treated animals, bile flow as well as cholesterol and bile acid outputs remained unchanged. Our fin dings constitute the first evidence that pharmacological modulation of biliary lipid secretion mediated by fibrates can be related to the ov erexpression of a specific liver gene product, the mdr2 P-glycoprotein , and are consistent with the hypothesis that the mdr2 P-glycoprotein isoform plays a crucial role in the secretion of biliary phospholipid.