Fibrates induce mdr2 gene expression and biliary phospholipid secretion in the mouse

Area of Science:

• Hepatology
• Molecular Biology
• Pharmacology

Background:

• Murine mdr2 gene disruption results in absent biliary phospholipids.
• Fibrates are known to influence lipid metabolism.

Purpose of the Study:

• To investigate if fibrate-induced increases in biliary phospholipid output are mediated by the hepatic mdr2 gene and its product, P-glycoprotein.
• To determine the role of mdr2 P-glycoprotein in biliary phospholipid secretion.

Main Methods:

• Mice were treated with various fibrates (ciprofibrate, clofibrate, bezafibrate, fenofibrate, gemfibrozil).
• Mdr2 mRNA levels and P-glycoprotein expression were quantified using molecular and immunological techniques.
• Biliary phospholipid output, bile flow, cholesterol, and bile acid outputs were measured.

Main Results:

• Fibrates significantly increased mdr2 mRNA levels in the liver, with effects specific to the mdr2 gene.
• P-glycoprotein levels on the canalicular plasma membrane increased in treated mice.
• Biliary phospholipid output significantly increased in mice treated with ciprofibrate, clofibrate, and bezafibrate.
• A strong positive correlation was observed between biliary phospholipid output and mdr2 mRNA levels.

Conclusions:

• Fibrate-induced pharmacological modulation of biliary lipid secretion is linked to the overexpression of mdr2 P-glycoprotein.
• The findings support the hypothesis that mdr2 P-glycoprotein plays a critical role in biliary phospholipid secretion.
• This study provides the first evidence for the involvement of mdr2 P-glycoprotein in regulating biliary lipid secretion.