Enhancement of mdr2 gene transcription mediates the biliary transfer of phosphatidylcholine supplied by an increased biosynthesis in the pravastatin-treated rat.
An increase of biliary lipid secretion is known to occur in the rat under sustained administration of statin-type 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase inhibitors. The present study has addressed critical mechanisms of hepatic lipid synthesis and phosphatidylcholine (PC) biliary transport in the rat fed with a 0.075% pravastatin diet for 3 weeks. After treatment, biliary secretion of PC and cholesterol increased to 233% and 249% of controls, while that of bile salts was unchanged. Activity of cytidylyltransferase (CT), a major regulatory enzyme in the CDP-choline pathway of PC synthesis, was raised in both microsomal and cytosolic fractions (226% and 150% of controls), and there was an increase to 187% in the mass of active enzyme as determined by Western blot of microsomal protein using an antibody specific to CT. Cytosolic activity of choline kinase, another enzyme of the CDP-choline pathway, also increased to 175% of controls. In addition, there was an over eightfold increase in the HMG CoA reductase activity and mRNA. Thus, an increased PC and cholesterol synthetic supply to hepatocytes appeared as a basic mechanism for the biliary hypersecretion of these lipids. Notwithstanding the increased synthesis, hepatic PC content was unchanged, suggesting an enhanced transfer of this lipid into bile. Indeed, there was a sevenfold increase of multidrug resistance gene 2 (mdr2) gene mRNA coding for a main PC canalicular translocase. Thus, hypersecretion of biliary PC in the model studied can be explained by an up-regulation of mdr2 gene transcription and its P-glycoprotein product mediating the biliary transfer of PC supplied by an increased biosynthesis.
Carrella
M
M
Cattedra di Gastroenterologia, Facoltà di Medicina e Chirurgia, Università degli Studi di Udine, Italy.
Feldman
D
D
Cogoi
S
S
Csillaghy
A
A
Weinhold
P A
PA
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010713:Phosphatidylcholines / Q000378:metabolism*; D017035:Pravastatin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects*
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D010713:Phosphatidylcholines; D002784:Cholesterol; C095122:multidrug resistance protein 3; D017035:Pravastatin