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.

Biliary excretion of chylomicron remnant cholesterol in the rat: responses to the expansion of their plasma pool and promoting role of stimulated bile-acid synthesis.

1. Chylomicron remnants, the intermediate intestinal lipoproteins carrying the bulk of dietary cholesterol, are actively taken up and degraded in the hepatocytes, releasing cholesterol which can be excreted in bile. To study this pathway, a mass of remnants, leading to a consistent rise in hepatic cholesterol, was administered as an intravenous bolus in rats with chronic bile fistula equilibrated by water, electrolyte and taurocholate infusions, and changes in biliary lipids and bile acids were evaluated for up to 24 h in comparison with baseline. 2. A mean 16% increase in the net output of bile acids was observed at each time interval after lipoprotein injection, accounting for a 24h cumulative excretion of approximately one-third of the administered cholesterol mass. These changes did not reach statistical significance however. The cholesterol output and concentrations of all biliary lipids did not vary either. Without taurocholate replacement, remnants injection was followed by a 15-20% decrease in bile acid and bile lipid secretion, presumably due to an insufficient hepatic bile-acid flux. 3. When [3H]cholesterol-labelled remnants were administered at the same mass in the chronic equilibrated bile fistula model, 21% of injected radioactivity was excreted in 24h, distributing mostly in acidic rather than neutral sterols (20.02 +/- 1.85 compared with 1.07 +/- 0.04), with an acidic to neutral sterol mean ratio of 16. 4. To exclude interfering effects from the administered cholesterol mass and chronic bile fistula, 3H-labelled remnants were also studied as a cholesterol trace injected in rats with acute bile fistula.(ABSTRACT TRUNCATED AT 250 WORDS)