The pravastatin-induced decrease of biliary cholesterol secretion is not directly related to an inhibition of cholesterol synthesis in humans

Abstract

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported to suppress biliary cholesterol secretion and saturation. It remains unproven whether this is mediated by inhibition of cholesterol synthesis. Therefore, the effect of a long-term administration of pravastatin on cholesterogenesis and on biliary lipid secretion was investigated in seven healthy volunteers. Placebo or 40 mg of pravastatin were taken daily at bedtime for 5 weeks using a double-blind crossover design. During the last week, 12 hours after the last drug intake 0.04 mmol [1-13 C]acetate/kg · h and 0.5 g polyethylene glycol 4,000/h were infused intraduodenally for 15 hours. Plasma and duodenal bile samples were collected hourly. Thereafter, the decay of [ 13 C]labeled plasma cholesterol was measured during the following 3 days. The fractional and absolute syntheses of plasma and biliary cholesterol were determined by gas chromatography mass spectrometry using mass isotopomer distribution analysis. At the end of the pravastatin period plasma total and low-density lipoprotein (LDL) cholesterol had decreased by 20% and 24%, respectively. Similarly, pravastatin suppressed biliary secretion rates of cholesterol, total bile acids and phospholipids (P F .05) by 46%, 36%, and 51%. As a consequence, cholesterol saturation index remained unchanged. However, fractional syntheses of cholesterol were comparable (P G .05) on placebo compared with pravastatin with 3.1% versus 4.0% in plasma and 4.3% versus 5.2% in bile after 15 hours, respectively. The mean absolute synthesis rates amounted to 0.3 mg/kg/h on placebo versus 0.4 on pravastatin (P G .05). In conclusion, the pravastatin-induced reduction of biliary cholesterol secretion is not directly related to an inhibition of cholesterol synthesis. (HEPATOLOGY 1999;30:14-20.)A variety of defects are realized to explain the pathogenesis of cholesterol gallstone formation, including cholesterol supersaturation as well as gallbladder hypomotility, rapid nucleation, and a mucin hypersecretion. Most likely a sustained cholesterol supersaturation of bile 1 owing to hepatic hypersecretion of cholesterol 2 stands at the beginning of this process. In animal studies the origin of biliary secreted cholesterol has been well defined. In rats and hamsters the amount of newly synthesized cholesterol secreted into bile amounts to 8% to 18% and 2% to 5%, respectively. [3][4][5][6] In humans, most of the indirect evidence using standard radioisotope kinetics supported that 20% of biliary cholesterol were derived from de novo synthesis, 7 the majority being preformed cholesterol supplied by high-density lipoprotein cholesterol. 8 We have recently shown that the mass isotopomer distribution analysis (MIDA) technique allows for the direct measurement of the 4% to 5% of newly synthesized cholesterol formed from [ 13 C]acetate in bile and also that a significantly higher proportion of de novo cholesterol is secreted into bile as opposed to plasma in healthy individuals' circulation. 9 Thus, it seems tha...

Cholesterol attenuates cytoprotective effects of phosphatidylcholine against bile salts

“…Most recently, Schonewille et al have reported that rosuvastatin, atorvastatin and lovastatin enhance the biliary cholesterol secretion 51 . In contrast, pravastatin induces a decrease in the biliary cholesterol secretion in healthy volunteers 52 . Bile containing normal levels of bile salts, PC and cholesterol does not lead to hepatocellular damage.…”

Statins increase hepatic cholesterol synthesis and stimulate fecal cholesterol elimination in mice

“…For instance, in line with data reported previously, we found increased biliary cholesterol secretion in statintreated mice. However, a reduction of biliary cholesterol secretion and saturation index has been observed in humans treated with pravastatin (17,24) or lovastatin (54). In addition, statin use was associated with a reduction in the risk of gallstone disease (55), supporting decreased rather than increased biliary cholesterol secretion rates.…”

“…The effects on biliary secretion may indicate inhibition of hepatic cholesterol synthesis in humans. However, the few early studies in statin-treated humans that applied direct methods to measure cholesterol synthesis and failed to prove a reduced cholesterol synthesis (16) or even pointed toward increased cholesterol synthesis (17) indicate that whole body cholesterol synthesis may also be augmented in humans. If increased cholesterol synthesis after statin treatment is also the case in humans, then it would be important to investigate whether this would also lead to enhanced fecal excretion of neutral sterols or if the newly synthesized cholesterol undergoes a different fate.…”

Statin use and the risk of gallstone disease: a population-based case–control study

“…Statins can reduce hepatic cholesterol biosynthesis and thereby decrease biliary cholesterol secretion [11]. Animal studies have indicated that statins can prevent the gallstone formation [12][13][14].…”