The effects of the 3-hydroxy, 3-methylglutaryl coenzyme a reductase inhibitor pravastatin on bile composition and nucleation of cholesterol crystals in cholesterol gallstone disease

Smit, J.W.A.; Erpecum, Karel J. van; Renooij, Willem; Stolk, M. F. J.; Edgar, Patrick; Doornewaard, Heleen; vanBerge-Henegouwen, Gerard P.

doi:10.1002/hep.1840210608

Cited by 25 publications

(20 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Secretion of biliary cholesterol, bile acids, and of phospholipids decreased by 46%, 36%, and 51% after pravastatin, respectively. As a consequence, cholesterol saturation of bile remained essentially unchanged as described previously, [57][58][59] although some investigators found a decrease during pravastatin. 23,60 Notably, pravastatin and cerivastatin 61 administration may differ from lovastatin and simvastatin because of less effective lowering of biliary cholesterol saturation compared with bile acid and phospholipid secretion.…”

Section: Discussionsupporting

confidence: 76%

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

et al. 1999

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionsupporting

confidence: 76%

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

et al. 1999

View full text Add to dashboard Cite

show abstract

“…28 In fact, statins are reported to decrease the cholesterol saturation index of duodenal bile and to dissolve gallstones in some patients 48 but not in gallstone patients in general. 49 We have proposed 50 that the identification of common gallstone genes (LITH or GBD) should be based on complementary evidence from (1) genetic studies in mice and/or humans, (2) phenotypic characterization of genetically defined animal models (for example, knockout or transgenic mice), and (3) epidemiological studies defining the overall clinical relevance. All these criteria are fulfilled by ABCG5/G8.…”

Section: Discussionmentioning

confidence: 99%

Increased gallstone risk in humans conferred by common variant of hepatic ATP-binding cassette transporter for cholesterol

et al. 2007

View full text Add to dashboard Cite

Genomewide scans of inbred strains of mice have linked the genes encoding the hepatocanalicular cholesterol transporter ABCG5/G8 to gallstone formation. Five nonsynonymous coding single-nucleotide polymorphisms (SNPs) in the orthologous human genes are associated with differences in serum cholesterol and plant sterol levels. We now tested these ABCG5/G8 SNPs for linkage and association with gallstone susceptibility in humans. Prospectively, we collected data from 178 white individuals with gallbladder stones or history of cholecystectomy in 84 families and from 70 stone-free controls, as confirmed by abdominal ultrasound. We performed nonparametric linkage (NPL) analysis of affected sib pairs (ASPs) and association tests of cases and controls. In ASPs, gallstones were strongly linked to the D19H variant of the ABCG8 gene (NPL score ‫؍‬ 7.1; P ‫؍‬ 4.6 ؋ 10 ؊13 ). The risk of gallstones in carriers of the 19H allele was significantly increased in randomly selected cases from the ASP cohort compared to the stone-free controls (OR ‫؍‬ 3.018; P ‫؍‬ 0.017). Consistent with the mouse model, heterozygosity for the lithogenic ABCG8 allele was associated with gallstones in humans; 21.4% of gallstone patients carried the heterozygous D19H genotype, compared with 8.6% of controls (OR ‫؍‬ 2.954; P ‫؍‬ 0.026). Conclusion: The linkage and association studies identified the cholesterol transporter ABCG5/G8 as a genetic determinant of gallstone formation, or LITH gene, in humans. The function of this transporter and the results of the genetic study taken together indicate that in gallstone-susceptible carriers of the ABCG8 19H allele, cholesterol cholelithiasis is secondary to increased hepatobiliary cholesterol secretion. (HEPATOLOGY 2007;46:793-801.)

show abstract

“…Statins are regarded as a relatively safe medicine, with mild side-effects, even for long-term use in patients with hypercholesterolemia [19], and there have been no reports in which statins increase the risk of gallstone formation [12,20]. Most studies have demonstrated that statins reduce, or do not increase, the cholesterol saturation index in bile [21][22][23][24]. Controversy still exists over the effects of statins on ABCA1 expression in macrophages and other cells [25][26][27][28][29].…”

Section: Introductionmentioning

confidence: 97%

HMG-CoA Reductase Inhibitors (Statins) Activate Expression of PPARα/PPARγ and ABCA1 in Cultured Gallbladder Epithelial Cells

et al. 2009

View full text Add to dashboard Cite

In gallbladder epithelial cells (GBEC), PPARalpha and PPARgamma ligands modulate inflammation by suppression of TNFalpha production and prevent excessive accumulation of cholesterol by ABCA1 activation. Recently, HMG-CoA reductase inhibitors (statins) were shown to activate PPARalpha and PPARgamma in various cells but no studies of their effects in GBEC have been conducted. The objective of this study was, therefore, to determine the effects of statins on PPAR and ABCA1 expression and the anti-inflammatory effect of statins in GBEC. Canine GBEC were cultured on Petri dishes. Expression of the proteins PPARalpha, PPARgamma, and ABCA1 was measured by western blotting analysis after treatment with simvastatin, pravastatin, NO-pravastatin, PPARalpha ligand, or PPARgamma ligand in the culture media. Expression of ABCA1 and LXRalpha mRNAs was estimated by RT-PCR. Expression of TNFalpha mRNA was measured by RT-PCR after 24 h pre-treatment with the statins, preceding 1 h of lipopolysaccharide (LPS) loading. Simvastatin, pravastatin, and NO-pravastatin increased expression of the proteins PPARalpha, PPARgamma, and ABCA1, and expression of the mRNA of ABCA1 and LXRalpha in GBEC. Pre-treatment with simvastatin, pravastatin, and NO-pravastatin suppressed the production of TNFalpha mRNA induced by LPS. In conclusion, statins probably contribute to the preservation of GBEC function by activation of PPARalpha and PPARgamma, which have anti-inflammatory effects by suppression of pro-inflammatory cytokines, and ABCA1 activation mediated by LXRalpha, which prevents the accumulation of cholesterol in GBEC.

show abstract

The effects of the 3-hydroxy, 3-methylglutaryl coenzyme a reductase inhibitor pravastatin on bile composition and nucleation of cholesterol crystals in cholesterol gallstone disease

Cited by 25 publications

References 43 publications

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

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

Increased gallstone risk in humans conferred by common variant of hepatic ATP-binding cassette transporter for cholesterol

HMG-CoA Reductase Inhibitors (Statins) Activate Expression of PPARα/PPARγ and ABCA1 in Cultured Gallbladder Epithelial Cells

Contact Info

Product

Resources

About