Effects of simvastatin on hepatic cholesterol metabolism, bile lithogenicity and bile acid hydrophobicity in patients with gallstones

Smith, Jeffery L.; Roach, Paul D.; Wittenberg, Lee; Riottot, Michel; Pillay, S. P.; Nestel, Paul J.; Nathanson, L. K.

doi:10.1046/j.1440-1746.2000.02231.x

Cited by 31 publications

(22 citation statements)

References 54 publications

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“…Although statin-induced upregulation of cholesterol absorption has been extensively described, based on statin-induced increases in plant sterol levels (6,16,4) , this is less well established by studies in which cholesterol absorption was directly measured. In fact, some of these studies actually indicate that statins do not increase cholesterol absorption at all (29,30) . Thus, statin-induced changes in plant sterol levels might not be a refl ection of changes in cholesterol absorption but merely of one of the mechanisms by which statins achieve cholesterol lowering.…”

Section: Discussionmentioning

confidence: 99%

Baseline cholesterol absorption and the response to ezetimibe/simvastatin therapy: a post-hoc analysis of the ENHANCE trial

Jakulj

Vissers

Groen

et al. 2010

Journal of Lipid Research

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Section: Discussionmentioning

confidence: 99%

Baseline cholesterol absorption and the response to ezetimibe/simvastatin therapy: a post-hoc analysis of the ENHANCE trial

Jakulj

Vissers

Groen

et al. 2010

Journal of Lipid Research

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“…3B). One might have expected mRNA levels to be decreased given that total hepatic ACAT activity is decreased in patients with cholesterol gallstones (4,27). The significance of this change is unclear, but it serves as an example that a RT-qPCR method as described here may prove to be a useful noninvasive diagnostic tool, particularly for patients predisposed to cholesterol gallstones, allowing screening of blood samples for defects in lipid metabolism.…”

Section: Comparison Of Individuals Representing Different Background mentioning

confidence: 95%

Quantitative analysis of the expression of ACAT genes in human tissues by real-time PCR2

Smith

Rangaraj

Simpson

et al. 2004

Journal of Lipid Research

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ACAT (also called sterol o -acyltransferase) catalyzes the esterification of cholesterol by reaction with longchain acyl-CoA derivatives and plays a pivotal role in the regulation of cholesterol homeostasis. Although two human ACAT genes termed ACAT-1 and ACAT-2 have been reported, prior research on differential tissue expression is qualitative and incomplete. We have developed a quantitative multiplex assay for each ACAT isoform after RT treatment of total RNA using TaqMan real-time quantitative PCR normalized to ␤ -actin in the same reaction tube. This enabled us to calculate the relative abundance of transcripts in several human tissues as an ACAT-2/ACAT-1 ratio. In liver (n ‫؍‬ 17), ACAT-1 transcripts were on average 9-fold (range, 1.7-to 167-fold) more abundant than ACAT-2 , whereas in duodenal samples (n ‫؍‬ 10), ACAT-2 transcripts were on average 3-fold (range, 0.39-to 12.2-fold) more abundant than ACAT-1 . ACAT-2 was detected for the first time in peripheral blood mononuclear cells. Interesting differences in ACAT-2 mRNA expression were evident in subgroup analysis of samples from different sources. These results demonstrate quantitatively that ACAT-1 transcripts predominate in human liver and ACAT-2 transcripts predominate in human duodenum and support the notion that ACAT-2 has an important regulatory role in liver and intestine. Since its initial discovery in rat liver (1, 2), ACAT activity has been detected in a diverse range of tissues and cell types (3) and is known to play an important role in cell biology and in the pathogenesis of important lipid-related diseases such as atherosclerosis (3) and cholesterol gallstones (4). For example, ACAT has been shown to play a pivotal functional role in the intestinal absorption of cholesterol, the hepatic secretion of VLDL, the biosynthesis of steroid hormones, the production of cholesteryl esters in macrophages (foam cells) in atheroma, and the secretion of biliary cholesterol. From a biochemical and physiological perspective, ACAT is one of the central enzymes regulating plasma and biliary cholesterol concentrations. An excess of plasma cholesterol can lead to atherosclerosis, and an increased secretion of cholesterol in bile can predispose individuals to cholesterol gallstones. Not surprisingly, ACAT has been the focus of considerable research during the past decade because of its obvious pharmacological relevance.Two ACAT genes are known in humans. The first ACAT gene, cloned by Chang and colleagues (5) in 1993, is now termed ACAT-1 . The second, ACAT-2 , was cloned in 1998 (6-8). The two genes have 47% overall nucleotide identity (5, 8) and encode specific ACAT proteins that have 43% amino acid sequence identity and 63% similarity. These landmark studies (5-8) using gel-based detection of ACAT mRNA (RT-PCR and Northern blot analysis) provide evidence that ACAT-2 is expressed primarily in liver and inAbbreviations: PBMC, peripheral blood mononuclear cells; RTqPCR, RT treatment of RNA followed by quantitative real-time PCR.1 The official name fo...

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“…Second, the time dependence of the observed risk reduction was assessed in only one study in which the risk reduction became evident only after longer-term statin use of 1 year or more. By contrast, to our knowledge, the previous clinical trials investigating a possible effect of statins on bile lithogenicity that reported such an effect did so after short-term use [3][4][5][6]. Third, bringing together all available evidence from the literature, high levels of LDL per se (i.e., the most important indication for statins) are unlikely to be independently linked to an increased risk of gallstone formation.…”

Section: "…Statin Users Tended To Have Other More Relevant Risk Factmentioning

confidence: 80%

“…In addition, cholesterol supersaturation, accelerated nucleation and crystallization and gallbladder hypomotility have also been demonstrated to contribute to gallstone formation. To date, various animal studies and small clinical studies in humans have been performed, revealing conflicting results as to whether the use of statins may decrease bile lithogenicity [3][4][5][6][7][8][9]. In theory, decreased cholesterol biosynthesis may lead to decreased hepatic cholesterol secretion and consequently to increased bile solubility, which may lower the risk of gallstone formation.…”

Section: "Gallstones Are An Important Cause Of Morbidity In the Westementioning

confidence: 99%

Is there a link between long-term statin use and reduced gallstone risk?

Bodmer

Meier²

2010

Clinical Lipidology

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Effects of simvastatin on hepatic cholesterol metabolism, bile lithogenicity and bile acid hydrophobicity in patients with gallstones

Cited by 31 publications

References 54 publications

Baseline cholesterol absorption and the response to ezetimibe/simvastatin therapy: a post-hoc analysis of the ENHANCE trial

Baseline cholesterol absorption and the response to ezetimibe/simvastatin therapy: a post-hoc analysis of the ENHANCE trial

Quantitative analysis of the expression of ACAT genes in human tissues by real-time PCR2

Is there a link between long-term statin use and reduced gallstone risk?

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