Ezetimibe prevents cholesterol gallstone formation in mice

Zúñiga, Silvia; Molina, Helia; Azócar, Lorena; Amigo, Ludwig; Nervi, Flavio; Pimentel, Fernando; Jarufe, Nicolás; Arrese, Marco; Lammert, Frank; Miquel, Juan Francisco

doi:10.1111/j.1478-3231.2008.01808.x

Cited by 62 publications

(34 citation statements)

References 50 publications

(74 reference statements)

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“…Ezetimibe has not been shown to increase the risk of gall stones perhaps because the drug has its primary effect in reducing cholesterol absorption. Indeed in the golden Syrian hamster Ezetimibe reduced diet-induced increase in biliary cholesterol [99], and, in gallstone-susceptible mice fed lithogenic diets, Ezetimibe prevented gall stone formation [100]. Inhibition of NPC1L1 by Ezetimibe is associated with an improvement in hepatic steatosis.…”

Section: Gene Regulation Of Chylomicron Metabolismmentioning

confidence: 99%

The Chylomicron: Relationship to Atherosclerosis

Tomkin

Owens

2012

International Journal of Vascular Medicine

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The B-containing lipoproteins are the transporters of cholesterol, and the evidence suggests that the apo B48-containing postprandial chylomicron particles and the triglyceride-rich very low density lipoprotein (VLDL) particles play an important part in the development of the plaque both directly and indirectly by their impact on LDL composition. The ratio of dietary to synthesised cholesterol is variable but tightly regulated: hence intervention with diet at best reduces serum cholesterol by <20% andusually <10%. Statins are the mainstay of cholesterol reduction therapy, but they increase cholesterol absorption, an example of the relationship between synthesis and absorption. Inhibition of cholesterol absorption with Ezetimibe, an inhibitor of Niemann Pick C1-like 1 (NPC1-L1), the major regulator of cholesterol absorption, increases cholesterol synthesis and hence the value of adding an inhibitor of cholesterol absorption to an inhibitor of cholesterol synthesis. Apo B48, the structural protein of the chylomicron particle, is synthesised in abundance so that the release of these particles is dependent on the amount of cholesterol and triglyceride available in the intestine. This paper will discuss cholesterol absorption and synthesis, chylomicron formation, and the effect of postprandial lipoproteins on factors involved in atherosclerosis.

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Section: Gene Regulation Of Chylomicron Metabolismmentioning

confidence: 99%

The Chylomicron: Relationship to Atherosclerosis

Tomkin

Owens

2012

International Journal of Vascular Medicine

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“…It is also found that high doses of estrogen augment intestinal cholesterol absorption [102], contributable in part to an up-regulated expression of intestinal sterol influx transporter Niemann-Pick C1 like 1 protein (NPC1L1) via the intestinal ESR1 pathway [115]. Because of species differences, NPC1L1 is expressed in the livers of humans and hamsters [116,117,118], but not in mouse livers [117,119,120]. Together with hepatic lipid transporters such as ABCG5/G8 on cholesterol secretion, ABCB11 on bile salt secretion and ABCB4 on phospholipid secretion [1], NPC1L1 may participate in the regulation of biliary cholesterol secretion.…”

Section: Molecular Mechanisms Underlying the Effect Of Estrogen On Gamentioning

confidence: 99%

New insights into the molecular mechanisms underlying effects of estrogen on cholesterol gallstone formation

Wang

Liu

Clegg

et al. 2009

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

109

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Epidemiological and clinical studies have found that at all ages women are twice as likely as men to form cholesterol gallstones, and this gender difference begins since puberty and continues through the childbearing years, which highlight the importance of female sex hormones. Estrogen is a crucial hormone in human physiology and regulates a multitude of biological processes. The actions of estrogen have traditionally been ascribed to two closely related classical nuclear hormone receptors, estrogen receptor 1 (ESR1) and ESR2. Recent studies have revealed that the increased risk for cholesterol gallstones in women vs. men is related to differences in how the liver metabolizes cholesterol in response to estrogen. A large number of human and animal studies have proposed that estrogen increases the risk of developing cholesterol gallstones by increasing the hepatic secretion of biliary cholesterol, which, in turn, leads to an increase in cholesterol saturation of bile. Furthermore, it has been identified that hepatic ESR1, but not ESR2, plays a major role in cholesterol gallstone formation in mice in response to high doses of 17β-estradiol. The mechanisms mediating estrogen’s action has become more complicated with the recent identification of a novel estrogen receptor, G protein-coupled receptor 30 (GPR30), a member of the seven-transmembrane G protein-coupled receptor superfamily. In this review, we provide an overview of the evidence for the lithogenic actions of estrogen through ESR1 and discuss the cellular and physiological actions of GPR30 in estrogen-dependent processes and the relationship between GPR30 and classical ESR1 on gallstone formation.

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“…This may result from decreased hepatic cholesterol biosynthesis and consequently reduced cholesterol concentrations in bile. Further mouse models [101,102] found ezetimibe to exert its protective effect through the reduced absorption of intestinal cholesterol coupled with an increased bile flow. This is an exciting area of research that holds preventative potential in high-risk groups.…”

Section: Environmental Factorsmentioning

confidence: 99%

Gallstones: Environment, Lifestyle and Genes

Stokes

Krawczyk

Lammert³

2011

Dig Dis

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Gallstone disease represents one of the most common and costly gastroenterological disorders. In Germany, 0.25% of the population undergo cholecystectomy per year, and cholelithiasis incurs annual medical expenses of more than USD 6.5 billion in the United States. The paradigm of environmental risk factors for gallstones has lately been challenged by genetic studies in experimental models and humans. The analysis of more than 40,000 Swedish twin pairs with gallstones demonstrated that genetic factors account for 25% of the phenotypic variance. Since then, studies employing genome-wide association analysis, case-control cohorts and analysis of sib-pairs in families with gallstones have expanded our knowledge of ‘gallstone genes’. Indeed, gallstone disease phenotypes are likely to result from the complex interaction of genetic factors, chronic overnutrition with carbohydrates, depletion of dietary fibre and other not fully defined environmental factors including physical inactivity and infections. This hypothesis is supported by the profound increases of cholesterol gallstone prevalence rates in Native Americans, post-war European countries and current urban centres in East Asia, all of which were associated with ‘westernized’ nutrition. Herein, we summarise the spectrum of environmental and genetic risk factors which should pave the way to ‘personalised’ strategies for the prevention and therapy of gallstones.

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Ezetimibe prevents cholesterol gallstone formation in mice

Abstract: In a murine model of GSD, EZET prevented gallstone formation by reducing intestinal cholesterol absorption and increasing bile salt-dependent and -independent bile flow. EZET could be useful in preventing GSD disease in susceptible patients.

Cited by 62 publications

References 50 publications

The Chylomicron: Relationship to Atherosclerosis

The Chylomicron: Relationship to Atherosclerosis

New insights into the molecular mechanisms underlying effects of estrogen on cholesterol gallstone formation

Gallstones: Environment, Lifestyle and Genes

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