38 In other studies, statins neither influenced biliary cholesterol secretion nor reduced cholesterol saturation indices in general.39 The data from our patients, which are given as means, indicate that subgroups of patients are at higher (genetic) risk of stone formation. In these cases, increased cholesterol synthesis could be a critical additional factor driving stone formation, and they could benefit from drugs lowering cholesterol

Selleckchem JQ1 synthesis, which has indeed been observed on an individual basis.40 With respect to ezetimibe, studies in mouse models and a single study in humans41, 42 have shown that it can reduce biliary cholesterol secretion and cholesterol concentrations in gallbladder bile. In this respect, future prospective studies using surrogate markers of cholesterol synthesis and transport in large cohorts of patients under cholesterol-lowering therapy are warranted. Previously, it has been postulated that in selected patients ratios of serum campesterol and sitosterol to cholesterol reflect the biliary cholesterol secretion rates.43 Because in our study we used the surrogate markers for cholesterol transport

and synthesis, which indicated a link between cholesterol homeostasis and GSD, we further strengthened our findings by analysis of biliary lipid compositions, demonstrating that gallstone patients display increased biliary levels of both phytosterols and cholesterol. These results are in line with data published by Miettinen et al.44 Their

analysis of 150 individuals with cholesterol stones showed preferentially increased see more levels of plant sterols in bile from cholesterol gallstone patients.44 The latest analysis of a cohort of pediatric patients with gallstones indicated that increased cholesterol synthesis 17-DMAG (Alvespimycin) HCl and decreased cholesterol absorption are likely to underlie the formation of gallbladder stones in younger individuals.45 Interestingly, the same profile is characteristic for another liver phenotype, fatty liver disease.46 As fatty liver is one of the risk factors for gallstone formation,47 distorted cholesterol homeostasis may represent a metabolic link between both entities. Moreover, we observed pronounced differences across the ethnic groups (Fig. 2). These results, together with lower cholesterol levels in Chilean individuals as compared with Germans, point to a more pronounced prolithogenic phenotype in Chileans and at least partially explain the previously reported differences of gallstone prevalence rates among the ethnicities included in the current study.21-23 In summary, serum sterol levels represent surrogate markers indicating that gallstone-susceptible patients display enhanced secretion of cholesterol and non-cholesterol sterols into bile, which is coupled with an increased synthesis of new cholesterol. Furthermore, increased cholesterol synthesis might be secondary to decreased intestinal cholesterol absorption resulting from gain-of-function of the ABCG5/8 transporter system.