Cholesterol gallstone disease, one of the commonest digestive diseases in western countries, is induced by an imbalance in cholesterol metabolism, which involves intestinal absorption, hepatic biosynthesis, and biliary output of cholesterol, and its conversion to bile acids. Several components of the metabolic syndrome (e.g., obesity, type 2 diabetes, dyslipidemia, and hyperinsulinemia) are also well-known risk factors for gallstones, suggesting the existence of interplay between common pathophysiological pathways influenced by insulin resistance, genetic, epigenetic, and environmental factors. Cholesterol gallstones may be enhanced, at least in part, by the abnormal expression of a set of the genes that affect cholesterol homeostasis and lead to insulin resistance. Additionally, epigenetic mechanisms (mainly DNA methylation, histone acetylation/deacetylation, and noncoding microRNAs) may modify gene expression in the absence of an altered DNA sequence, in response to different lithogenic environmental stimuli, such as diet, lifestyle, pollutants, also occurring in utero before birth. In this review, we will comment on various steps of the pathogenesis of cholesterol gallstones and interaction between environmental and genetic factors. The epigenomic approach may offer new options for therapy of gallstones and better possibilities for primary prevention in subjects at risk. 1. Introduction Cholesterol gallstone disease is one of the most prevalent and most costly digestive diseases requiring hospital admission, since its prevalence ranges from 10% to 15% in adults. Medical expenses for gallstone treatment exceeded $4 billion in facility charges in 2004 in the United States [1] and rise to $6.5 billion when surgical complications occur [2]. The formation and growth of cholesterol gallstones, which accounts for 75% of the gallstones in westernized countries [3–5], are secondary to abnormal cholesterol homeostasis [6]. Of note, the main risk factors for cholesterol gallstone disease (e.g., obesity, type 2 diabetes, dyslipidemia, and hyperinsulinemia) are also well-known components of the metabolic syndrome [7–11], supporting the hypothesis that gallstone disease is just another component of the metabolic syndrome [12–14] (Table 1). Due to the high prevalence of the metabolic syndrome, it has been suggested that the phenotype of cholesterol gallstones may result from the interaction between insulin resistance, genetic factors, and a number of environmental factors [15]. A series of gallstone (LITH) genes have been identified, which affect cholesterol
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