Current Views on Genetics and Epigenetics of Cholesterol Gallstone Disease

Abstract

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.

Prevalence, clinical investigation, and management of gallbladder disease in Rett syndrome

“…In comparison with control individuals, these mice had higher lipid concentrations thought to arise from systemic dyslipidaemia, which is also a risk factor for gallstones. 34 Although the underlying mechanisms are unknown, the mouse data support the idea that genes involved in lipid homeostasis are regulated by chromatinremodelling complexes that involve the MECP2 gene. 35 Biological processes associated with gallbladder function, such as cholesterol metabolism, biliary lipid secretion, lipid transport, and gallbladder contractility, are regulated by a variety of transcription factors and nuclear receptors including the liver X receptor, the farnesoid X receptor, and the oestrogen receptor alpha (ESR1).…”

Composition Difference of Cholesterol-, Pigment- and Mixed-type Gallstones, and Their Formation Mechanisms

“…The bacteria in infected bile easily produce a large number of β-glucose acid glycosides, which can hydrolyze bilirubinate into non-conjugated bilirubin (UCB); UCB can react with calcium ions to form calcium bilirubinate precipitation. When the activity of β-glucose increases, the concentration of UCB will increase, it leads an increase of the incidence of pigment gallstones [10].…”

Role of Serum Lipids in Gallstone Pathogenesis: A Case–control Study From Punjab

“…Multiple risk factors responsible for the GS formation include modifiable factors such as lifestyle factors (reduced physical activity, rapid weight loss, fasting, parity, and oral contraceptives [6,7]); dietary factors (high fat, high cholesterol, high refined carbohydrates, and low fiber [6]); metabolic syndrome (obesity, diabetes mellitus, dyslipidemia, and hyperinsulinemia [8][9][10][11]); and disease (Cirrhosis and Crohn's disease [4,12]). In contrast to this, non-modifiable factor includes family history, ethnicity, female sex, and increasing age [6,13]. Interaction between genetic factors, lipid metabolism, intestinal factors, and gallbladder hypomotility is important for the complete understanding of GS formation [2,14,15].…”

“…Lipids are the essential constituent of our body, which have the ability to maintain equilibrium and rule the cellular functions of our body. Hence, any abnormality in the lipid metabolism will lead to hypersecretion of hepatic cholesterol into bile in comparison to other lipids, which results in supersaturation of bile that further continues to grow and develop into solid cholesterol crystals [6,16,17].…”