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Figure 1: Current view on the complex interplay of pathogenic factors in cholesterol gallstone formation. The combination of multiple disturbances affecting cholesterol homeostasis in bile is essential for cholesterol gallstone formation. LITH genes and genetic defects play a crucial role in the formation of cholesterol gallstones. A large number of LITH genes have been identified in mouse models of cholesterol gallstones, and based on mouse studies, several human LITH genes have been identified, and their contributions to the formation of cholesterol gallstones are now being investigated. Hepatic hypersecretion of biliary cholesterol leads to unphysiological supersaturation of gallbladder bile with cholesterol. At the enterocyte (small intestine) level, absorption of cholesterol is enhanced via the Niemann-Pick C1-like 1 (NPC1L1) pathway. In bile, as a consequence, accelerated phase transitions of cholesterol occur, which are facilitated by prolonged gallbladder stasis due to impaired gallbladder motility and immune-mediated gallbladder inflammation, as well as hypersecretion of mucins and accumulation of mucin gel in the gallbladder lumen [6, 17]. In bile, growth of solid plate-like cholesterol monohydrate crystals to form gallstones is a consequence of persistent hepatic hypersecretion of biliary cholesterol together with enhanced gallbladder mucin secretion and incomplete evacuation by the gallbladder due to its impaired motility function [6, 29]. The two inlets on the left depict the major pathways of cholesterol absorption and secretion at the enterocyte level and at the hepatocyte level, respectively, as mediated by specific transporter proteins. Also, relative cholesterol hypersecretion into hepatic bile may or may not be accompanied by normal, high, or low secretion rates of biliary bile acids or phospholipids. Although NPC1L1 is expressed in the liver, its mRNA expression and protein concentrations are very low compared to those in the small intestine, thereby suggesting that hepatic NPC1L1 could have a minor role in regulating biliary cholesterol secretion.