Abstract
The cholecystokinin A receptor (CCKAR) is expressed predominantly in the gallbladder and small intestine in the digestive system, where it is responsible for CCK’s regulation of gallbladder and small intestinal motility. The effect of CCKAR on small intestinal transit is a physiological response for regulating intestinal cholesterol absorption. The CCKAR gene has been identified to be an important gallstone gene, Lith13, in inbred mice by a powerful quantitative trait locus analysis. Knockout of the CCKAR gene in mice enhances cholesterol cholelithogenesis by impairing gallbladder contraction and emptying, promoting cholesterol crystallization and crystal growth, and increasing intestinal cholesterol absorption. Clinical and epidemiological studies have demonstrated that several variants in the CCKAR gene are associated with increased prevalence of cholesterol cholelithiasis in humans. Dysfunctional gallbladder emptying in response to exogenously administered CCK-8 is often found in patients with cholesterol gallstones, and patients with pigment gallstones display an intermediate degree of gallbladder motility defect. Gallbladder hypomotility is also revealed in some subjects without gallstones under several conditions: pregnancy, total parenteral nutrition, celiac disease, oral contraceptives and conjugated estrogens, obesity, diabetes, the metabolic syndrome, and administration of CCKAR antagonists. The physical–chemical, genetic, and molecular studies of Lith13 show that dysfunctional CCKAR enhances susceptibility to cholesterol gallstones through two primary mechanisms: impaired gallbladder emptying is a key risk factor for the development of gallbladder hypomotility, biliary sludge (the precursor of gallstones), and microlithiasis, as well as delayed small intestinal transit augments cholesterol absorption as a major source for the hepatic hypersecretion of biliary cholesterol and for the accumulation of excess cholesterol in the gallbladder wall that further worsens impaired gallbladder motor function. If these two defects in the gallbladder and small intestine could be prevented by the potent CCKAR agonists, the risk of developing cholesterol gallstones could be dramatically reduced.
Highlights
Based on accumulated evidence from epidemiological and clinical studies, as well as from animal and in vitro physical–chemical experiments, a critical concept on the pathophysiology and pathogenesisGenes 2020, 11, 1438; doi:10.3390/genes11121438 www.mdpi.com/journal/genesGenes 2020, 11, 1438 of cholesterol cholelithiasis has been proposed [1]
Five primary defects work together to enhance cholesterol cholelithogenesis, which include (i) Lith genes and genetic factors; (ii) hepatic hypersecretion of biliary cholesterol, inducing cholesterol-supersaturated gallbladder bile, i.e., high cholesterol saturation index (CSI); (iii) rapid cholesterol nucleation and crystallization and accelerated growth of solid cholesterol crystals; (iv) dysfunctional gallbladder motility, leading to impaired gallbladder emptying and refilling with mucin hypersecretion and gel formation, promoting the development of biliary sludge, i.e., the precursor of gallstones; (v) intestinal factors, including increased delivery of the cholesterol absorbed from the small intestine to the liver for biliary hypersecretion, alterations in gut microbiota, and sluggish intestinal transit
Compelling evidence has strongly suggested that the pathogenesis of cholesterol gallstone Compelling evidence has strongly suggested that the pathogenesis of cholesterol gallstone formation is determined by Lith genes, and by hepatic hypersecretion of biliary cholesterol, formation is determined by Lith genes, and by hepatic hypersecretion of biliary supersaturated gallbladder bile, rapid cholesterol nucleation and crystallization through several cholesterol, supersaturated gallbladder bile, rapid cholesterol nucleation and crystallization through intermediate steps, dysfunctional gallbladder motility, and increased intestinal cholesterol absorption several intermediate steps, dysfunctional gallbladder motility, and increased intestinal cholesterol with a dramatic change in gut microbiota [3]
Summary
Based on accumulated evidence from epidemiological and clinical studies, as well as from animal and in vitro physical–chemical experiments, a critical concept on the pathophysiology and pathogenesis. Five primary defects work together to enhance cholesterol cholelithogenesis, which include (i) Lith genes and genetic factors; (ii) hepatic hypersecretion of biliary cholesterol, inducing cholesterol-supersaturated gallbladder bile, i.e., high cholesterol saturation index (CSI); (iii) rapid cholesterol nucleation and crystallization and accelerated growth of solid cholesterol crystals; (iv) dysfunctional gallbladder motility, leading to impaired gallbladder emptying and refilling with mucin hypersecretion and gel formation, promoting the development of biliary sludge, i.e., the precursor of gallstones; (v) intestinal factors, including increased delivery of the cholesterol absorbed from the small intestine to the liver for biliary hypersecretion, alterations in gut microbiota, and sluggish intestinal transit. We summarize the latest progress in the discovery of Lith and its genetic analysis in mice and humans, as well as the lithogenic mechanisms of Lith at a cellular and molecular level and its critical role in pathogenesis of cholesterol gallstone disease in mice, and in humans
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