Abstract
Epidemiological data shows that cholesterol cholelithiasis is a disease that demonstrates one of the highest increases in incidence among digestive diseases during the past 50 years. Impairment of gallbladder contractions causes bile stasis, and stasis of supersaturated bile in the gallbladder favors cholesterol crystallization and gallstone formation. However, it remains unclear if the etiology of gallstone formation is multifactorial or genetic. We recently determined the transcriptional start site of the human CCK-A receptor (R) gene and found two polymorphisms (-81A/G, -128G/T). We also cloned the genomic structures of CCK-AR in rats and mice, and generated CCK-AR gene knockout (-/-) mice. Sludge and gallstone formation were significantly higher in CCK-AR(-/-) mice than in CCK-AR(+/+) mice at 12 and 24 months of age. The plasma cholesterol levels, daily food intake, and body weight were not significantly different between CCK-AR(+/+) and (-/-) mice. Sludge and gallstone formation were not observed at 6 months of age. The homozygote (GG/TT) polymorphism of the human CCK-AR gene was associated with a significantly higher percentage of body fat. As the incidence of cholesterol gallstones has been correlated with obesity, polymorphism of CCK-AR enhanced gallstone formation is likewise a cause, indirectly, via obesity. In conclusion, a decrease in the strength of gallbladder contractions, possibly induced by alterations in the CCK-AR gene, as well as by CCK-AR gene polymorphism, was shown to promote gallstone formation. [Jpn J Physiol 54 Suppl:S59 (2004)]
