Roles of cholesterol and bile salts in the pathogenesis of gallbladder hypomotility and inflammation: cholecystitis is not caused by cystic duct obstruction

Abstract

A large number of human and animal studies have challenged the hypothesis that cystic duct obstruction by gallstones causes cholecystitis. These studies suggest that lithogenic bile that can deliver high cholesterol concentrations to the gallbladder wall causes hypomotility and creates a permissive environment that allows normal concentrations of hydrophobic bile salts to inflame the mucosa and impair muscle function inhibiting gallbladder emptying. High concentrations of cholesterol increase its diffusion rates through the gallbladder wall where they are incorporated into the sarcolemmae of muscle cells by caveolin proteins. High caveolar cholesterol levels inhibit tyrosine-induced phosphorylation of caveolin proteins required to transfer receptor-G protein complexes into recycling endosomes. The sequestration of these receptor-G protein complexes in the caveolae results in fewer receptors recycling to the sarcolemmae to be available for agonist binding. Lower internalization and recycling of CCK-1 and other receptors involved in muscle contraction explain gallbladder hypomotility. PGE2 receptors involved in cytoprotection are similarly affected. Cells with a defective cytoprotection failed to inactivate free radicals induced by normal concentrations of hydrophobic bile salts resulting in chronic inflammation that may lead to acute inflammation. Ursodeoxycholic acid salts (URSO) block these bile salts effects thereby preventing the generation of free radicals in muscle cells in vitro and development of cholecystitis in the ligated common bile duct in guinea pigs in vivo. Treatment with URSO improves muscle contraction and reduces the oxidative stress in patients with symptomatic cholesterol gallstones by lowering cholesterol concentrations and blocking the effects of hydrophobic bile salts on gallbladder tissues.

Serum 25-hydroxyvitamin D concentrations in dogs with gallbladder mucocele

“…Gallbladder hypokinesia is defined as gallbladder hypomotility in response to normal physiologic stimuli and results in pathogenic alterations to bile including supersaturation of cholesterol and hydrophobic bile acids [3,4]. Exposure of gallbladder epithelial and smooth muscle cells to concentrated biliary constituents causes hypersecretion of mucus and inflammation via oxidative damage (H 2 O 2 ) and lipid peroxidation; the consequences of which results in the development of gallbladder sludge, mucus plugs, gallstones, cholecystitis, and biliary colic [5][6][7][8][9][10]. Biliary stasis has been linked to many common conditions in humans including obesity, hyperglycemia, hypothyroidism, hypertriglyceridemia, acalculous cholecystitis, pregnancy, and vitamin D deficiency [11][12][13][14][15][16].…”

An Analysis of the Role of the Indigenous Microbiota in Cholesterol Gallstone Pathogenesis

“…In fact, the data demonstrate that the overall concentration of gallbladder cholesterol is significantly decreased in germ-free mice. This decrease in cholesterol concentration may be due to increased Muc1 expression because Muc1 induction has been shown to increase cholesterol absorption from gallbladder bile which in turn has been shown to promote gallbladder inflammation and hypomotility [37], [38].…”

The expression of hepatic carboxypeptidase E is decreased in patients with cholesterol gallstone

“…Notably, plasma CCK level was significantly decreased in patients with gallstones. [ 14 ] A reduced and delayed postprandial gallbladder contractility and impaired CCK release in the early postprandial phase have been shown to be significantly associated with gallstone disease. [ 15 ] In this study we found decreased plasma CCK level and increased biliary cholesterol and CSI in CGS patients compared with non-CGS patients.…”