Effects of cholesterol on CCK-1 receptors and caveolin-3 proteins recycling in human gallbladder muscle

Cong, Ping; Pricolo, Victor E.; Biancani, Piero; Behar, José

doi:10.1152/ajpgi.00064.2010

Cited by 18 publications

(21 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Cholesterol decreases Ca 2+ channel function and excitatory receptor activation (15, 27). These changes may also result in decreased fluidity of cholesterol-enriched membranes, particularly in caveolar regions (28, 29). For instance, an elevated concentration of cholesterol in the plasma membrane increases expression of caveolin-3 causing sequestration of CCK-1 receptors and therefore supporting the lower binding of CCK in affected smooth muscle (28, 29).…”

Section: Discussionmentioning

confidence: 99%

Disruption of gallbladder smooth muscle function is an early feature in the development of cholesterol gallstone disease

Lavoie

Nausch

Zane

et al. 2012

Neurogastroenterology Motil

View full text Add to dashboard Cite

Background Decreased gallbladder smooth muscle (GBSM) contractility is a hallmark of cholesterol gallstone disease, but the interrelationship between lithogenicity, biliary stasis and inflammation are poorly understood. We studied a mouse model of gallstone disease to evaluate the development of GBSM dysfunction relative to changes in bile composition and the onset of sterile cholecystitis. Methods BALB/cJ mice were fed a lithogenic diet for up to 8 weeks, and tension generated by gallbladder muscle strips was measured. Smooth muscle Ca2+ transients were imaged in intact gallbladder. Key Results Lipid composition of bile was altered lithogenically as early as one week, with increased hydrophobicity and cholesterol saturation indexes; however, inflammation was not detectable until the fourth week. Agonist-induced contractility was reduced from weeks 2 through 8. GBSM normally exhibits rhythmic synchronized Ca2+ flashes, and their frequency is increased by carbachol (3μM). After one week, lithogenic diet-fed mice exhibited disrupted Ca2+ flash activity, manifesting as clustered flashes, asynchronous flashes or prolonged quiescent periods. These changes could lead to a depletion of intracellular Ca2+ stores, which are required for agonist-induced contraction, and diminished basal tone of the organ. Responsiveness of Ca2+ transients to carbachol was reduced in mice on the lithogenic diet, particularly after 4-8 weeks, concomitant with appearance of mucosal inflammatory changes. Conclusions & Inferences These observations demonstrate that GBSM dysfunction is an early event in the progression of cholesterol gallstone disease and that it precedes mucosal inflammation.

show abstract

Section: Discussionmentioning

confidence: 99%

Disruption of gallbladder smooth muscle function is an early feature in the development of cholesterol gallstone disease

Lavoie

Nausch

Zane

et al. 2012

Neurogastroenterology Motil

View full text Add to dashboard Cite

show abstract

“…In the gallbladder, cholesterol‐induced hypomotility is believed to occur through at least two intracellular mechanisms: (1) the inhibitory effect of cholesterol on action potentials and Ca 2+ currents in smooth muscle (Jennings et al 1999), and (2) CCK‐1R (previously CCK‐A)‐mediated activation of phospholipase C leading to signal‐transduction decoupling of CCK when gallbladder sarcolemmae become enriched in cholesterol (Yu et al 1998; Xiao et al 1999). It appears that an increase in caveolar cholesterol inhibits Cav3 phosphorylation in gallbladder sarcolemmae, a vital step in the recycling and reintegration of CCK‐1R–G protein complexes into non‐caveolar portions of the smooth muscle plasma membranes (Cong et al 2010). This inhibition of Cav3 phosphorylation, along with sequestration of CCK‐1R–G protein complexes in caveolae, most probably explains why CCK ‘finds’ fewer CCK‐1Rs to bind to in cholesterol‐enriched, as compared with normal sarcolemmae (Cong et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Augmented cholesterol absorption and sarcolemmal sterol enrichment slow small intestinal transit in mice, contributing to cholesterol cholelithogenesis

Xie

Kotecha

Andrade

et al. 2012

The Journal of Physiology

View full text Add to dashboard Cite

Key points• Peristaltic function of the small intestine is compromised in cholelithogenic humans and in animal models of cholesterol gallstones.• In a mouse gallstone model fed a cholesterol-and cholic acid-enriched diet, we show that slowing of small intestinal transit is due to absorption of excess cholesterol molecules from the upper small intestine followed by their incorporation into sarcolemmal membranes of smooth muscle cells.• Blocking cholesterol absorption with ezetimibe (Zetia), an inhibitor of intestinal sterol transport, prevents cholesterol enrichment of sarcolemmal membranes and normalizes the motility disorder.• Although the primary source of intestinal cholesterol in mice is the lithogenic diet, in most cholesterol gallstone-prone humans, the small intestine is flooded continuously with an abundance of liver-secreted cholesterol molecules via bile.• Our findings imply that small intestinal hypomotility will amplify the cholelithogenic state because of hyperabsorption of cholesterol and 'secondary' bile salt synthesis by the gut's anaerobic microbiota.Abstract Cholesterol gallstones are associated with slow intestinal transit in humans as well as in animal models, but the molecular mechanism is unknown. We investigated in C57L/J mice whether the components of a lithogenic diet (LD; 1.0% cholesterol, 0.5% cholic acid and 17% triglycerides), as well as distal intestinal infection with Helicobacter hepaticus, influence small intestinal transit time. By quantifying the distribution of 3 H-sitostanol along the length of the small intestine following intraduodenal instillation, we observed that, in both sexes, the geometric centre (dimensionless) was retarded significantly (P < 0.05) by LD but not slowed further by helicobacter infection (males, 9.4 ± 0.5 (uninfected), 9.6 ± 0.5 (infected) on LD compared with 12.5 ± 0.4 and 11.4 ± 0.5 on chow). The effect of the LD was reproduced only by the binary combination of cholesterol and cholic acid. We inferred that the LD-induced cholesterol enrichment of the sarcolemmae of intestinal smooth muscle cells produced hypomotility from signal-transduction decoupling of cholecystokinin (CCK), a physiological agonist for small intestinal propulsion in mice. Treatment with ezetimibe in an amount sufficient to block intestinal cholesterol absorption caused small intestinal transit time to return to normal. In most cholesterol gallstone-prone humans, lithogenic bile carries large quantities of hepatic cholesterol into the upper small intestine continuously, thereby reproducing this dietary effect in mice.

show abstract

“…Their sequestration within caveolae further decreases the turnover of CCK-1 R from endosomes to PM; this leads to fewer CCK-1 R available for CCK-8 binding and weaker muscle contraction. 20,21 Cholesterol overabundance in PM may also impair cytoprotective mechanisms of GBSM by decreasing the binding of PGE2 to its receptors in the same manner as CCK-1 R. As a result, the catalase response and degree of free radical inactivation is lower despite a similar PGE2 level. 22,23 Hydrophobic bile salts inhibit GBSM contraction by generating free radicals (H 2 O 2 ) that damage PM receptors and then inhibit CCK-induced contraction.…”

Section: Gallbladder Motilitymentioning

confidence: 99%

Cholesterol gallstone disease: focusing on the role of gallbladder

Chen

Kong

2015

Laboratory Investigation

View full text Add to dashboard Cite

Gallstone disease (GSD) is one of the most common biliary tract diseases worldwide in which both genetic and environmental factors have roles in its pathogenesis. Biliary cholesterol supersaturation from metabolic defects in the liver is traditionally seen as the main pathogenic factor. Recently, there have been renewed investigative interests in the downstream events that occur in gallbladder lithogenesis. This article focuses on the role of the gallbladder in the pathogenesis of cholesterol GSD (CGD). Various conditions affecting the crystallization process are discussed, such as gallbladder motility, concentrating function, lipid transport, and an imbalance between pro-nucleating and nucleation inhibiting proteins.

show abstract

Effects of cholesterol on CCK-1 receptors and caveolin-3 proteins recycling in human gallbladder muscle

Cited by 18 publications

References 32 publications

Disruption of gallbladder smooth muscle function is an early feature in the development of cholesterol gallstone disease

Disruption of gallbladder smooth muscle function is an early feature in the development of cholesterol gallstone disease

Augmented cholesterol absorption and sarcolemmal sterol enrichment slow small intestinal transit in mice, contributing to cholesterol cholelithogenesis

Cholesterol gallstone disease: focusing on the role of gallbladder

Contact Info

Product

Resources

About