Excess membrane cholesterol alters human gallbladder muscle contractility and membrane fluidity

Chen, Qian; Amaral, Joseph F.; Biancani, Piero; Behar, José

doi:10.1016/s0016-5085(99)70190-3

Cited by 117 publications

(108 citation statements)

References 36 publications

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“…It has been described that aging compromises gallbladder function and drives to an elevated incidence of cholesterol gallstones in old individuals (Chen et al 1999;van de Heijning et al 1999;Xu and Shaffer 1996). We found that aging modifies neurological control of guinea pig gallbladder and impairs contractile response as the result of alterations in the contractile machinery without affecting calcium release from intracellular stores (Gomez-Pinilla et al 2006).…”

Section: Introductionsupporting

confidence: 47%

Aging impairs Ca2+ sensitization pathways in gallbladder smooth muscle

Macias

Gomez‐Pinilla

Camello-Almaraz

et al. 2011

AGE

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Calcium sensitization is an important physiological process in agonist-induced contraction of smooth muscle. In brief, calcium sensitization is a pathway that leads to smooth muscle contraction independently of changes in [Ca 2+ ] i by mean of inhibition of myosin light chain phosphatase. Aging has negative impacts on gallbladder contractile response due to partial impairment in calcium signaling and alterations in the contractile machinery. However, information regarding aging-induced alterations in calcium sensitization is scanty. We hypothesized that the calcium sensitization system is negatively affected by age. To investigate this, gallbladders were collected from adult (4 months old) and aged (22-24 months old) guinea pigs. To evaluate the contribution of calcium sensitization pathways we assayed the effect of the specific inhibitors Y-27632 and GF109203X on the "in vitro" isometric gallbladder contractions induced by agonist challenges. In addition, expression and phosphorylation (as activation index) of proteins participating in the calcium sensitization pathways were quantified by Western blotting. Aging reduced bethanechol-and cholecystokinin-evoked contractions, an effect associated with a reduction in MLC20 phosphorylation and in the effects of both Y-27632 and GF109203X. In addition, there was a drop in ROCK I, ROCK II, MYPT-1 and PKC expression and in the activation/phosphorylation of MYPT-1, PKC and CPI-17 in response to agonists. Interestingly, melatonin treatment for 4 weeks restored gallbladder contractile responses due to re-establishment of calcium sensitization pathways. These results demonstrate that agerelated gallbladder hypocontractility is associated to alterations of calcium sensitization pathways and that melatonin treatment exerts beneficial effects in the recovery of gallbladder contractility.

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Section: Introductionsupporting

confidence: 47%

Aging impairs Ca2+ sensitization pathways in gallbladder smooth muscle

Macias

Gomez‐Pinilla

Camello-Almaraz

et al. 2011

AGE

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“…Another natural CCK1R-expressing cell system, human gallbladder smooth-muscle cells, has also been reported to exhibit the same types of cholesterol sensitivity (45)(46)(47)(48)(49)(50). Smooth-muscle cells from gallbladders of patients having cholesterol gallstones have been shown to have elevated membrane cholesterol, whereas those from patients having pigment gallstones have normal levels of cholesterol ( 46 ).…”

Section: Discussionmentioning

confidence: 99%

Differential sensitivity of types 1 and 2 cholecystokinin receptors to membrane cholesterol

Potter

Harikumar

et al. 2012

Journal of Lipid Research

109

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Recent studies indicate that membrane cholesterol can associate with G protein-coupled receptors (GPCRs) and affect their function. Previously, we reported that manipulation of membrane cholesterol affects ligand binding and signal transduction of the type 1 cholecystokinin receptor (CCK1R), a Class A GPCR. We now demonstrate that the closely related type 2 cholecystokinin receptor (CCK2R) does not share this cholesterol sensitivity. The sequences of both receptors reveal almost identical cholesterol interaction motifs in analogous locations in transmembrane segments two, three, four, and fi ve. The disparity in cholesterol sensitivity between these receptors, despite their close structural relationship, provides a unique opportunity to defi ne the possible structural basis of cholesterol sensitivity of CCK1R. To evaluate the relative contributions of different regions of CCK1R to cholesterol sensitivity, we performed ligand binding studies and biological activity assays of wildtype and CCK2R/CCK1R chimeric receptor-bearing Chinese hamster ovary cells after manipulation of membrane cholesterol. We also extended these studies to site-directed mutations within the cholesterol interaction motifs. The results contribute to a better understanding of the structural requirements for cholesterol sensitivity in CCK1R and provides insight into the function of other cholesterol-sensitive Class A GPCRs. Cholesterol is an important lipid component of the eukaryotic plasma membrane that has substantial effects on the physicochemical characteristics of the membrane. These include effects on the membrane rigidity and fl uidity, as well as its dimensions ( 1-3 ).

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“…Of note is that gallbladder hypomotility may also result from absorption of cholesterol from supersaturated bile by the gallbladder epithelial cell (50,51). Moreover, cholesterol molecules b Based upon measurements of physical growth and sexual maturation, the different age groups of mice were considered to be in the following stages of maturation: 8-weeks, young adult; 36-weeks, older adult; and 50-weeks, aged (30,31 from saturated bile could pass across the epithelium and may be incorporated into the sarcolemma of the gallbladder smooth muscle cells (52), which inhibits signal transduction when CCK bonds to CCK-A receptors in the gallbladder (53)(54)(55) and impairs gallbladder contractile function. In addition, the prolonged presence of gallbladder sludge and stones may be responsible for enlarged gallbladders with poor emptying in C57L mice.…”

Section: Downloaded Frommentioning

confidence: 99%

Aging per se is an independent risk factor for cholesterol gallstone formation in gallstone susceptible mice

Wang

2002

Journal of Lipid Research

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Cholesterol gallstones occur rarely in childhood and adolescence and increase linearly with age in both genders. To explore whether aging per se increases cholesterol saturation of bile and gallstone prevalence, and to investigate age-related changes in hepatic and biliary lipid metabolism, we studied gallstone-susceptible C57L mice and resistant AKR mice of both genders fed 8 weeks with a lithogenic diet containing 1% cholesterol, 0.5% cholic acid, and 15% butter fat starting at (young adult) 8, (older adult) 36, and (aged) 50-weeks-of-age. After the 8-week feeding, gallstone prevalence, gallbladder size, biliary lipid secretion rate, and HMG-CoA reductase activity were significantly greater but cholesterol 7 ␣ -hydroxylase activity was lower in C57L mice of both genders compared with AKR mice. Increasing age augmented biliary secretion and intestinal absorption of cholesterol, reduced hepatic synthesis and biliary secretion of bile salts, and decreased gallbladder contractility, all of which increased susceptibility to cholesterol cholelithiasis in C57L mice. We conclude that aging per se is an independent risk factor for cholesterol gallstone formation. Because aging increases significantly biliary cholesterol hypersecretion and gallstone prevalence in C57L mice carrying Lith genes, it is highly like that Longevity Cholesterol gallstone disease is influenced by a complex interaction of genetic and environmental factors (1) that determine the hypersecretion of biliary cholesterol into hepatic bile (2) and subsequently the precipitation of cholesterol crystals in gallbladder bile (3). Epidemiological and clinical investigations (4-8) have shown that cholesterol gallstones occur infrequently in childhood and adolescence, and the prevalence of cholesterol gallstone disease increases linearly with age in both genders and approaches 50% at age 70 in females. Furthermore, elderly individuals are at high risk for developing complications of gallstones and mortality from surgery is often unacceptably high in patients older than 65 (9-11). Although cholesterol saturation of bile is significantly higher in elderly Swedes (12) and Chilean women (13) and age correlates positively with increased hepatic cholesterol secretion rate (12), it has not been established how aging per se influences hepatic and biliary cholesterol metabolism. Furthermore, numerous studies on age-related hepatic cholesterol and bile salt metabolism (14-20), biliary cholesterol secretion and composition (12,13,21,22), gallbladder contraction function (23-26), and intestinal cholesterol absorption (27, 28) have been performed in humans and in different animal species; however, effects of aging on these parameters varied tremendously, being either normal, diminished, or elevated compared to young subjects. In particular, little is known whether aging per se influences cholesterol gallstone formation. In this study, using a unique genetically gallstone-susceptible C57L mouse model with Lith genes (2, 3, 29) compared to resistant AKR mice, we in...

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Excess membrane cholesterol alters human gallbladder muscle contractility and membrane fluidity

Cited by 117 publications

References 36 publications

Aging impairs Ca2+ sensitization pathways in gallbladder smooth muscle

Aging impairs Ca2+ sensitization pathways in gallbladder smooth muscle

Differential sensitivity of types 1 and 2 cholecystokinin receptors to membrane cholesterol

Aging per se is an independent risk factor for cholesterol gallstone formation in gallstone susceptible mice

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