Targeted disruption of the murine cholecystokinin-1 receptor promotes intestinal cholesterol absorption and susceptibility to cholesterol cholelithiasis

Wang, David Q.–H.; Schmitz, Frank; Kopin, Alan S.; Carey, Martin C.

doi:10.1172/jci16801

Cited by 94 publications

(61 citation statements)

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“…The mRNA levels of these genes in OVX wild-type mice receiving no E 2 and fed the lithogenic diet for 12 days are set at 1. Treatment of E 2 at 6 µg/day significantly increases mRNA levels of Muc2 , Muc5ac , Muc5b , Acat2 , Abcg5 , Abcg8 , Abca1 , and Sr-b1 in OVX wild-type, GPR30( Ϫ / Ϫ ), and ER ␣ ( ) and CCK-1R( Ϫ / Ϫ ) mice fed the lithogenic diet ( 24,39 ). In the present study, we found that gallbladder contractile dysfunction caused by E 2 also promotes rapid growth of solid cholesterol crystals mainly in E 2 -treated OVX wild-type mice with the highest CSI value.…”

Section: Discussionmentioning

confidence: 99%

Estrogen induces two distinct cholesterol crystallization pathways by activating ERα and GPR30 in female mice

Bari

Wang

Liu

et al. 2015

Journal of Lipid Research

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The precipitation of classical parallelogram-shaped cholesterol monohydrate crystals from supersaturated gallbladder bile is the fi rst irreversible physical-chemical event during the early stage of cholesterol gallstone formation ( 1 ). It is well known that estrogen has a critical role in the pathogenesis of cholesterol cholelithiasis because gallstone prevalence is markedly higher in women than in men at all ages in every population studied ( 2 ). Many clinical studies have found that the use of oral contraceptives and conjugated estrogens in premenopausal and postmenopausal women signifi cantly increases the prevalence of gallstones ( 3-5 ). Because elevated estrogen levels have a linear and positive relationship with the duration of gestation, the risk of gallstone formation becomes higher in the third trimester of pregnancy ( 6 ). Increasing parity is a risk factor for gallstones, especially in younger women. Similar lithogenic effects are also found in men with prostatic cancer during estrogen therapy ( 7,8 ). These epidemiological and clinical studies have clearly demonstrated that high susceptibility to gallstone formation in women compared with men is related to differences in how the liver metabolizes cholesterol in response to estrogen ( 9 ).We have found that the classical estrogen receptor ␣ (ER ␣ ), but not ER ␤ , in the liver plays a critical role in the pathogenesis of 17 ␤ -estradiol (E 2 )-induced gallstones in female mice ( 10 ). Despite these observations, the metabolic abnormalities underlying the lithogenic effect of E 2 on gallstone formation is not fully understood because the targeted deletion of the Er ␣ gene cannot completely protect against gallstone formation in ovariectomized (OVX) female mice treated with high doses of E 2 ( 11 ). Moreover, the discovery of the G protein-coupled receptor 30 (GPR30), a novel estrogen receptor, has led to a new question of whether it is involved in the lithogenic effect of

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Section: Discussionmentioning

confidence: 99%

Estrogen induces two distinct cholesterol crystallization pathways by activating ERα and GPR30 in female mice

Bari

Wang

Liu

et al. 2015

Journal of Lipid Research

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“…Furthermore, the essential importance of small intestinal transit rates as a determining factor of cholesterol absorption often ignored in prior investigations, has been validated in previous reports of human studies 22 and in mouse studies by us. 23 We have now used a highly accurate methodology to verify that loss of ABCG8 function does not influence small intestinal transit rates, indicating that this variable is not responsible for differences in intestinal absorption efficiency of sterols in Abcg8 Ϫ/Ϫ mice. Overall, our broad experimental approaches indicate that ABCG8 with its partner ABCG5 provides a barrier to cholesterol and sitostanol accumulation in the body by promoting partial efflux of cholesterol and nearly complete efflux of sitostanol from the enterocyte into the intestinal lumen for fecal elimination.…”

Section: Discussionmentioning

confidence: 99%

“…17 Measurement of Small Intestinal Transit Time. Because sluggish small intestinal motility increases the efficiency of cholesterol absorption, 22,23 we explored whether deletion of Abcg8 alone influences small intestinal transit rate according published methods. 13 Because loss of ABCG8 function could result in a significant increase in intestinal absorption of radiolabeled sitostanol, we used [ 51 Cr]sodium (i.e., Na 2 [ 51 Cr]O 4 ) as a nonabsorbable reference marker in this study.…”

Section: Methodsmentioning

confidence: 99%

“…Small intestinal transit time can be a powerful factor in determining absorption of intestinal sterols. 23 Figure 5 shows the identical luminal distributions of [ 51 Cr]sodium along the small intestine of Abcg8 Ϫ/Ϫ and wild-type mice. Mean values for the geometric centers of the distribution profiles of radioactivity were 11.2 Ϯ 1.7 and 12.7 Ϯ 2.2 for wild-type and Abcg8 Ϫ/Ϫ mice, respectively.…”

Section: Effects Of Abcg8 On Absorption and Lymphaticmentioning

confidence: 97%

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Quantifying anomalous intestinal sterol uptake, lymphatic transport, and biliary secretion in Abcg8 −/− mice†‡

et al. 2007

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Sitosterolemia is caused by mutations in either ABCG5 or ABCG8, but simultaneous mutations of these genes have never been observed. To explore whether ABCG8, the sterol efflux (hemi-)transporter, plays a major role in determining intestinal absorption efficiency and hepatic secretion rates of cholesterol and sitostanol, we performed direct measurements of the absorption and lymphatic transport of these sterols in mice with chronic biliary and lymphatic fistulae, as well as the transport rates of radiolabeled cholesterol and sitostanol from plasma high-density lipoprotein (HDL) into bile in male Abcg8 ؊/؊ and wild-type mice. We observed that the absorption and lymphatic transport rates of radiolabeled cholesterol and sitostanol were increased by Ϸ40% and Ϸ500%, respectively, in Abcg8 S itosterolemia is a rare autosomal, recessively inherited disorder that is characterized mainly by elevated plasma levels of plant sterols (phytosterols) and with normal or only moderately increased cholesterol levels. 1 Sitosterolemic patients display hyperabsorption of cholesterol and phytosterols and reduced secretion of these sterols into bile. 2,3 Patel et al. 4 were the first to map the sitosterolemia locus, STSL, to human chromosome 2p21, between D2S2294 and D2S2298. Using a positional cloning approach as well as microarray analysis of murine complementary DNAs from intestines and livers of mice treated with a liver X receptor (LXR) agonist, 2 groups 5,6 independently identified the adjacent genes, ABCG5 and ABCG8, encoding adenosine triphosphatebinding cassette (ABC) hemi-transporters that are mutated in sitosterolemia. Unlike other ABC transporters that encode proteins with 12-transmembrane domains, these 2 proteins function as a unique heterodimer forming a 12-transmembrane protein complex essential for sterol transport activity. 7 Heterodimerization of ABCG5 and ABCG8 is also necessary for their translocation from endoplasmic reticulum to the plasma membrane. 8 Based on these observations, as well as the similarity of the clinical and biochemical phenotypes, it has been proposed that both ABCG5 and ABCG8 function as obligate heterodimers in the transmembrane "flipping" of sterols. 9 A mouse model with disruption of both Abcg5 and Abcg8 results in a phenotype similar to that of human disease. 10Abbreviations: ABC, adenosine triphosphate-binding cassette (transporter); HDL, high-density lipoprotein; LXR, liver X receptor. From the

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“…Postprandial gallbladder volumes are increased and gallbladder emptying in response to cholecystokinin (CCK) is impaired in patients with gallstones [8], probably as a result of absorption of cholesterol from supersaturated bile by gallbladder wall. Excess cholesterol in smooth-muscle cells stiffens sarcolemmal membranes and decouples the G-protein-mediated signal transduction of the CCK, thereby paralyzing gallbladder contractile function [12].…”

Section: Introductionmentioning

confidence: 99%

Reduced bile duct contractile function in rats with chronic hyperglycemia

Liu¹,

Su²,

Wang³

et al. 2010

Health

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The incidence of gallstone is higher in patients with diabetes mellitus than in general population. It is generally attributed to hypomotility and lowered emptying function of the gallbladder. In this study, we investigate if chronic hyperglycemia is correlated with reduced contractile function of the bile ducts in rat. Hyperglycemic rats were induced by streptozotocin-nicotinamide treatment. Hyperglycemic rats were sacrificed eight months after induction and bile ducts were removed for the subsequent studies. The bile duct contractility of the normal rats is consistently higher than that of the hyperglycemic rats. The contractities were measured to be 5.5 ± 0.2 mg vs. 4.2 ± 0.1 mg without CCK stimulation, and 5.5 ± 0.3 mg vs. 7.9 ± 0.4 mg with CCK stimulation, respectively for hyperglycemic and normal rats. There was no significant difference in plasma CCK concentration in hyperglycemic rats and normal rats. The expression of CCK-A receptor protein in the bile duct tissue was decreased in hyperglycemic rats compared with that of the normal rats, and it may, at least in part, responsible for a reduced contractility. A reduced bile duct motility may cause bile retention, and may be one of the factors predispose to gallstone formation in type 2 diabetes patients, which is characterized with chronic hyperglycemia.

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Targeted disruption of the murine cholecystokinin-1 receptor promotes intestinal cholesterol absorption and susceptibility to cholesterol cholelithiasis

Cited by 94 publications

References 58 publications

Estrogen induces two distinct cholesterol crystallization pathways by activating ERα and GPR30 in female mice

Estrogen induces two distinct cholesterol crystallization pathways by activating ERα and GPR30 in female mice

Quantifying anomalous intestinal sterol uptake, lymphatic transport, and biliary secretion in Abcg8 −/− mice†‡

Reduced bile duct contractile function in rats with chronic hyperglycemia

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