Leptin-resistant obese mice do not form biliary crystals on a high cholesterol diet

INTRODUCTION: Human obesity is associated with leptin resistance and cholesterol gallstone formation. Previously, we demonstrated that leptin-resistant (Lep(db)) obese mice fed a low cholesterol diet have enlarged gallbladders, but a decreased cholesterol saturation index, despite elevated serum cholesterol. Obese humans, however, consume a high cholesterol diet. Therefore, we hypothesized that on a high cholesterol diet, leptin-resistant mice would have cholesterol saturated bile and would form biliary crystals. METHODS: Eight-week old female lean control (n = 70) and leptin-resistant (n = 72) mice were fed a 1% cholesterol diet for 4 weeks. All animals then had cholecystectomies. Bile was collected, grouped into pools to determine cholesterol saturation index (CSI), and examined for cholesterol crystals. Serum cholesterol and leptin were also measured. RESULTS: Gallbladder volumes for Lep(db) mice were enlarged compared with the lean mice (35.8 microl versus 19.1 microl, P < 0.001), but the CSI for the Lep(db) mice was lower than for the lean animals (0.91 versus 1.15, P < 0.03). The obese animals did not form cholesterol crystals, whereas the lean animals averaged 2.2 crystals per high-powered field (hpf) (P < 0.001). Serum cholesterol and leptin were also elevated (P < 0.001) in the obese animals. CONCLUSIONS: These data suggest that Lep(db) obese mice fed a high cholesterol diet have increased gallbladder volume and decreased biliary cholesterol saturation and crystal formation despite elevated serum cholesterol compared with lean control mice. We conclude that the link among obesity, diet, and gallstone formation may not require hypersecretion of biliary cholesterol and may be related to the effects of diabetes, hyperlipidemia, or both on gallbladder motility.     

Gallbladder motility in agouti-yellow and leptin-resistant obese mice

BACKGROUND: Obesity is a polygenic disorder that is associated with gallstone disease. We have previously shown that leptin deficiency in obese mice correlates with decreased gallbladder motility, suggesting that leptin plays a role in the link between gallstone disease and obesity. However, most obese humans are leptin-resistant, and relatively few are leptin-deficient. To confirm that leptin dysfunction is responsible for impaired gallbladder motility in obese mice, we hypothesized that leptin-resistant obese mice (Lep(db)) would have abnormal gallbladder motility while obese mice with intact leptin function (Agouti Yellow, A(y)) would have normal gallbladder motility. MATERIALS AND METHODS: Eighteen lean control (C57BL/6J), 10 A(y) and 12 Lep(db) female mice were fasted overnight, weighed, and livers and gallbladders were harvested. Liver weights and gallbladder volumes were measured. Gallbladder contractile responses (N/cm(2)) to acetylcholine (10(-5)M), neuropeptide Y (10(-8,-7,-6) M) and cholecystokinin (10(-10,-9,-8,-7)M) were determined in muscle bath chambers. Results were analyzed by analysis of various (ANOVA) and with the Mann-Whitney Rank Sum Test. RESULTS: Both Agouti yellow (A(y)) and leptin-resistant (Lep(db)) obese mice had body weights, liver weights and gallbladder volumes that were significantly greater (P < 0.01) than lean control mice. Leptin-resistant obese mice had gallbladder responses to acetylcholine, neuropeptide Y and cholecystokinin that were significantly less (P < 0.01) than both lean control and Agouti yellow obese mice. CONCLUSIONS: These data suggest that (1). leptin-resistant obese mice (Lep(db)) have abnormal gallbladder motility and (2). obese mice with normal leptin metabolism (A(y)) have normal gallbladder response to neurotransmitters. We conclude that leptin represents a link between obesity, gallbladder motility and gallstone formation.     

High dietary carbohydrates decrease gallbladder volume and enhance cholesterol crystal formation

BACKGROUND: Animal and human data suggest that a diet high in refined carbohydrates leads to gallstone formation. However, no data are available on the role of dietary carbohydrates on gallbladder volume or on cholesterol crystal formation. Therefore, we tested the hypothesis that a high carbohydrate diet would alter gallbladder volume and enhance cholesterol crystal formation. METHODS: At 8 weeks of age, 60 lean and 36 obese leptin-deficient female mice were fed a 45% carbohydrate diet while an equal number of lean and obese mice were fed a 75% carbohydrate diet for 4 weeks. All animals then underwent cholecystectomy, and gallbladder bile volume was recorded. Bile was pooled, filtered, and maintained in a water bath at 37 degrees C for 14 days. Birefringent cholesterol crystals in bile were counted daily; crystal observation time and crystal mass were determined. RESULTS: The crystal observation time was significantly shortened in both lean and obese mice on the 75% diet compared with their counterparts on the 45% diet. The crystal mass was significantly increased in the lean mice on the 75% diet compared with the 45% diet. Gallbladder volumes were significantly reduced in both lean and obese mice on the 75% diet compared with their counterparts on the 45% diet. CONCLUSIONS: These data suggest that a high carbohydrate diet decreases gallbladder volume, shortens cholesterol crystal observation time, and increases crystal mass. We conclude that dietary carbohydrates may play a role in cholesterol gallstone formation by altering biliary motility and by enhancing crystal formation.     

Leptin regulates gallbladder genes related to gallstone pathogenesis in leptin-deficient mice

BACKGROUND: Little is known about the genetic factors that cause alterations in gallbladder motility, cholesterol crystal nucleation, biliary lipids, and, ultimately, cholesterol gallstones. Obese, leptin-deficient (Lep(ob)) mice have large gallbladder volumes with decreased contraction in vitro and are predisposed to cholesterol crystal formation. Leptin administration to these mice causes weight loss and restores gallbladder function. We hypothesize that administration of leptin to Lep(ob) mice would cause weight loss, decrease gallbladder volume, and change gallbladder genes related to gallbladder motility, nucleating factors, and lipid metabolism. STUDY DESIGN: Twenty-four 8-week-old Lep(ob) mice were fed a nonlithogenic diet for 4 weeks. Twelve mice received daily IP saline injections, and 12 received 5 mug/g recombinant leptin. Gallbladder mRNA was pooled and analyzed on murine genome microarray chips. Selected genes were confirmed by real-time polymerase chain reaction (PCR) in a second group of mice treated by the same protocol. RESULTS: Leptin-deficient mice given leptin had significant weight loss and reductions in gallbladder volume. These mice had upregulation of the leptin receptor (p = 0.007; PCR = 1.1-fold increase) but downregulation of leptin (p = 0.003; PCR = 13.5-fold decrease). Leptin upregulated the cholecystokinin A receptor (p < 0.001; PCR = 3.1-fold increase), acetylcholine beta2 receptor (p = 0.005), and the Ca+-calmodulin-dependent protein kinase (p = 0.002) genes. Leptin also altered immunoglobulin heavy chain 4 (p = 0.005; PCR = 17.7-fold increase), mucin 3 (p = 0.006), and carboxylesterase (p = 0.016; PCR = 2.5-fold decrease) genes. Leptin downregulated 3-hydroxy 3-methylglutaryl coenzyme A reductase (p = 0.006; PCR = 2.5-fold decrease) and LDL receptor (p = 0.003). CONCLUSIONS: Leptin modulates obesity and regulates gallbladder genes related to cholesterol gallstone pathogenesis.     

Diabetes and hyperlipidemia correlate with gallbladder contractility in leptin-related murine obesity

Obesity is associated with many comorbid conditions including diabetes, hyperlipidemia, and gallstones. However, the interaction among these modalities remains unclear. We recently demonstrated that both leptin-deficient and leptin-resistant obese mice have impaired biliary motility. These obese mice also are diabetic and hyperlipidemic. Therefore, we tested the hypothesis that serum glucose, insulin, cholesterol, and triglyceride levels would correlate with gallbladder contractility. Thirty-four lean control, 10 lean heterozygous leptin-deficient, 18 obese homozygous leptin-deficient, and 12 obese homozygous leptin-resistant mice were fed a nonlithogenic chow diet while nine lean control and nine obese homozygous leptin-deficient mice were fed a high-cholesterol diet for 4 weeks. In vitro gallbladder responses to cholecystokinin (CCK; 10^-8 mol/L), acetylcholine (ACh; 10^-5 mol/L), and neuropeptide Y (NPY; 10^-6 mol/L) were measured. Serum glucose, insulin, cholesterol, and triglyceride levels were measured from pooled serum from an additional 704 animals. Gallbladder responses were greatest for CCK, intermediate for ACh, and least for NPY. Serum glucose, insulin, cholesterol, and triglyceride levels and body weight all correlated similarly, negatively, and significantly (P < 0.001) with gallbladder contractility. Hyperglycemia, insulin-resistance, hyperlipidemia, and body weight in obese mice with leptin dysfunction are associated with poor gallbladder contractility, which in turn may contribute to the association between obesity and gallstone formation. Presented in part at Digestive Disease Week 2003, SSAT Plenary Session and Residents’ Conference, Orlando, Florida, May 17–22, 2003 (oral presentation); and at the Association for Academic Surgery, Poster Session, Boston, Massachusetts, November 7–9, 2002. Supported by grant NIH R-01 DK44279 from the National Institutes of Health.     

Gallbladder myocytes are short and cholecystokinin-resistant in obese diabetic mice

BACKGROUND: Obesity is associated with diabetes and gallstone formation. Obese leptin-deficient (Lepob) and leptin-resistant (Lepdb) mice are hyperglycemic and have enlarged gallbladders with diminished response in vitro to cholecystokinin (CCK) and acetylcholine (ACh). Whether this phenomenon is secondary to hyperosmolar myocytes and/or decreased neuromuscular transmission remains unclear. We hypothesize that myocytes from Lepob and Lepdb obese mice would not respond normally to neurotransmitters. METHODS: Cholecystectomy was performed on 39 lean, 19 Lepob, and 20 Lepdb 12-week-old female mice. The gallbladder was divided and enzymatically digested. Half of each gallbladder's myocytes had contraction induced by CCK (10(-8) mol/L, n = 38) or ACh (10(-5) mol/L, n = 40). RESULTS: Body weights, gallbladder volumes, and serum glucoses were greater for Lep(ob) and Lepdb mice compared to controls (P < .001). Resting myocyte lengths from Lepob and Lepdb mice were 93% and 91% of the length of controls (P < .001). In response to CCK, lean myocytes shortened 6% (P < .01), while myocytes from obese mice demonstrated no shortening. None of the myocytes demonstrated significant shortening with ACh. CONCLUSIONS: These data suggest that gallbladder myocytes from obese mice are (1) foreshortened and (2) have a diminished response to cholecystokinin. We conclude that altered leptin and/or increased glucose may foreshorten myocytes and decrease response to cholecystokinin.     

Ezetimibe ameliorates cholecystosteatosis

BACKGROUND: Cholecystosteatosis is the accumulation of gallbladder wall fats leading to decreased gallbladder emptying. Ezetimibe inhibits intestinal fat absorption and prevents murine gallstone formation. However, the influence of ezetimibe on gallbladder emptying and cholecystosteatosis has not been studied. Therefore, we tested the hypothesis that ezetimibe would improve gallbladder motility by preventing the buildup of fats in the gallbladder wall. METHODS: Forty lean female mice were fed either a control diet or a lithogenic diet for 6 weeks. Half of the mice on each diet received ezetimibe. At 11 weeks of age, all mice were fasted overnight and underwent gallbladder ultrasonography to determine ejection fraction. One week later, the mice were fasted and underwent cholecystectomy. Bile was examined for cholesterol crystals. The gallbladders were snap-frozen for lipid analysis. RESULTS: The lithogenic diet significantly (P < 0.05) increased serum cholesterol, biliary crystals, gallbladder wall cholesterol and cholesterol/phospholipid ratio, and decreased gallbladder ejection fraction. All of these abnormalities were reversed (P < 0.05) by the addition of ezetimibe to the diet. CONCLUSIONS: These data suggest that ezetimibe lowers serum cholesterol, prevents biliary crystals, and normalizes gallbladder wall fat and function. We conclude that ezetimibe ameliorates cholecystosteatosis and may be an effective agent for gallstone prevention.     

Nonobese diabetic mice have diminished gallbladder motility and shortened crystal observation time

Diabetes and obesity are strongly associated and are risk factors for cholesterol gallstone disease. Leptinde ficient and leptin-resistant diabetic obese mice have enlarged, hypomotile gallbladders. In addition, bile from gallbladders of leptin-deficient mice has enhanced cholesterol crystal formation, whereas bile from gallbladders of leptin-resistant mice has delayed crystal observation time. To determine the effect of diabetes alone, we hypothesized that leptin-normal, nonobese diabetic (NOD) mice would have reduced biliary motility and rapid crystal formation. Twenty control and 9 prediabetic and 11 diabetic NOD, 12- to 26-week-old mice underwent glucose measurement and cholecystectomy for muscle bath stimulation with neurotransmitters. An additional group of 200 control and 78 NOD 12-week-old mice underwent microscopic bile examination for cholesterol crystal formation. Compared with control mice, prediabetic NOD mice had similar glucose levels and gallbladder volumes. Diabetic NOD mice had higher sugar levels and larger gallbladder volumes (P < 0.001) than control mice. Prediabetic NOD gallbladders had less contractility (P < 0.01) than control gallbladders, and contractility worsened (P < 0.01) in diabeticNODmice.NODmice formed cholesterol crystals earlier than did control mice (P<0.05). Nonobese diabetic NOD mice have (1) decreased gallbladder contraction to neurotransmitters, which worsens with development of diabetes, and (2) rapid crystal formation. We conclude that diabetes alone alters gallbladder motility and cholesterol crystal formation. Presented at Digestive Disease Week, 2004 SSAT Plenary Session, and Residents’ Conference, New Orleans, Louisiana, May 15–21, 2004 (oral presentation). This work was supported by National Institutes of Health grant R01-DK44279.     

Ciliary neurotrophic factor restores gallbladder contractility in leptin-resistant obese diabetic mice

BACKGROUND: Obesity and diabetes are major risk factors for cholesterol gallstones, and the majority of obese people are leptin-resistant. Our previous work has shown that both leptin-deficient (Lepob) and leptin-resistant (Lepdb) obese diabetic mice have decreased in vitro gallbladder motility. Leptin administration to leptin-deficient (Lepob) animals restores gallbladder motility and reverses obesity and hyperinsulinemia. However, additional leptin in leptin-resistant obesity would not be expected to improve obesity-related parameters. Recent studies demonstrate that ciliary neurotrophic factor (CNTF) reduces weight and hyperinsulinemia in leptin-resistant obesity. Our hypothesis is that CNFT would cause weight loss, lower blood sugars, and restore gallbladder contractility in leptin-resistant (Lepdb) mice. MATERIALS AND METHODS: 20 C57b/6J and 20 Lepdb 8-week-old female mice were injected daily with either intraperitoneal saline or 0.3 microg/g CNTFAx15 for 17 days. Gallbladders were mounted in muscle baths and stimulated with acetylcholine, neuropeptide Y, and cholecystokinin. Gallbladder volume, serum glucose, insulin, liver weight, liver fat, and gallbladder responses were measured. Data were analyzed by ANOVA. RESULTS: Saline treated obese mice had greater body weight and obesity parameters, but decreased gallbladder contractility to neurotransmitters compared to saline treated lean mice. CNTF administration to obese mice decreased body weight and obesity parameters, and restored gallbladder contractility. CNTF treated lean animals had weight loss and decreased gallbladder contraction to acetylcholine and cholecystokinin compared to saline treated lean animals. CONCLUSIONS: Ciliary neurotrophic factor (CNTF) causes 1) weight loss, 2) improvement of diabetes, and 3) alterations in gallbladder motility that is improved in obese mice but decreased in lean mice. We conclude that CNTF may improve gallbladder contractility in leptin-resistant obesity with diabetes.     

Altered bile composition during cholesterol gallstone formation: cause or effect?

Gallbladder stasis, increased gallbladder absorption, and elevated biliary levels of calcium, hydrogen ion, and bilirubin have been implicated as factors potentially critical to cholesterol crystal precipitation. Previous studies, however, have analyzed bile only when crystals or gallstones have already formed. Therefore, we tested the hypothesis that changes in bile composition are a late effect, occurring only after crystal formation. Adult male prairie dogs were fed a standard nonlithogenic control diet (n = 7) or a lithogenic 1.2% cholesterol diet for 5, 9, or 14 days to cause cholesterol saturation (n = 7), cholesterol monohydrate crystals (n = 7), or gallstones (n = 7). Gallbladder bile was examined microscopically for crystals, and analyzed for ionized calcium, bilirubin, pH, total protein, and biliary lipids. The ratio of gallbladder to hepatic bile radiolabeled cholic acid specific activity (Rsa) was calculated as an index of gallbladder stasis. Cholesterol saturation index was calculated. The results demonstrate that increased gallbladder bile cholesterol saturation and total protein concentration precede cholesterol monohydrate crystal precipitation. However, changes in gallbladder ionized calcium, unconjugated bilirubin, pH, stasis, and absorption were noted only after crystals and gallstones had already formed. These data indicate that alterations in gallbladder bile calcium, bilirubin, pH, stasis, and absorption are not early changes, but occur simultaneously with or after crystal formation. Increased biliary protein, however, which was elevated prior to nucleation, may be an important mediator of cholesterol precipitation in cholesterol-saturated bile.     

The effects of ethinylestradiol, a glucose diet and streptozotocin induced diabetes mellitus on gallstone formation and biliary lipid composition in the hamster

Possible risk factors for gallstone formation were examined and the concentrations of biliary lipids and each bile acid in the hepatic and gallbladder bile of hamsters were quantified. Forty female golden Syrian hamsters were divided into 4 groups according to diet; Group I, given control chow, Group II, given an ethinylestradiol and cholesterol supplemented diet, Group III, given a glucose rich diet without induced diabetes mellitus, and Group IV, given a glucose rich diet with diabetes mellitus induced by streptozotocin injection. The formation of cholesterol crystals but not gallstones was induced in Group II associated with a significantly decreased total bile acid concentration in the gallbladder bile but not in the hepatic bile. The formation of cholesterol gallstones and crystals with significantly higher concentrations of cholesterol and phospholipid was observed in Group III, while neither the formation of gallstones nor lithogenicity was enhanced by diabetes mellitus. However, a quite different lithogenicity was evident between the hepatic and gallbladder bile of the Group IV animals. These results suggest that neither the consumption of oral contraceptives nor diabetes mellitus induces gallstone formation, but that these factors can be responsible for dysfunction of the gallbladder.     

The effects of ethinylestradiol,a glucose diet and streptozotocin induced diabetes mellitus on gallstone formation and biliary lipid composition in the hamster

Possible risk factors for gallstone formation were examined and the concentrations of biliary lipids and each bile acid in the hepatic and gallbladder bile of hamsters were quantified. Forty female golden Syrian hamsters were divided into 4 groups according to diet; Group I, given control chow, Group II, given an ethinylestradiol and cholesterol supplemented diet, Group III, given a glucose rich diet without induced diabetes mellitus, and Group IV, given a glucose rich diet with diabetes mellitus induced by streptozotocin injection. The formation of cholesterol crystals but not gallstones was induced in Group II associated with a significantly decreased total bile acid concentration in the gallbladder bile but not in the hepatic bile. The formation of cholesterol gallstones and crystals with significantly higher concentrations of cholesterol and phospholipid was observed in Group III, while neither the formation of gallstones nor lithogenicity was enhanced by diabetes mellitus. However, a quite different lithogenicity was evident between the hepatic and gallbladder bile of the Group IV animals. These results suggest that neither the consumption of oral contraceptives nor diabetes mellitus induces gallstone formation, but that these factors can be responsible for dysfunction of the gallbladder.     

Role of gallbladder mucus in the pathogenesis of cholesterol gallstones

Recent observations indicate that the hepatic secretion of lithogenic bile, gallbladder mucus hypersection, and gallbladder stasis are all critical factors in the pathogenesis of cholesterol gallstones. Using the prairie dog gallstone model, we investigated the interaction of these factors and the sequence in which they develop. The results of this study indicated that (1) gallbladder bile mucus concentration is elevated before cholesterol precipitation and increases progressively with the formation of cholesterol crystals, (2) cystic duct resistance increases in the presence of cholesterol crystals, but not fine, sonicated crystals increase cystic duct resistance. We conclude that these alterations trigger a self-perpetuating cycle of mucus hypersecretion, cholesterol crystallization, and gallbladder stasis which culminates in the formation of cholesterol gallstones.     

胆宁片对胆囊胆固醇结石的防治作用

目的：研究胆宁片对胆囊胆固醇结石有无防治作用并初步探讨其机制。方法：豚鼠120只随机均分为4组：胆宁片组建立胆囊胆固醇结石模型后给予胆宁片,同时与熊去氧胆酸(UDCA)组及空白组、致石组对照,测定血、胆汁生化及肝、胆囊病理。结果：胆宁片组成石率为17％显著低于致石组的73％．其致石指数(LI)及血甘油三酯(TG)与肝脂肪变性显著低于致石组。结论：胆宁片对胆囊胆固醇结石有良好的防治作用并可缓解肝脂肪变性。     

The pathophysiological characteristics of bile from patients with gallstones: the role of prostaglandins and mucin in gallstone formation

Bile was obtained from 82 patients with various biliary tract diseases and concentrations of prostagloandins, leukotriens, mucin, and a number of lithogenic components were measured in order to evaluate the role of these substances in the pathogenesis of gallstone formation. The characteristics of bile in cases of cholesterol gallstones included high concentrations of prostaglandins and hexosamine and a high cholesterol saturation index. Prostaglandin E2 and prostaglandin F2 alpha concentrations in bile were correlated with hexosamine concentration, and prostaglandins and hexosamine were found to be actively synthesized and secreted in the gallbladder. Prostaglandins E2 and F2 alpha may therefore stimulate mucin secretion in the gallbladder with supersaturated bile. The characteristics of bile in cases of calcium bilirubinate gallstones included a high detection rate for bacteria, high beta-glucuronidase activity, a high percentage of unconjugated bilirubin, a low cholesterol saturation index and high concentrations of prostaglandins and hexosamine. Moreover, the synthesis and secretion of prostaglandins in the biliary tract were accelerated in cases of infected bile. Thus, hypersecretion of mucin, stimulated by prostaglandins, my participate in the onset and development of biliary tract infection or in the formation of calcium bilirubinate gallstones. Regarding the role of prostaglandins and mucin, the hypotheses for gallstone formation previously reported by many authors are supported by the clinical data obtained in the current study.     

Steatocholecystitis: the influence of obesity and dietary carbohydrates

INTRODUCTION: We have recently demonstrated that obese and lean mice fed a high fat diet have increased gallbladder wall fat and decreased gallbladder contractility, cholecystosteatosis. Animal and human data also suggest that diets high in refined carbohydrates lead to gallstone formation. However, no data are available on the role of dietary carbohydrates on gallbladder wall fat and inflammation. Therefore, we tested the hypothesis that both obesity and dietary carbohydrates would increase gallbladder fat and cytokines, steatocholecystitis. METHODS: At 8 wk of age, 47 lean and 22 obese female mice were fed a 45% carbohydrate (CHO) diet while an equal number of lean and obese mice were fed a 75% CHO diet for 4 wk. All mice underwent cholecystectomy, and the gallbladders were snap-frozen. Individual and total lipids were measured by gas chromatography. Interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and IL-6 were measured by enzyme-linked immunosorbent assay. Data were analyzed by analysis of variance and Tukey test. RESULTS: Gallbladder total fat, triglycerides, and cholesterol were maximum (P < 0.001) in obese mice on the 75% CHO diet. Gallbladder TNF-alpha and IL-1beta as well as serum cholesterol levels showed a similar pattern (P < 0.001). Gallbladder saturated free fatty acids and IL-6 levels were highest (P < 0.001) in obese mice on the 45% CHO diet. CONCLUSIONS: These data suggest that (1) both obesity and dietary carbohydrates increase gallbladder total fat, triglycerides, cholesterol, TNF-alpha, and IL-1beta and (2) obesity also increases gallbladder free fatty acids and IL-6. Therefore, we conclude that obesity is associated with steatocholecystitis and that a high carbohydrate diet exacerbates this phenomenon.     

瘦素对血脂及胆汁成分的调节在胆囊胆固醇结石形成中的作用

目的:分析胆囊胆固醇结石患者瘦素与血脂及胆囊内胆汁成分的关系,探讨瘦素在胆囊胆固醇结石形成中的作用。方法:选择胆囊胆固醇结石接受腹腔镜胆囊切除术的患者30例(结石组)与同期因胆囊息肉行腹腔镜胆囊切除术的患者22例(息肉组),检测患者血清总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)、瘦素、胆囊胆汁中的TC与总胆汁酸(TBA)水平,以及胆囊壁组织瘦素受体mRNA水平。结果:与息肉组比较,结石组血清TC、TG、LDL、瘦素水平以及胆囊内胆汁TC/TBA含量比率与胆囊组织瘦素受体mRNA水平均明显升高,而血清HDL明显降低(均P0.05)。结石组的血清瘦素水平与血清TG、TC及胆汁TC均呈正相关(r=0.633,P=0.002;r=0.224,P=0.025;r=0.384,P=0.000),与HDL和TBA呈负相关(r=-0.205,P=0.014;r=-0.548,P=0.024)呈负相关,而息肉组血清瘦素与以上指标间均无关(均P0.05)。结论:瘦素参与了胆囊胆固醇结石的形成,瘦素及其受体水平的升高可能与胆囊胆固醇结石患者胆固醇代谢异常、胆囊胆汁成分失调密切相关。     

Analysis of gallbladder bile in morbid obesity

Thirty-seven per cent of our grossly obese patients selected for gastric bypass had cholesterol gallstones. To document the composition of the biliary lipids prior to weight loss, the bile taken from eleven obese patients at the time of gastric bypass was analyzed and the results compared with those in eleven nonobese patients undergoing elective surgery. There was extreme supersaturation of both gallbladder and hepatic bile in all obese patients. The gallbladder bile of all obese patients fell well outside the micellar zone whereas the bile from all but one of the controls fell within the micellar zone. These data provide biochemical support for the clinical association of obesity and cholesterol gallstone formation and are evidence against the possibility that gastric bypass is a lithogenic operation.     

从胆石成因研究谈胆石病预防的新策略

胆囊胆固醇结石病发病率有不断增加趋势。在胆石病发病机制中,胆汁胆固醇过饱和是胆石形成的必要条件。近年来的研究显示,胆石病患者肝肠循环脂质代谢异常是导致胆汁胆固醇过饱和的分子生物学基础：包括肝脏高密度脂蛋白受体增加胆固醇的摄入、胆小管侧膜胆固醇转运蛋白增加向胆汁中分泌以及经小肠摄人体内的胆固醇增加。大量实验证据表明,对肝肠循环脂质代谢异常进行有效干预,通过降低肝脏胆固醇负荷及其分泌,抑制小肠胆固醇摄取等多个环节,维持胆汁胆固醇的平衡,有望成为预防胆石形成的一系列新的措施。