Bile acids substituted in the 6 position prevent cholesterol gallstone formation in the hamster

The aim of the present study is to examine the efficacy of 6-hydroxy substituted bile acids on the prevention of cholesterol gallstones in a new hamster model of cholesterol cholelithiasis. Male golden Syrian hamsters were fed a nutritionally adequate semipurified lithogenic diet consisting of casein, cornstarch, soluble starch, butterfat, corn oil, and cellulose plus 0.3% cholesterol. Six different bile acids were added to this diet at the 0.05% level: chenodeoxycholic acid, ursodeoxycholic acid, hyodeoxycholic acid, murideoxycholic acid, 6 beta-methyl-hyodeoxycholic acid, and 6 alpha-methyl-murideoxycholic acid. At the end of the 6-wk feeding period, the control group receiving the lithogenic diet had a 55% incidence of gallstones. It was found that all bile acids had inhibited the formation of cholesterol gallstones; complete prevention of gallstones was observed with all 4 3,6-dihydroxy bile acids, whereas chenodeoxycholic acid and ursodeoxycholic acid were somewhat less effective (80% and 75% prevention, respectively). The accumulation of cholesterol in serum and liver induced by the lithogenic diet was inhibited to some extent by all of the bile acids; hyodeoxycholic acid, murideoxycholic acid, and 6 beta-methyl hyodeoxycholic acid were most effective in this respect. The administered bile acids tended to predominate in bile in the case of chenodeoxycholic acid, hyodeoxycholic acid, and 6 beta-methyl-hyodeoxycholic acid. In contrast, ursodeoxycholic acid seemed to be converted to chenodeoxycholic acid and murideoxycholic acid to hyodeoxycholic acid. Only 4% of the 6-methyl analogue of murideoxycholic acid, 6 alpha-methyl-murideoxycholic acid, was recovered in gallbladder bile. These experiments show that the new hamster model of cholesterol cholelithiasis is suitable for gallstone-prevention studies. It was not possible to draw definite conclusions concerning the mechanism of action of the administered bile acids on the basis of cholesterol saturation or the presence of liquid crystals. The detailed mechanism of gallstone prevention by hydrophilic bile acids in this model remains to be elucidated.     

Gallbladder filling and emptying during cholesterol gallstone formation in the prairie dog. A cholescintigraphic study

We studied gallbladder bile flow before, during, and after cholesterol gallstone formation in the prairie dog using infusion cholescintigraphy with 99mTc-diethyl iminodiacetic acid. In 18 fasting animals partitioning of bile between gallbladder and intestine was determined every 15 min for 140 min, and gallbladder response to cholecystokinin (5 U/kg X h) was calculated from the gallbladder ejection fraction. Ten prairie dogs were then placed on a 0.4% cholesterol diet and 8 on a regular diet, and the studies were repeated 1, 2, and 6 wk later. The proportion of hepatic bile that entered the gallbladder relative to the intestine varied from one 15-min period to the next, and averaged 28.2% +/- 5.1% at 140 min. Partial spontaneous gallbladder emptying (ejection fraction 11.5% +/- 5.6%) was intermittently observed. Neither the number nor the ejection fraction of spontaneous gallbladder contractions changed during gallstone formation. By contrast, the percent of gallbladder emptying in response to cholecystokinin decreased from 72.1% +/- 5% to 25.9% +/- 9.3% (p less than 0.025) in the first week and was 14.3% +/- 5.5% at 6 wk (p less than 0.01 from prediet values, not significant from first week). Gallbladder filling decreased from 28.2% +/- 5.1% to 6.7% +/- 3% (p less than 0.01), but this change was only observed after 6 wk, when gallstones had formed. This study shows that bile flow into the gallbladder during fasting is not constant; the gallbladder contracts intermittently; gallbladder emptying in response to exogenous cholecystokinin is altered very early during gallstone formation; and gallbladder filling remains unaffected until later stages, when gallstones have formed.     

Factors affecting the measurement of cholesterol nucleation in human gallbladder and duodenal bile

The study of cholesterol gallstone disease would be facilitated if the nucleation time of cholesterol crystals could be measured in duodenal bile and was correlated with nucleation occurring in vivo. Therefore, our aims were to determine (a) if nucleation time could be measured in duodenal bile, (b) the effect of bacteria, phospholipase, protease, and dilution on the measurement of nucleation time, and (c) the ability of nucleation time of duodenal bile to reflect changes occurring in vivo that promote the formation of gallstones and, therefore, the potential usefulness of nucleation time in predicting and studying the formation of gallstones. Gallbladder bile was obtained from 27 patients undergoing elective cholecystectomy and 19 patients undergoing diagnostic duodenal biliary drainage. Among the 14 bile samples collected by drainage that nucleated within 21 days, mean nucleation time was 6.3 +/- 2.8 days. The addition of inhibitors of phospholipase or protease prolonged nucleation time slightly. Bacteria were cultured from one bile sample at the time of collection and five samples at the time of nucleation. The addition of antibiotics had no effect on nucleation time. Dilution of bile collected at cholecystectomy to the concentration of duodenal bile prolonged nucleation time. In 4 of 5 obese patients receiving a very low calorie diet and predisposed to gallstones, the nucleation time in duodenal bile shortened, and the shortest nucleation times were associated with the formation of cholesterol crystals in vivo. Thus, measurement of nucleation time in duodenal bile may be useful in predicting and studying the formation of cholesterol gallstones.     

Endogenous Hypercholecystokininemia,But Not Aspirin,Reduces the Gallstone Incidence in the Hamster Model

Borch K, Chu M, Kullman E, Carlsson B, Rehfeld JF. Endogenous hypercholecystokininemia, but not aspirin, reduces the gallstone incidence in the hamster model. Scand J Gastroenterol 1994;29:740-743.

Background: Studies in humans and rodents indicate that gallstone development may be prevented by inhibiting gallbladder mucus hypersecretion with non-steroidal anti-inflammatory drugs or by preventing stasis of gallbladder bile with administration of cholecystokinin. Methods: The effect of oral aspirin and pancreaticobiliary diversion with endogenous hypercholecystokininemia on crystal and gallstone formation was studied in Syrian golden hamsters fed a lithogenic diet for 8 weeks. Results: None of the control animals fed a normal diet developed gallstones or crystals in gallbladder bile. Gallstones developed in 67% of the animals fed a lithogenic diet only. The gallstone prevalence did not differ significantly in animals on a lithogenic diet and a daily aspirin dose of 6 mg/kg (gallstone prevalence, 60%) or 100 mg/kg (gallstone prevalence, 70%), whereas it was significantly lower in animals with endogenous hypercholecystokininemia on a lithogenic diet (gallstone prevalence, 29%). The prevalence of crystals in gallbladder bile did not differ significantly between any of the experimental groups. Conclusions: It is concluded that in hamsters on a lithogenic diet, aspirin does not prevent gallstone formation, whereas endogenous hypercholecystokininemia reduces the prevalence of stones without affecting the occurrence of crystals in gallbladder bile.     

环氧合酶2抑制剂在胆固醇结石形成中的作用

目的　探讨选择性环氧合酶 2 (COX 2 )抑制剂塞莱昔布 (celexibo)在家兔实验性胆固醇结石形成中的作用。方法　普通家兔 30只平均分为 3组 :成石组饲以高胆固醇饲料 ,实验组在高胆固醇饲料基础上按每天 10mg/kg体重加饲塞莱昔布 ,空白组饲以普通饲料。 7周后 ,观察各组胆囊胆汁结晶情况、胆囊上皮黏膜炎症情况及COX 2含量。结果　实验组比成石组形成胆固醇结晶机会明显减少 (9/ 10、2 / 10 ,χ2 =9 988,P <0 0 5 ) ;成石组比空白组胆囊黏膜炎症程度明显升高 (U =2 3,W =6 8,P <0 0 5 ) ,实验组与成石组相比 ,炎症程度显著降低 (U =18,W =6 3,P <0 0 1)。成石组胆囊黏膜COX 2表达量明显高于空白组 (0 0 5 5± 0 0 0 6、0 0 17± 0 0 0 3,P <0 0 0 1) ,实验组比成石组COX 2表达量明显降低 (0 16 9± 0 0 0 1、0 0 5 5± 0 0 0 6 ,P <0 0 0 1)。结论　胆固醇结石形成可能包含炎症机制 ,COX 2参与胆固醇结石的形成过程 ,且COX 2抑制剂可以抑制胆固醇结石的形成。     

Comparison of effects of cholecystokinin and erythromycin on bile chemistry and gallstone formation in aged guinea pigs.

BACKGROUND: There has been considerable interest in gall bladder motility in recent years. We compared the effects of cholecystokinin (CCK) and erythromycin on bile chemistry and gallstone formation in aged guinea pigs. METHODS: Two groups of guinea pigs (1-mo and 3-y old; n=40 each) were studied. Each group was divided into four subgroups of 10 animals each; one subgroup received lithogenic diet, one each received CCK or erythromycin daily in addition to lithogenic diet for 4 weeks, and one received normal diet. After 4 weeks, the presence of gallstones or sludge was recorded and bile composition including concentrations of bile acid, cholesterol, lecithin and protein concentrations was studied. RESULTS: No gallstones were observed in the 1-mo-old animals. In the 3-year-old animals, 9 of 10 guinea pigs on lithogenic diet and 4 of 10 in each treatment subgroup and the normal diet subgroup developed gallstones. CCK and erythromycin had similar effects on bile chemistry and stone formation. CONCLUSIONS: Aging increases the formation of gallstones in guinea pigs. Erythromycin is as effective as CCK in reducing gallstone formation by improving gall bladder motility.     

Low-dose ursodeoxycholic acid prolongs cholesterol nucleation time in gallbladder bile of patients with cholesterol gallstones

The high rate of stone recurrence represents a drawback of non-surgical therapy of cholesterol gallstone disease. Although most studies report that long-term bile acid treatment does not have protective effects, preliminary results suggest that low-dose ursodeoxycholic acid decreases the rate of gallstone recurrence in a subgroup of younger patients. To clarify the underlying mechanism we investigated whether low-dose ursodeoxycholic acid treatment influences biliary cholesterol saturation and/or nucleation time of cholesterol. Ten patients with cholesterol gallstones and functioning gallbladder received 250 mg ursodeoxycholic acid/day at bedtime 6-10 days prior to cholecystectomy. Eleven patients with cholesterol gallstones without treatment served as controls. Cholesterol crystals were present in the gallbladder bile of 7 out of the 10 patients receiving ursodeoxycholic acid and in all control biles. Ursodeoxycholic acid treatment significantly (P less than 0.02) decreased the cholesterol saturation index (mean +/- S.E.: 0.94 +/- 0.05 vs. 1.43 +/- 0.18) and led to an approximately 5-fold prolongation (P less than 0.005) of the cholesterol nucleation time (mean +/- S.E.: 12.0 +/- 2.4 vs. 2.3 +/- 0.7 days). We conclude that low-dose ursodeoxycholic acid might be effective in the prevention of post-dissolution gallstone recurrence by both decreasing cholesterol saturation and prolonging cholesterol nucleation time.     

Dissolution of cholesterol gallstones in mice by the oral administration of a fatty acid bile acid conjugate

Gallstones, mostly cholesterol stones, affect some 15% of the population. Oral bile salts dissolve human cholesterol gallstones, but with low efficacy, and surgery remains the main therapeutic option. Fatty acid bile acid conjugates (FABACs) were shown to prevent formation of cholesterol gallstones in experimental animals. The aim of this study was to test whether these compounds could dissolve preexisting cholesterol gallstones via oral administration. Inbred, gallstone-susceptible C57J/L mice were given a lithogenic diet for 2 months, and the presence of gallstones was ascertained. The mice were then switched to a regular diet while part of them were given in addition C20-FABAC, by gavage, at a dose of 0.5 or 3 mg per animal per day. All mice tested had cholesterol gallstones after 2 months on the lithogenic diet. In study I, after 2 months on the regular diet, 3 of 4 (75%) of the controls had gallstones, whereas none of the 6 FABAC-fed animals (3 mg/d) had stones (P =.033). In study II, evaluating 2 FABAC doses, after 2 months on the regular diet, 8 of 8 (100%) of the controls had gallstones, which were found in 2 of 7 (28%) and 1 of 8 (12%) of the mice supplemented with 0.5 mg/d (P =.007) or 3 mg/d (P =.001) FABAC, respectively. On a molar basis, the dose of 0.5 mg FABAC is equivalent to 14 mg/kg/d of a bile acid. In conclusion, FABACs given orally can dissolve preexisting cholesterol gallstones in mice. This was accomplished with a dose of FABAC equivalent to the dose of bile acids used in human gallstone dissolution.     

7-Methyl bile acids: effects of chenodeoxycholic acid, cholic acid, and their 7 beta-methyl analogues on the formation of cholesterol gallstones in the prairie dog

The purpose of this study was to compare the effects of the naturally occurring bile acids (chenodeoxycholic acid and cholic acid) with their 7-methyl analogues (3 alpha,7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic acid and 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acid) on gallstone formation and prevention and cholesterol metabolism in the prairie dog. Sixty animals were fed a semipurified diet, containing 0.4% cholesterol, with one of the following acids (0.1%): chenodeoxycholic, cholic, 3 alpha,7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic, or 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acid. This concentration of dietary bile acids amounts to a dose of 27-30 mg/kg.day. After 8 wk, 89% of control animals had gallstones and 94% had cholesterol crystals. Chenodeoxycholic and 3 alpha,7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic acids decreased the incidence of gallstones to 50%. Cholic acid and 3 alpha,7 alpha,12 alpha-tri-hydroxy-7 beta-methyl-5 beta-cholanoic acid did not prevent gallstone formation. The liver cholesterol level was decreased by chenodeoxycholic acid, whereas cholic and 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acids increased serum and liver cholesterol. Each administered bile acid became the predominant biliary bile acid and 7-methyl analogues did not increase secondary bile acids. Fecal analysis of radioactive metabolites using 14C-labeled 7-methyl analogues showed that these compounds are resistant to bacterial 7-dehydroxylation. It was concluded that 3 alpha,7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic acid inhibited gallstone formation as effectively as chenodeoxycholic acid, whereas both cholic and 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acids were not effective. The effects of 7-methyl analogues on the parameters of cholesterol metabolism that we studied were similar to those of their parent compounds, chenodeoxycholic and cholic acids. Thus, 3 alpha,7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic acid but not 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acid offers promise in cholelitholytic therapy for the prevention and possibly dissolution of cholesterol gallstones.     

Gallstone prevention in prairie dogs: comparison of chow vs. semisynthetic diets

The effects of a standard rodent chow were compared with those of a semisynthetic diet of known composition (with and without added cholesterol) in the prairie dog model of cholesterol cholelithiasis. Gallstone incidence was 40% higher in animals fed a semisynthetic diet plus cholesterol compared to chow plus cholesterol. The semisynthetic diet plus cholesterol caused significant increases in tissue cholesterol levels (serum, liver and bile) and lithogenic index, but significant decreases in the activity of hepatic 3-hydroxy-3-methyl-glutaryl coenzyme A reductase and cholesterol 7 alpha-hydroxylase compared to chow plus cholesterol. Histologic study of liver sections revealed that the semisynthetic diet plus cholesterol resulted in moderate to marked portal tract changes characterized by bile duct proliferation, inflammatory infiltration and fibrosis, whereas the cholesterol-supplemented chow diet caused only slight bile duct proliferation with minimal inflammation and fibrosis in the portal areas. Dietary hyodeoxycholic acid prevented cholesterol gallstones and biliary cholesterol crystals when added to either chow plus cholesterol or semisynthetic plus cholesterol diets. The hyodeoxycholic acid supplements also prevented the development of severe histopathologic alterations along the portal tracts. Biliary cholesterol levels were elevated in prairie dogs fed cholesterol plus hyodeoxycholic acid; these animals had liquid crystals in the bile, and hyodeoxycholic acid and its 6 beta-isomer became the major biliary bile acids. A semisynthetic diet plus cholesterol is superior to a high cholesterol chow diet for gallstone formation and prevention studies, but in prolonged feeding experiments, the potential hepatotoxicity of this diet in the prairie dog must be appreciated.     

Composition and immunofluorescence studies of biliary "sludge" in patients with cholesterol or mixed gallstones

BACKGROUND/AIMS: Gallbladder bile from patients with cholesterol or mixed gallstones frequently contains biliary "sludge", a suspension of cholesterol monohydrate crystals and pigment granules embedded in mucin and proteins. The composition of biliary "sludge" and the preferential localization of mucin and proteins could be an indicator for its potential role in gallstone formation. METHODS: Ultracentrifugation (100000 g/l h) was used to precipitate "sludge" from bile, and the concentration difference of its main components between native bile and ultracentrifuged bile samples was calculated. After purification of the sediment, immunolocalization was performed for the detection of mucin, IgA, albumin, aminopeptidase, and anionic polypeptide fraction using polyclonal and monoclonal antibodies. RESULTS: The amount of sludge in gallbladder bile was 4.26 mg/ml-0.78 (mean+/-SEM) in patients with cholesterol and 2.51 mg/ml+/-0.39 in patients with mixed stones and cholesterol was the main component (48.9+/-4.6% and 44.4+/-7.1%). The sediment appeared as a mixture of vesicular aggregates and pigment particles which were linked by a gel matrix of mucin containing cholesterol crystals. While anionic polypeptide fraction and aminopeptidase were associated to pigments, IgA was uniformly spread in the crystalline parts of "core-like" structures, and albumin, when it was present, appeared as randomly located small spots. CONCLUSIONS: Our study demonstrates that the cholesterol content and the distribution pattern of mucin and different proteins is similar in the sediments of biliary "sludge" to that previously shown in cholesterol and mixed gallstones. This suggests that biliary "sludge" represents an early stage of gallstone formation in these patients.     

Deficiency of Niemann‐Pick C1 protein protects against diet‐induced gallstone formation in mice

Background/aims: Receptor‐mediated endocytosis is a critical cellular mechanism for the uptake of lipoprotein cholesterol in the liver. Because Niemann‐Pick C1 (NPC1) protein is a key component for the intracellular distribution of cholesterol originating from lipoprotein endocytosis, it may play an important role in controlling biliary cholesterol secretion and gallstone formation induced by a lithogenic diet. Methods: We studied biliary cholesterol secretion, gallbladder lipid composition and gallstone formation in NPC1‐deficient mice fed a low‐fat lithogenic diet (1.5% cholesterol and 0.5% cholic acid) compared with control animals under the same diet. Results: The lipid secretion response to the lithogenic diet was impaired in NPC1 (?/?) mice, leading to a decreased cholesterol output and an increased hepatic cholesterol concentration compared with the lithogenic diet‐fed wild‐type mice. A decreased cholesterol saturation index was found in the gallbladder bile of NPC1 (+/?) and (?/?) mice after lithogenic diet feeding. Consequently, mice with a partial or a total deficiency of NPC1 had a drastically lower frequency of gallbladder cholesterol crystals and a reduced prevalence of gallstones. Conclusion: Hepatic NPC1 expression is an important factor for regulating the biliary secretion of diet‐derived cholesterol as well as for diet‐induced cholesterol gallstone formation in mice.     

Impaired biliary cholesterol secretion and decreased gallstone formation in apolipoprotein E-deficient mice fed a high-cholesterol diet

BACKGROUND & AIMS: Because apolipoprotein E (apoE) is a key cholesterol transport molecule involved in the hepatic uptake of chylomicron cholesterol, it may play a critical role in controlling bile cholesterol elimination and cholesterol gallstone formation induced by dietary cholesterol. To test this hypothesis, we studied biliary lipid secretion and gallstone formation in apoE-deficient mice fed cholesterol-rich diets. METHODS: Bile lipid outputs and gallstone sequence events were analyzed in apoE-deficient mice fed a high-cholesterol diet or a lithogenic diet compared with control animals. RESULTS: A high-cholesterol diet increased biliary cholesterol secretion and gallbladder bile cholesterol concentration in wild-type mice; the increase in bile cholesterol secretion was significantly attenuated in apoE-deficient mice. ApoE knockout mice fed a high-cholesterol lithogenic diet had a markedly lower frequency of gallbladder bile cholesterol crystal and gallstone formation than wild-type mice, which was most likely a result of the decreased cholesterol saturation index found in gallbladder bile of apoE-deficient mice. CONCLUSIONS: These results show that apoE expression is an important factor for regulating both biliary secretion of diet-derived cholesterol as well as diet-induced cholesterol gallstone formation in mice.     

Oleic acid-induced cholelithiasis in the rabbit: conversion of dietary oleic acid to cholestanol as a cause of calcium-bile salt gallstones

Rabbits fed a diet rich in oleic acid develop gallstones consisting of calcium salts of (5 alpha)-glyco-allodeoxycholic acid. To study the metabolic pathway of oleic acid, we followed the changes in plasma, hepatic and biliary lipids in this animal model. In addition, to also determine the role played by intestinal microflora on biliary lipid metabolism, we added kanamycin to the oleic acid diet. Oleic acid-fed rabbits rapidly developed hypercholesterolemia. This was associated with an increase in liver 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, accumulation of cholesterol as well as cholestanol in the liver and progressive saturation of cholesterol in bile. [14C]oleic acid fed orally to rabbits was recovered in liver extracts as both cholesterol and cholestanol. With oleic acid feeding, there was a progressive increase in glyco-allodeoxycholic acid culminating in the formation of gallstones. Kanamycin supplement to the oleic acid diet resulted in the same changes in plasma and hepatic sterol metabolism compared with oleic acid-fed rabbits. There was, however, a striking difference in the biliary bile acid profile. Kanamycin supplementation dramatically reduced the proportion of 5 alpha-dihydroxy bile acids, increased the proportion of 5 beta-trihydroxy bile acids and completely abolished gallstone formation. We postulate that, in the rabbit, oleic acid is used as a carbon source for cholesterol synthesis, and a high oleic acid diet increases hepatic cholesterogenesis. Hepatic cholesterol is then metabolized to form cholestanol, followed by (5 alpha)-glyco-allocholic acid which is secreted into bile and transformed by gut bacteria to form (5 alpha)-allodeoxycholic acid. Kanamycin abolished gallstone formation by inhibiting intestinal bacterial dehydroxylation.     

Inhibitory effects of pravastatin, a competitive inhibitor of hydroxymethylglutaryl coenzyme A reductase, on cholesterol gallstone formation in prairie dogs.

The effects of pravastatin on cholesterol gallstone formation were determined in prairie dogs. We fed 10 prairie dogs 1% cholesterol with or without 0.05% (w/w) pravastatin (n = 5, each) for 4 weeks. In addition, another 5 prairie dogs were fed a standard rodent chow as a control. Only the animals fed 1% cholesterol without pravastatin treatment formed cholesterol gallstones. Gallbladder bile from cholesterol-fed animals contained cholesterol monohydrate crystals, whereas those treated with pravastatin contained no crystal. Furthermore, marked increases in tissue cholesterol levels (serum, liver and bile), and in biliary mucous glycoprotein levels were evident in cholesterol-fed animals, whereas pravastatin treatment normalized these levels. These findings raise the possibility that such inhibitors might have a future role to play in the prevention of cholesterol gallstone formation and/or recurrence.     

高胆固醇饮食对胆结石形成的研究

通过高胆固醇饮食对胆结石形成的动物试验 ,探讨高胆固醇饮食的成石原因和机理 ,为在饮食上预防胆结石的形成提供试验依据 ,为胆结石的临床治疗和病人的康复提出理论依据 ,并为今后胆固醇结石的研究提供适宜的动物模型。本研究以狗作为试验动物 ,用 0 3%的高胆固醇饲料进行试验喂养 ,连续喂养 6周 ,观察动物胆结石的形成 ,测定血中胆固醇和甘油三酯水平 ,分析胆汁中成分的改变。在试验四周内试验组动物形成胆结石 ,且成石率为 10 0 % ,结石直径为 1mm～ 11mm。试验组动物血清胆固醇和甘油三酯水平显著提高 (p <0 0 1) ,胆汁中胆固醇和胆固醇结晶显著升高 (p <0 0 1)。通过高胆固醇膳食 ,试验动物血清及胆固醇和甘油三酯水平增加 ,胆汁中胆固醇增加 ,成石性胆汁形成。提示胆固醇代谢的异常变化在胆囊结石中起作用。     

Lovastatin alters biliary lipid composition and dissolves gallstones: a long-term study in prairie dogs

Lovastatin, an inhibitor of the rate-limiting enzyme in cholesterol biosynthesis, is widely used to treat hypercholesterolemia. We investigated the long-term effects of lovastatin alone and in combination with ursodeoxycholic acid on biliary lipid composition and gallstone dissolution. Forty-two prairie dogs were fed 1.2% cholesterol diet for 5 weeks, and cholecystectomy was performed on 6 animals to confirm gallstones. The remaining animals were maintained on a 0.4% cholesterol diet and were randomized to receive placebo, lovastatin (3.3 mg/g diet), ursodeoxycholic acid (10 mg/g), or combination of both drugs. After 10 weeks, animals underwent cholecystectomy. Dissolution response to therapy was determined, and serum and biliary lipids were measured. All treatment groups had significant reductions in serum cholesterol. Lovastatin treatment reduced both hepatic and gallbladder bile cholesterol, altered bile acid composition, and induced a 79% total response compared to placebo. Although ursodeoxycholic treatment induced a 44% response, long-term combination treatment elevated both gallbladder bile cholesterol and calcium and failed to produce an augmented response. These data suggest that lovastatin therapy alone may promote gallstone dissolution in humans.     

Effect of ursodeoxycholic acid administration on nucleation time in human gallbladder bile

The object of this study was to determine the effects of ursodeoxycholic acid administration on metastability in human gallbladder bile, as reflected by nucleation time. Bile samples from 10 patients with cholesterol gallstones who underwent preoperative ursodeoxycholic acid treatment exhibited a significantly longer median nucleation time (16 days) than those from 11 patients with cholesterol gallstones who received no preoperative treatment (4 days) (p less than 0.01). On the other hand, the median nucleation times of bile samples from 15 patients with noncholesterol gallstones and 24 patients without gallstones were 15 and 14 days, respectively. In addition, 3 mo of treatment with ursodeoxycholic acid significantly elevated the serum concentration of the antinucleating factor apolipoprotein A-I, from 133.3 +/- 12.3 to 148.6 +/- 13.2 mg/dl (p less than 0.05). These findings suggest that ursodeoxycholic acid retards cholesterol crystal nucleation, thereby inhibiting cholesterol gallstone formation. It is also possible that serum apolipoprotein A-I plays a role in this process.     

Role of cholic acid in the dietary induction of cholesterol gall-bladder stones in mice

The diet of male Swiss mice was supplemented with cholesterol and different bile acids, or the plant sterol diosgenin, to determine the effect on cholesterol metabolism and gallstone formation. Cholic acid enhanced intestinal cholesterol absorption and markedly increased cholesterol levels in serum, liver and bile. In contrast, chenodeoxycholic acid, ursodeoxycholic acid and hyodeoxycholic acid inhibited the increase in cholesterol absorption and liver cholesterol content produced by a cholesterol-supplemented diet. Biliary cholesterol reached saturated levels in mice fed cholesterol and cholic acid or diosgenin, but gallstones were observed only in association with the cholic acid-containing diet. This diet also induced marked gall-bladder enlargement with mucus glycoprotein hypersecretion. These results indicate that both supersaturated bile and gall-bladder mucus production may be necessary for the development of gallstones in mice.