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.     

Modeling plasma lipoprotein-bile lipid relationships: Differential impact of psyllium and cholestyramine in hamsters fed a lithogenic diet

Hamsters fed a lithogenic diet become hyperlipemic with elevated very-low-density lipoprotein (VLDL) and high-density lipoprotein 2 (HDL₂) cholesterol pools and develop lithogenic bile in which chenodeoxycholate (cheno) typically predominates. The relationship between these distorted lipoprotein and bile lipid profiles and gallstone induction was investigated in male Syrian hamsters fed for 5 weeks a gallstone-inducing purified diet (5% butter, 0.4% cholesterol) or the same diet supplemented with 5% psyllium or 1% cholestyramine, agents known to alter bile acid metabolism. The gallstone diet essentially doubled plasma cholesterol level, whereas psyllium decreased it to near normal, and cholestyramine to a subnormal level, while correcting the distorted distribution of cholesterol among lipoproteins. Both the gallstone diet and psyllium produced cholesterol-laden livers, in contrast to subnormal values produced by cholestyramine. Fecal bile acid excretion was increased eightfold with cholestyramine and fourfold with psyllium relative to the value produced by the gallstone diet and a literature control value. Supersaturated bile developed with the gallstone diet (lithogenic index [LI], 2.3 ± 0.6), whereas the LI was decreased by psyllium (1.2 ± 0.4) and cholestyramine (0.7 ± 0.3). The gallstone diet decreased the concentration of bile acids in gallbladder bile, but greatly increased the percentage of taurochenodeoxycholic acid, whereas psyllium preferentially decreased all taurine-conjugated bile acid levels and expanded glycocholate output. Cholestyramine greatly decreased the secretion of biliary cholesterol and cheno independent of its conjugation. Accordingly, psyllium increased the glycine to taurine ratio of gallbladder bile fivefold, whereas cholestyramine did not affect this ratio, but increased the cholate to cheno ratio dramatically (25-fold) as compared with a threefold increase with psyllium. This combination of biliary lipid and bile acid alterations induced coordinated responses in the LI and the hydrophobicity index (HI) such that cholesterol gallstones developed in 11 of 12 hamsters fed the gallstone diet, whereas only one of 11 of the psyllium-fed and none of 12 cholestyramine-fed hamsters had cholesterol stones. Thus, psyllium and cholestyramine differentially increased bile acid excretion, which improved the lipoprotein profile and inhibited cholesterol gallstone formation. Both agents operated by different means to decrease biliary cholesterol secretion and the percentage of cheno, which decreased the LI and HI, respectively.     

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.     

Aspirin does not inhibit cholesterol cholelithiasis in two established animal models.

The effect of aspirin on cholesterol cholelithiasis was examined in the hamster and the prairie dog. In the prairie dog, diets were composed of semipurified components of chow, plus cholesterol (1.2%), with and without aspirin. Animals were studied for either 2 weeks or 4 weeks. Cholesterol gallstones were present in all groups at the end of each period; aspirin did not alter the incidence of cholelithiasis. All animals studied had cholesterol crystals in the bile when they were killed. Liver cholesterol levels in prairie dogs with and without aspirin tended to be lower in animals fed chow than in animals fed semipurified diets. There were no significant differences in cholesterol levels in the plasma or bile. The cholesterol saturation index of all biles approached unity when animals were fed chow with aspirin; animals fed the semipurified diets had cholesterol saturation indices of less than 1.0. The prairie dogs fed aspirin plus cholesterol in the semipurified diet showed increased levels of biliary chenodeoxycholic acid amidates and concomitant decreased levels of cholic acid amidates compared with animals fed the same diet without aspirin. Hamsters fed aspirin plus cholesterol in a semipurified diet tended to have a greater incidence of gallstones than animals given no aspirin (80% vs. 55%). Liver and bile cholesterol levels were similar with and without aspirin; plasma cholesterol levels increased significantly with aspirin [14.20 vs. 7.80 mmol/L (549 vs. 301 mg/dL)]. Lithogenic indices in all hamsters were above unity; biliary lipids, total lipid concentration, and biliary bile acid composition were similar. These results show that the addition of aspirin to a lithogenic diet does not reduce the incidence of cholelithiasis.     

Identification of cholelithogenic enterohepatic helicobacter species and their role in murine cholesterol gallstone formation

BACKGROUND & AIMS: Helicobacter spp are common inhabitants of the hepatobiliary and gastrointestinal tracts of humans and animals and cause a variety of well-described diseases. Recent epidemiologic results suggest a possible association between enterohepatic Helicobacter spp and cholesterol cholelithiasis, chronic cholecystitis, and gallbladder cancer. To test this, we prospectively investigated the effects of Helicobacter spp infection in cholesterol gallstone pathogenesis in the highly susceptible C57L/J mouse model. METHODS: Helicobacter spp-free adult male C57L mice were infected with several different enterohepatic Helicobacter spp or left uninfected and fed either a lithogenic diet or standard mouse chow for 8 and 18 weeks. At the conclusion of the study, bile was examined microscopically and diagnostic culture and polymerase chain reaction were performed. RESULTS: Mice infected with Helicobacter bilis or coinfected with Helicobacter hepaticus and Helicobacter rodentium and fed a lithogenic diet developed cholesterol gallstones at 80% prevalence by 8 weeks compared with approximately 10% in uninfected controls. Monoinfections with H hepaticus , Helicobacter cinaedi , and H rodentium gave a cholesterol gallstone prevalence of 40%, 30%, and 20%, respectively; the latter 2 groups did not differ significantly from uninfected animals. Neither infected nor uninfected mice fed a chow diet developed cholesterol gallstones. CONCLUSIONS: These findings, along with prior epidemiologic studies, suggest that Helicobacter spp play a major role in the pathophysiology of cholesterol gallstone formation in mice and perhaps humans.     

Gallbladder mucin and cholesterol and pigment gallstone formation in hamsters

We measured gallbladder mucin production by hamsters fed diets lithogenic for either cholesterol or pigment gallstones. In hamsters on the cholesterol stone diet, gallbladder production of 3H-glucosamine-labeled mucin was elevated two- and seven-fold after 1 and 3 weeks, respectively. After 1 week cholesterol crystals were seen in a mucus gel on the gallbladder surface. In hamsters on the pigment stone diet, gallbladder mucin production was significantly elevated after 1 and 3 weeks. The first precipitation of pigment crystals was in mucus in bile or on the gallbladder surface. Black pigment stones grew by agglomeration of pigment crystals enmeshed in mucus. In conclusion, gallbladder mucin production is increased before cholesterol or pigment stone formation, and the earliest deposition of crystals is in mucus in bile or on the gallbladder surface.     

Biliary lipids and cholesterol crystal formation in leptin-deficient obese mice

Background. Obesity is often associated with increased biliary cholesterol secretion resulting in cholesterol gallstone formation. We have previously demonstrated that leptin-deficient C57Bl/6J Lep ob obese mice have abnormal biliary motility and are prone to cholesterol crystal formation. In addition, others have demonstrated that leptin-deficient mice when fed a lithogenic diet for eight weeks are not prone to gallstone formation. However, the biliary lipid and in vivo cholesterol crystal response of homozygous and heterozygous leptin-deficient mice to four weeks on a lithogenic diet has not been studied. Therefore, we tested the hypothesis that lithogenic diets influence gallbladder bile composition, serum lipids and cholesterol crystal formation in homozygous and heterozygous leptin-deficient mice compared to normal lean controls. Methods. 319 female lean control mice, 280 heterozygous lep ob obese mice and 117 homozygous lep ob obese mice were studied. Mice were fed either a lithogenic or control non-lithogenic chow diet for four weeks. Gallbladder volumes were measured, and bile was pooled to calculate cholesterol saturation indices. Serum cholesterol, glucose, and leptin levels were determined. Hepatic fat vacuoles were counted, and bile was observed microscopically for cholesterol crystal formation. Results. The lithogenic diet and mouse strain influenced body and liver weights, gallbladder volume, cholesterol crystal formation, serum cholesterol, glucose and leptin levels and hepatic fat vacuole numbers. However, only diet, not strain, altered biliary cholesterol saturation. Conclusion. The association among obesity, leptin, and gallstone formation may be primarily related to altered gallbladder motility and cholesterol crystal formation and only secondarily to biliary cholesterol saturation.     

Prevention of cholesterol gallstones by lignin and lactulose in the hamster

The effect on prevention of cholesterol gallstones by a nonfermentable type of fiber, lignin, and a fermentable fiber analogue, lactulose, was studied in hamsters fed an essential fatty acid deficient diet. Control animals had a high incidence of cholesterol gallstones (21 of 24) and lithogenic bile (lithogenic index 1.08). Animals fed lignin had significantly fewer gallstones (11 of 25), improved cholesterol saturation of gallbladder bile, and increased fecal bile acid excretion. Lactulose-fed animals had significantly fewer gallstones (12 of 24) but no significant change in cholesterol saturation of gallbladder bile or in fecal bile acid excretion. Serum cholesterol concentration was reduced, however, and fecal neutral steroid excretion was increased. Gallstones were completely prevented in animals fed both lignin and lactulose (0 of 22), but gallbladder bile cholesterol saturation was not significantly different from the lignin-fed group. Gallbladder bile mucopolysaccharide concentrations did not differ among groups. Lignin appears to prevent cholesterol gallstones in this model by improving cholesterol saturation of bile. The mechanism of action of lactulose is not yet clear.     

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.     

Effects of sphingolipid synthesis inhibition on cholesterol gallstone formation in C57BL/6J mice

Background: Sphingolipids play a very important role in cell membrane formation, signal transduction and plasma lipoprotein metabolism. The first rate‐limiting step in the sphingolipid biosynthetic pathway is catalyzed by serine palmitoyltransferase (SPT), and myriocin is a potent and specific inhibitor of SPT. We investigated the impact of SPT inhibition on cholesterol gallstone formation in C57BL/6J mice. Methods: Three groups of eight‐week‐old C57BL/6J mice were utilized. Each group consisted of 20 mice; group A, B, and C were fed normal chow, lithogenic diet with phosphate buffered saline, and lithogenic diet with myriocin (0.3 mg/kg), respectively, for 6 weeks. The ceramide levels in both serum and bile were assessed by high performance liquid chromatography analysis. Protein expression of ERK, JNK and p38 in the extracted gallbladder were determined by Western‐blot analysis. Results: Myriocin treatment caused a significant decrease in the rate of cholesterol gallstone formation. The lithogenic diet mice (group B) showed the highest ceramide activities in both the serum and bile among all the tested groups and there was significant suppression of the ceramide levels in both the serum and bile of the myriocin‐treated mice (group C, p < 0.05). Phosphorylation of p38 in the gallbladder was increased in the lithogenic‐diet mice and the expression of phosphorylated p38 was significantly suppressed in the myriocin treated mice. Conclusions: SPT inhibition by myriocin suppressed gallstone formation and the levels of ceramide in both the serum and bile. p38 in the cellular signaling pathways might be associated with cholesterol gallstone formation.     

Apolipoprotein A‐I deficiency does not affect biliary lipid secretion and gallstone formation in mice

Background/Aims: Apolipoprotein A‐I (apo A‐I) is the main protein component of plasma high‐density lipoproteins (HDL) and a key determinant of HDL cholesterol levels and metabolism. The relevance of HDL in controlling the traffic of cholesterol from plasma into bile has been partially addressed. The aim of this study was to evaluate the role of apo A‐I expression in controlling the secretion of biliary lipids as well as the risk of gallstone disease in vivo. Methods: We evaluated biliary lipid secretion and bile acid homeostasis in mice deficient for apo A‐I compared with wild‐type animals when fed with low‐ or high‐cholesterol diets. In addition, we assessed the importance of murine apoA‐I expression for gallstone formation after feeding a lithogenic diet. Results: Bile acid pool size and faecal excretion were within the normal range in chow‐ and cholesterol‐fed apo A‐I knockout (KO) mice. Basal biliary cholesterol secretion was comparable and increased similarly in both murine strains after cholesterol feeding. Lithogenic diet‐fed apo A‐I KO mice exhibited an impaired hypercholesterolaemic response owing to a lower increase in cholesterol levels transported in large lipoproteins. However, the lack of apo A‐I expression did not affect biliary cholesterol precipitation or gallstone formation in lithogenic diet‐fed mice. Conclusions: These findings indicate that biliary lipid secretion, bile acid metabolism and gallstone formation are independent of apo A‐I expression and plasma HDL cholesterol levels in mice.     

Gallbladder mucosal blood flow increases during early cholesterol gallstone formation.

Gallbladder absorption increases during early cholesterol gallstone formation and is influenced by the intraluminal presence of lithogenic bile. The effect of lithogenic bile on gallbladder mucosal blood flow is unknown. The current study tested the hypothesis that the presence of lithogenic gallbladder and hepatic bile enhances gallbladder mucosal blood flow in cholesterol-fed (0.4%) prairie dogs, as determined by hydrogen gas clearance. Gallbladder mucosal blood flow in control animals was 35.57 +/- 3.9 mL.min-1.100 g-1. In contrast, basal gallbladder mucosal blood flow in cholesterol-fed animals was significantly (P less than 0.01) increased to 64.94 +/- 8.7 mL.min-1.100 g-1. In crossover studies, the addition of lithogenic gallbladder bile to control animals (n = 6) resulted in a significant (P less than 0.025) 26% increase in gallbladder mucosal blood flow, whereas the addition of nonlithogenic gallbladder bile into gallbladders of cholesterol-fed prairie dogs resulted in a significant (P less than 0.025) 58% decrease in gallbladder mucosal blood flow. Similarly, hepatic bile crossover studies showed that the addition of lithogenic hepatic bile to control gallbladders significantly increased (P less than 0.025) gallbladder blood flow by 30%, whereas instillation of nonlithogenic hepatic bile in gallbladders of cholesterol-fed animals significantly (P less than 0.025) decreased gallbladder mucosal blood flow by 29%. These results suggest that alterations in gallbladder mucosal blood flow, influenced by the presence and absence of lithogenic bile, may play a role in cholesterol gallstone formation.     

Pigment gallstone formation in the cholesterol-fed guinea pig

Female Hartley guinea pigs fed a 0.5% cholesterol-supplemented diet were found to form pigmented gallstones after 6 weeks (17/23) and 12 weeks (11/11), while only 2 of 44 animals fed a trace cholesterol diet formed gallstones over a comparable period. The light brown stones consisted primarily of aggregates of fine granular crystals, morphologically similar to calcium bilirubinate crystals. The stones were soluble in 0.1 N sodium hydroxide and were found to contain a substance which co-migrated with unconjugated bilirubin during thin-layer chromatography. Despite hypercholesterolemia (202 +/- 34 vs. 59 +/- 22 mg per dl in controls, p less than 0.05) and fatty infiltration of the liver, cholesterol-fed animals had a lithogenic index of only 0.22 +/- 0.04 in gallbladder bile as compared to a lithogenic index of 0.02 +/- 0.01 in animals fed the trace cholesterol diet. Accordingly, no cholesterol monohydrate crystals were found in any animals. Hematocrits among cholesterol-fed animals (47.6 +/- 1.2%) were lower than those of controls (54.8 +/- 1.3%, p less than 0.05) probably as a result of the cholesterol-induced hemolytic anemia which has been reported by others in this species. Fasting gallbladder volume was greater in cholesterol-fed animals (2.4 +/- 0.18 ml) than in controls (1.7 +/- 0.11, p less than 0.0025), and a comparable increase in gallbladder dry tissue mass was found. There was no evidence of biliary obstruction, however, and the gallbladder contractile response to octapeptide cholecystokinin was comparable in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

T-cell function is critical for murine cholesterol gallstone formation

BACKGROUND & AIMS: The formation of cholesterol gallstones is a complex process involving contributions from genes and environmental factors. Although gallbladder inflammation is believed to be common during cholelithogenesis, the role of immunologic factors is unknown. METHODS: The role of adaptive immunity in cholesterol cholelithogenesis was analyzed utilizing immunocompetent Helicobacter spp.-infected and -uninfected BALB/c and congenic immunodeficient Rag2(-/-) (Rag) mice. Lymphocyte transfer studies were performed to determine which cellular subset was responsible for cholesterol gallstone formation. Also, gallbladder inflammation was quantified to determine the nature of the inflammatory response associated with cholelilithogenesis. RESULTS: When fed a lithogenic diet for 8 weeks, wild-type mice developed significantly more cholesterol gallstones (27%-80% prevalence) than Rag mice ( approximately 5%, P < .05). Helicobacter spp.-infected BALB/cJ mice displayed statistically significant increases in cholesterol gallstone prevalence compared with uninfected mice (81% vs. 39%; P < .05). Transfer of splenocytes or T lymphocytes to Rag2(-/-) mice increased stone prevalence markedly (26% and 40% respectively; P < .05), whereas transfer of B cells was not appreciably cholelithogenic (13%). The adaptive immune response increased the expression of gallbladder Muc genes and accumulation of mucin gel. In addition, T cells and cholesterol monohydrate crystals induced proinflammatory gene expression in the gallbladder, which likely contributes to gallbladder dysfunction. CONCLUSIONS: These studies indicate that T cells are critical in murine cholesterol cholelithogenesis. Furthermore, cholesterol monohydrate crystals induce expression of proinflammatory cytokines in a T-cell-dependent fashion. Acquired immunity and inflammation are likely to be crucial factors in cholesterol gallstone pathogenesis, rather then merely the result of cholelithogenesis.     

Association of caveolin-3 and cholecystokinin A receptor with cholesterol gallstone disease in mice

AIM: To investigate the role of caveolin-3 (CAV3) and cholecystokinin A receptor (CCKAR) in cholesterol gallstone disease (CGD).METHODS: To establish a mouse model of CGD, male C57BL/6 mice were fed with a lithogenic diet containing 1.0% cholic acid, 1.25% cholesterol and 15% fat; a similar control group was given a normal diet. The fresh liver weights and liver-to-body weight ratio were compared between the two groups after one month. Serum lipid profile and bile composition were determined with an autoanalyzer. The Cav3 and Cckar mRNA and CAV3 and CCKAR protein levels in the liver and gallbladder were determined via real-time polymerase chain reaction and Western blot, respectively.RESULTS: Establishment of the mouse CGD model was verified by the presence of cholesterol gallstones in mice fed the lithogenic diet. Compared with mice maintained on a normal diet, those fed the lithogenic diet had significantly higher mean liver-to-body weight ratio (0.067 ± 0.007 vs 0.039 ± 0.007, P < 0.01), serum total cholesterol (4.22 ± 0.46 mmol/L vs 2.21 ± 0.11 mmol/L, P < 0.001), bile total cholesterol (1.33 ± 0.33 mmol/L vs 0.21 ± 0.11 mmol/L, P < 0.001), and bile phospholipid concentrations (3.55 ± 1.40 mmol/L vs 1.55 ± 0.63 mmol/L, P = 0.04), but lower total bile acid concentrations (726.48 ± 51.83 μmol/L vs 839.83 ± 23.74 μmol/L, P = 0.007). The lithogenic diet was also associated with significantly lower CAV3 in the liver and lower CAV3 and CCKAR in the gallbladder compared with the control mice (all P < 0.05).CONCLUSION: CAV3 and CCKAR may be involved in cholesterol gallstone disease.     

Biliary lipid secretion,bile acid metabolism,and gallstone formation are not impaired in hepatic lipase-deficient mice

Whereas hepatic lipase (HL) has been implicated in lipoprotein metabolism and atherosclerosis, its role in controlling biliary lipid physiology has not been reported. This work characterizes plasma lipoprotein cholesterol, hepatic cholesterol content, bile acid metabolism, biliary cholesterol secretion, and gallstone formation in HL-deficient mice and C57BL/6 controls fed standard chow, a cholesterol-supplemented diet, or a lithogenic diet. Compared with C57BL/6 controls, HL knockout mice exhibited increased basal plasma high-density lipoprotein (HDL) cholesterol as well as reduced cholesterol levels transported in large lipoproteins in response to cholesterol-enriched diets. Hepatic cholesterol content and biliary cholesterol secretion of chow-fed HL knockout and wild-type mice were not different and increased similarly in both strains after feeding dietary cholesterol or a lithogenic diet. There were no differences in biliary bile acid secretion, bile acid pool size and composition, or fecal bile acid excretion between HL-deficient and control mice. HL knockout mice had a similar prevalence of gallstone formation as compared with control mice when both strains were fed with a lithogenic diet. In conclusion, the deficiency of HL has no major impact on the availability of lipoprotein-derived hepatic cholesterol for biliary secretion; HL expression is not essential for diet-induced gallstone formation in mice.     

Influence of fever on biliary elements of guinea pigs

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Slow intestinal transit: A motor disorder contributing to cholesterol gallstone formation in the ground squirrel

Impaired gallbladder motility is an established factor in cholesterol gallstone formation. We assessed whether altered small intestinal smooth muscle contractility with slow transit might potentiate gallstone formation by further impeding enterohepatic cycling of bile acids. Ground squirrels were fed a 1% or a trace (controls) cholesterol diet. Small intestinal transit was evaluated from ⁵¹Cr distribution in conscious, fasted animals 20 minutes after infusion into the proximal jejunum. Small intestinal and gallbladder smooth muscle contractility was determined in vitro. Biliary lipid secretion was measured from the cannulated common duct and the bile salt pool size calculated by isotope dilution. Gas-liquid chromatography (GLC) assessed bile salt profile. In animals on the 1% cholesterol diet, aboral transit was significantly delayed, the maximal contractile response to bethanechol was markedly increased (P <.05) with no change in median effective concentration in either circular or longitudinal muscle strips from both the jejunum and ileum, and the gallbladder contractile responses to bethanechol and cholecystokinin (CCK) were decreased. Cholesterol saturation index and the fraction of deoxycholic acid in the pool doubled, whereas the total bile salt pool size remained unchanged in cholesterol-fed animals. In this model, a high-cholesterol diet is associated with altered small intestinal smooth muscle contractility and prolonged small intestinal transit, in addition to diminished gallbladder contractility. The resulting sluggish enterohepatic cycling of bile salts, associated with expanded deoxycholate pool, contributes to cholesterol gallstone formation. (Hepatology 1996 Jun;23(6):1664-72)     

Cyclic nucleotides and glycoproteins during formation of cholesterol gallstones in prairie dogs

Male prairie dogs received in standard diets either 0.08% cholesterol (control, n = 30) or 1.2% cholesterol (lithogenic, n = 31). Animals were killed at days 2-4, 7, 10, 21, and 39 to determine the temporal sequence of changes in mucosal cyclic adenosine 3':5'-monophosphate in the gallbladder and of cholesterol saturation, glycoproteins, cholesterol crystals, and gallstones in bile of prairie dogs fed a cholesterol-rich lithogenic diet. Glycoprotein concentration in bile in the lithogenic group was significantly elevated compared to controls on all days of death. Saturation of bile and formation of cholesterol crystals occurred only in the lithogenic group, detected first after 7 days of feeding. Gallstones were found in the lithogenic group only. Elevation of cyclic adenosine 3':5'-monophosphate in the mucosa of gallbladders was found in the lithogenic group only, beginning at day 10. In summary, increased glycoproteins in bile preceded cholesterol saturation and crystallization which, in turn, preceded increased mucosal cyclic adenosine 3':5'-monophosphate.