Phosphatidylcholine-enriched diet prevents gallstone formation in mice susceptible to cholelithiasis

Cholesterol gallstones affect approximately 10–15% of the adult population in North America. Phosphatidylcholine (PC) is considered to be the main cholesterol solubilizer in bile. This study examined the effect of a PC-enriched diet on gallstone incidence in mice susceptible to cholelithiasis. The result obtained showed that the feeding of a lithogenic (LG) diet for 4 weeks or 8 weeks resulted in cholesterol gallstone incidences of 47% and 89%, respectively. These gallstone incidences were either reduced or prevented when the LG diet was enriched with 2% or 6% PC, respectively. The cholesterol saturation index (CSI) was reduced only in mice fed with LG + 6% PC diet as compared with mice fed the LG diet alone. However, in all groups, the CSI was significantly higher than in mice fed Purina chow diet. The biliary anionic polypeptide fraction (APF) was significantly increased in mice fed the LG + 2% PC diet and was reduced in those fed with LG + 6% PC diet.In conclusion, prevention or delay of gallstone formation was not due to a consistent effect on biliary lipid composition, suggesting a direct effect of PC on cholesterol solubilization and/or the effect of an additional nonlipid biliary component such as APF. Cholesterol gallstones affect approximately 10–15% of the adult population in North America. Phosphatidylcholine (PC) is considered to be the main cholesterol solubilizer in bile. This study examined the effect of a PC-enriched diet on gallstone incidence in mice susceptible to cholelithiasis. The result obtained showed that the feeding of a lithogenic (LG) diet for 4 weeks or 8 weeks resulted in cholesterol gallstone incidences of 47% and 89%, respectively. These gallstone incidences were either reduced or prevented when the LG diet was enriched with 2% or 6% PC, respectively. The cholesterol saturation index (CSI) was reduced only in mice fed with LG + 6% PC diet as compared with mice fed the LG diet alone. However, in all groups, the CSI was significantly higher than in mice fed Purina chow diet. The biliary anionic polypeptide fraction (APF) was significantly increased in mice fed the LG + 2% PC diet and was reduced in those fed with LG + 6% PC diet. In conclusion, prevention or delay of gallstone formation was not due to a consistent effect on biliary lipid composition, suggesting a direct effect of PC on cholesterol solubilization and/or the effect of an additional nonlipid biliary component such as APF. Gallstones may be divided into two major types: cholesterol gallstone and pigment stones. Cholesterol gallstones constitute >80% of stones in the Western world and are composed predominantly of cholesterol (1Trotman B.W. Ostrow J.D. Soloway R.D. Pigment vs cholesterol cholelithiasis: comparison of stone and bile composition.Am. J. Dig. Dis. 1974; 199: 585-590Crossref Scopus (168) Google Scholar). The mechanism of cholesterol gallstone formation has not been completely elucidated (2Portincasa P. van de Meeberg P. van Erpecum K.J. Palasciano G. VanBerge-Henegouwen G.P. An update on the pathogenesis and treatment of cholesterol gallstones.Scand. J. Gastroenterol. 1997; 223: 60-69Google Scholar). Research interest during the last two decades has been focused on the metabolism of biliary lipids and its relationship to gallstone formation (3Angelico M. Ginanni C.S. Masella R. Alvaro D. Cantafora A. Capocaccia L. Molecular composition of biliary phosphatidylcholines, as related to cholesterol saturation, transport and nucleation in human gallbladder bile.J. Hepatol. 1992; 15: 59-66Abstract Full Text PDF PubMed Scopus (23) Google Scholar, 4Tudyka J. Kratzer W. Maier C. Mason R. Wechsler J.G. 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Gallstones and inflammatory gallbladder diseases.in: Sherlock S. Dooley J. Diseases of the Liver and Biliary System. 10th edition. Blackwell Science, Oxford1997: 593-619Google Scholar). Biliary anionic polypeptide fraction (APF) is a small peptide (7 kDa) present in both normal and pathological biles (14Domingo N. Grosclaude J. Bekaert E.D. Chapman M.J. Shimizu S. Ayrault-Jarrier M. Ostrow J.D. Lafont H. Epitope mapping of the human biliary amphipathic anionic polypeptide (APF): similarity with a calcium-binding protein (CBP) isolated from gallstones and bile and immunologic cross-reactivity with apolipoprotein A-I.J. Lipid Res. 1992; 33: 1419-1430Abstract Full Text PDF PubMed Google Scholar). It has been demonstrated that APF is involved in the uptake of unesterified cholesterol (15Jourdheuil-Rahmani D. Charbonnier M. Domingo N. Luccioni F. Lafont H. Lairon D. Biliary anionic peptide fraction and apoA-I regulate intestinal cholesterol uptake.Biochem. Biophys. Res. Commun. 2002; 292: 390-395Crossref PubMed Scopus (15) Google Scholar) and stimulates cholesterol and PL transport to the bile (16Martigne M. Domingo N. Chanussot F. Nalbone G. Lafont H. Hauton J.C. Effect of bile anionic polypeptide fraction on the fate of cholesterol carried by liposomes in the rat.Proc. Soc. Exp. Biol. Med. 1988; 187: 229-234Crossref PubMed Scopus (15) Google Scholar, 17Martigne M. Melin M. Mahlberg F. Domingo N. Chanussot F. Lafont H. Hauton J.C. Detection and characterization of anionic polypeptide fraction binding sites in rat liver membranes and cultured hepatocytes.Biochim. Biophys. Acta. 1989; 979: 341-346Crossref PubMed Scopus (10) Google Scholar). It was also recently demonstrated that APF plays an important role in controlling the onset and rates of precipitation of calcium salts, bile pigments, and cholesterol in gallstone formation (18Konikoff F.M. Lechene P. Laufer H. Domingo N. Lafont H. Gilat H. Calcium and the anionic polypeptide fraction (APF) have opposing effects on cholesterol crystallization in model bile.J. Hepatol. 1997; 27: 707-715Abstract Full Text PDF PubMed Scopus (13) Google Scholar, 19Ostrow J.D. APF/CBP, an anionic polypeptide in bile and gallstones that may regulate calcium salt and cholesterol precipitation from bile.Hepatology. 1992; 16: 1493-1496Crossref PubMed Scopus (18) Google Scholar). Several in vitro studies showed a beneficial effect for (PC) on cholesterol and nucleation Z. M. Laufer H. Gilat T. Effect of phospholipids and their species on cholesterol and nucleation in human and model 1993; PubMed Scopus (38) Google Scholar, D. T. P. V. G. Effect of phospholipids and bile on cholesterol nucleation and cholesterol in gallbladder bile of with cholesterol Lipid Res. 1993; Full Text PDF PubMed Google Scholar). in studies have also that PC the biliary lipid secretion and bile is a in cholesterol M.J. V. A. The role of in the beneficial effects of on the secretion of biliary lipids in Biophys. Acta. PubMed Scopus Google Scholar). However, has not been a study on the effect of PC on cholelithiasis. The present study was to the effect of a diet enriched in PC on cholesterol gallstone formation in These mice have an to when fed the lithogenic (LG) diet composed of cholesterol, and mice for susceptible weeks were from the and were in a with were for to treatment and were to and the and were during the of the The components for the were from with the of and were obtained from and PLs from PC were obtained from was obtained from The bile salt and were from The LG diet was as M. Carey M.C. a major cholesterol gallstone formation of PubMed Scopus Google Scholar). The diet and The with PC a of the were In the mice were divided into of the were fed the LG diet for of the the LG diet 2% PC for 4 and in the LG 2% PC for 8 In the mice were fed a diet or the LG diet with 6% PC for 4 In was obtained between mice fed LG + 6% PC diet for 4 weeks or 8 weeks with to the incidence of the fed LG + 6% PC for 8 weeks was from the of the to the were to mice were by with 4 of An additional of was a showed of was an and the gallbladder was and examined for the of The bile was with a and bile was for was a of of bile, and bile were bile salt was by the J.M. of the for bile in bile.J. Lipid Res. Full Text PDF Google Scholar). Biliary lipids were as by and J. M. A for the and the of lipids from Biol. Full Text PDF PubMed Google Scholar), and PLs were as by the of in Biol. Full Text PDF PubMed Google Scholar). Cholesterol was from bile by the of and A for lipid and J. PubMed Scopus Google Scholar) and was a from The for the of and bile in bile was to that by S. D. of bile in by Lipid Res. Full Text Full Text PDF PubMed Google Scholar) and Cholesterol saturation index (CSI) was to the by Carey M.C. for the cholesterol saturation of bile.J. Lipid Res. 19: Full Text PDF PubMed Google Scholar). APF was isolated from bile to the by Lafont H. Domingo N. A. Kaler E.W. R. Ostrow J.D. A. APF/CBP, the anionic in bile and of and calcium-binding 1997; PubMed Scopus Google Scholar). In of human APF with was obtained by of bile for the of APF was by (14Domingo N. Grosclaude J. Bekaert E.D. Chapman M.J. Shimizu S. Ayrault-Jarrier M. Ostrow J.D. Lafont H. Epitope mapping of the human biliary amphipathic anionic polypeptide (APF): similarity with a calcium-binding protein (CBP) isolated from gallstones and bile and immunologic cross-reactivity with apolipoprotein A-I.J. Lipid Res. 1992; 33: 1419-1430Abstract Full Text PDF PubMed Google Scholar, H. Domingo N. A. Kaler E.W. R. Ostrow J.D. A. APF/CBP, the anionic in bile and of and calcium-binding 1997; PubMed Scopus Google Scholar). APF was from small peptide and residual by a hydrophobic H. Domingo N. A. Kaler E.W. R. Ostrow J.D. A. APF/CBP, the anionic in bile and of and calcium-binding 1997; PubMed Scopus Google Scholar). This in a on a by APF was by and as (14Domingo N. Grosclaude J. Bekaert E.D. Chapman M.J. Shimizu S. Ayrault-Jarrier M. Ostrow J.D. Lafont H. Epitope mapping of the human biliary amphipathic anionic polypeptide (APF): similarity with a calcium-binding protein (CBP) isolated from gallstones and bile and immunologic cross-reactivity with apolipoprotein A-I.J. Lipid Res. 1992; 33: 1419-1430Abstract Full Text PDF PubMed Google Scholar). on the the was and for an APF of The were by and was considered to be The LG diet and the LG diet 2% or 6% PC were all by the The mice showed after an was between and liver with However, mice fed with Purina chow diet showed a in the by in the liver not the incidence of the of precipitation of cholesterol crystals and cholesterol on the gallbladder and incidence of gallstones during 4 weeks and 8 weeks of treatment with the LG diet 2% and 6% In mice fed the Purina chow was incidence of gallstone formation or during the 4 weeks or 8 weeks of the In mice fed the LG was a 47% and incidence of gallstone formation 4 weeks and 8 respectively. In mice fed LG + 2% PC, of the mice after 4 weeks of was increased to after 8 weeks of However, cholesterol gallstone incidence was and increased to after 4 weeks and 8 respectively. When mice were fed the LG + 6% PC of the mice 4 incidence of gallstones was of and gallstones with in mice fed Purina lithogenic + 2% or lithogenic + 6% diet Purina LG + 2% LG + 6% diet Purina LG + 2% LG + 6% LG + 2% PC, LG with 2% LG + 6% PC, LG with 6% not The the incidence of gallstone and cholesterol gallstone formation with in mice fed the Purina LG + or LG + 6% PC The the of with or gallstone present in the a of the LG + 6% PC was from the study after 4 weeks of in a LG + 2% PC, LG with 2% LG + 6% PC, LG with 6% not The the incidence of gallstone and cholesterol gallstone formation with in mice fed the Purina LG + or LG + 6% PC The the of with or gallstone present in the a of the LG + 6% PC was from the study after 4 weeks of The LG diet effect on bile and bile secretion when compared with mice fed a Purina chow diet. However, the secretion of PLs and cholesterol was significantly an LG + 2% PC diet to the mice for 4 weeks or 8 weeks effect on bile bile or cholesterol secretion when compared with the LG diet However, feeding with the LG + 6% PC diet for 4 weeks a in bile bile and PL secretion not a effect on cholesterol secretion when compared with fed the LG diet and secretion of bile and cholesterol in bile obtained during from mice fed LG + 6% PC, and Purina chow for 4 are as of different from the bile salts composition of bile in mice the Purina chow diet and mice fed the LG and LG + 2% PC 4 weeks and 8 and LG + 6% PC 4 In the the major bile were by and bile and of the bile the LG + 2% PC, or LG + 6% PC for 4 weeks increased the of and reduced the of and However, was in the of The of obtained by the showed that bile was the major bile by bile of and bile were also with between composition of bile obtained from mice fed with Purina LG + or LG + when compared with LG diet for the when compared with LG + 6% PC diet for the when compared with LG diet for the when compared with LG + 6% PC diet for the when compared with LG diet for the when compared with LG + 6% PC diet for the when compared with LG diet for the when compared with LG + 6% PC diet for the when compared with diet for the when compared with diet for the when compared with diet for the when compared with diet for the + 2% PC when compared with diet for the when compared with diet for the when compared with diet for the when compared with diet for the + 6% PC when compared with diet for the when compared with diet for the when compared with diet for the + 2% PC when compared with LG diet for the The the bile composition of bile obtained from mice fed with Purina LG + or LG + 6% PC are as when compared with LG diet for the when compared with LG + 6% PC diet for the when compared with diet for the in a The the bile composition of bile obtained from mice fed with Purina LG + or LG + 6% PC are as The PC species obtained by the showed that the PC that was to the diet was composed of and The PC species obtained in bile of mice fed the LG + 2% PC, and LG + 6% PC were in all groups, and composed of These that composition not the composition of bile. the of bile and cholesterol in gallbladder bile. The LG diet increased the of cholesterol from to LG after 4 weeks of and was effect in the of bile and The of 2% PC to the LG diet increased the of cholesterol from to LG + 2% PC However, 6% PC significantly decreased the of cholesterol from to + 2% PC LG + 6% PC significantly higher as compared with the LG increased the biliary effect on the of was The gallbladder bile lipid composition after 8 weeks of treatment was not significantly different from that after 4 weeks of bile lipid composition in mice fed with LG + LG + 6% PC, or Purina chow for 4 + 2% was considered was considered was considered + 6% bile The the gallbladder bile and lipid composition obtained from mice with LG + LG + 6% PC, or Purina chow obtained after 8 weeks of treatment were not significantly different from the obtained after 4 weeks of are as was considered in a bile The the gallbladder bile and lipid composition obtained from mice with LG + LG + 6% PC, or Purina chow obtained after 8 weeks of treatment were not significantly different from the obtained after 4 weeks of are as the CSI in the gallbladder bile obtained from mice fed with LG + 2% PC, and LG + 6% PC The CSI was significantly increased in the LG feeding 2% PC and 6% PC in the LG diet reduced the CSI by and when compared with gallbladder bile obtained from mice fed the LG diet alone. The CSI in the gallbladder bile obtained from mice fed the LG diet enriched in 2% or 6% PC significantly higher than the CSI of the bile obtained from the gallbladder of mice fed the Purina chow diet. that the LG and LG + 2% PC a in APF in gallbladder bile when compared with the Purina chow diet. However, feeding the LG + 6% PC diet showed a not in APF when compared with the Purina chow diet. Several are with and are the major in the formation of cholesterol were to cholesterol gallstone formation in It has also been that cholesterol gallstone between to in different of mice S. T. in and the effect of on the gallstone formation in Med. 19: PubMed Scopus Google the LG diet is for the formation of cholesterol gallstones M. Carey M.C. a major cholesterol gallstone formation of PubMed Scopus Google Scholar, Carey M.C. characterization of that to cholesterol in of gallbladder bile.J. Lipid Res. 1997; Full Text PDF PubMed Google Scholar). The of mice biliary cholesterol bile with cholesterol, and a of cholesterol gallstone formation Carey M.C. characterization of that to cholesterol in of gallbladder bile.J. Lipid Res. 1997; Full Text PDF PubMed Google Scholar, D. F. Carey M.C. biliary cholesterol as a to cholesterol gallstone formation in 1997; Scholar). PC, the major PL present in bile, is for the of cholesterol from bile. Several studies in showed that PC the bile formation by the secretion of bile and biliary lipids M.J. S. G. T. V. Effects of on lipid transport and cholesterol metabolism in PubMed Scopus Google Scholar, M.J. V. A. The role of in the beneficial effects of on the secretion of biliary lipids in Biophys. Acta. PubMed Scopus Google Scholar). The of study was to the effect of PC on cholesterol gallstone formation in susceptible The showed that a 2% PC fed for 4 weeks and 8 weeks reduced cholesterol gallstone formation This effect was with a in CSI and a in biliary APF In mice fed the LG + 6% PC incidences of gallstones were after 4 weeks and 8 weeks of This was with a in CSI and effect on APF However, 6% PC in the LG diet increased the bile and secretion of bile and PLs The LG + 2% PC diet not a effect on bile bile or in biliary lipid secretion as compared with the LG diet alone. The in bile in mice fed the LG + 6% PC diet be by the in biliary bile secretion F. A. L. M.C. feeding of a diet enriched in phospholipids bile formation and the bile transport in Biophys. Acta. 1994; PubMed Scopus (20) Google Scholar). However, the in biliary PL secretion be due to the that PC can uptake by the and PC can be either from the or from the N. L. H. A.M. Lafont H. Chanussot F. effect of in by of biliary lipid J. PubMed Scopus Google Scholar). It has been that in model bile, PC can delay cholesterol crystallization time, PC F.M. D.E. Carey M.C. species and of during cholesterol crystallization from bile model bile.J. Lipid Res. 1994; Full Text PDF PubMed Google Scholar). showed that species and composition of biliary PC were not by the LG or the LG + PC by M. F. D. Carey M.C. D. protein in of biliary cholesterol during gallstone formation in J. PubMed Scopus Google Scholar), the the biliary cholesterol in to the LG diet in susceptible The obtained from the present study that cholesterol secretion was significantly higher in mice fed the LG diet as as the LG + 2% and LG + 6% PC in comparison with obtained from mice fed the Purina chow diet. However, with PC decreased cholesterol when compared with obtained from mice fed the LG diet In is the bile in mice is also present A.M. A study of bile metabolism in the and Soc. Exp. Biol. Med. PubMed Scopus Google Scholar, of bile salts in the The of North Scholar). with an in biliary and a in as as T. of in mice by 1986; PubMed Scopus Google Scholar). the major bile in mice fed the LG or the LG + PC was also a in the of in bile obtained from mice fed the LG or the LG + PC was in the of Several studies have an in biliary in cholesterol gallstone and the pathogenesis of 1988; 29: PubMed Scopus Google Scholar, cholesterol solubilization and nucleation in gallbladder bile.Hepatology. Google Scholar), and has also been that an increased in bile cholesterol crystallization and the formation of cholesterol Berge Henegouwen G.P. Van der composition of phospholipids in bile in effect of on Acta. PubMed Scopus Google Scholar). In was demonstrated that is was with human J. N. T. S. H. J. of in supersaturated bile of with cholesterol gallstone and its with de of cholesterol and bile in gallbladder and small intestinal Google Scholar). In a in biliary in mice fed the LG diet. This is to be of the higher of in the bile of and is the bile from However, PC of the LG diet not affect the of in comparison with the LG diet to and M. to the formation of cholesterol gallstones in PubMed Scopus Google Scholar), of bile were LG diet However, bile were not in that PC not affect the of bile the that the effect of PC on gallstone formation is not related to consistent changes in biliary lipid or bile APF was as of a bile M. Melin M. Mahlberg F. Domingo N. Chanussot F. Lafont H. Hauton J.C. Detection and characterization of anionic polypeptide fraction binding sites in rat liver membranes and cultured hepatocytes.Biochim. Biophys. Acta. 1989; 979: 341-346Crossref PubMed Scopus (10) Google Scholar). is present in higher in biliary vesicles compared with the biliary was to in vesicles in Z. Lafont H. J. Domingo N. F. Gilat T. The of the biliary anionic polypeptide fraction between cholesterol carriers in bile and its effect on Hepatol. 1994; Full Text PDF PubMed Scopus (18) Google Scholar). In mice fed the LG + 2% PC the APF was bile lipids were the were This that such a diet the of a bile enriched with APF. This a major effect on the gallstone formation APF in as a molecule in the of cholesterol gallstone The more of 6% PC in a in bile salts an be with the to the as The of D. The Google Scholar) and a in the suggesting a effect of the CSI in the effect of of PC The in APF was in with F. Domingo N. Lafont H. of and on the biliary secretion of anionic polypeptide the major of the biliary J. Gastroenterol. 1992; 27: PubMed Scopus Google Scholar). that the may by the APF and The reduced CSI and formation of a biliary form APF to be in the in a diet with In conclusion, study that PC reduced cholesterol gallstone formation in susceptible mice fed the LG diet. This is with a in CSI as as an in the secretion of APF in mice with 2% PC in the LG diet. When the of PC in the diet that the in the CSI and the of the are more important for gallstone formation than is an in APF The also that bile bile and PL secretion in the 6% and 2% mice may with the biliary secretion of APF. This was by a from the Liver

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