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Effects of Biliary Phospholipids on Cholesterol Crystallization and Growth in Gallstone Formation

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Abstract

The prevalence of cholesterol gallstone disease is increasing, primarily due to the global epidemic of obesity associated with insulin resistance, and this trend leads to a considerable healthcare, financial, and social burden worldwide. Although phospholipids play an essential role in maintaining cholesterol solubility in bile through both mixed micelles and vesicles, little attention has been paid to the impact of biliary phospholipids on the pathogenesis of cholesterol gallstone formation. A reduction or deficiency of biliary phospholipids results in a distinctly abnormal metastable physical–chemical state of bile predisposing to supersaturation with cholesterol. Changes in biliary phospholipid concentrations influence cholesterol crystallization by yielding both liquid crystalline and “anhydrous” crystalline metastable intermediates, evolving into classical parallelogram-shaped cholesterol monohydrate crystals in supersaturated bile. As a result, five distinct crystallization pathways, A–E, have been defined, mainly based on the prime habits of liquid and solid crystals in the physiological or pathophysiological cholesterol saturation of gallbladder and hepatic bile. This review concisely summarizes the chemical structures and physical–chemical properties of biliary phospholipids and their physiological functions in bile formation and cholesterol solubility in bile, as well as comprehensively discusses the latest advances in the role of biliary phospholipids in cholesterol crystallization and growth in gallstone formation, largely based on the findings from clinical and animal studies and in vitro experiments. The insights gleaned from uncovering the cholelithogenic mechanisms are expected to form a fundamental framework for investigating the hitherto elusive events in the earliest stage of cholesterol nucleation and crystallization. This may help to identify better measures for early diagnosis and prevention in susceptible subjects and effective treatment of patients with gallstones.

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References

  1. Wang DQ, Portincasa P. Gallstones: recent advances in epidemiology, pathogenesis, diagnosis and management. New York: Nova Biomedical; 2017. p. 1–676.

    Google Scholar 

  2. Peery AF, Crockett SD, Murphy CC, Jensen ET, Kim HP, Egberg MD, Lund JL, et al. Burden and cost of gastrointestinal, liver, and pancreatic diseases in the united states: update 2021. Gastroenterology. 2022;162:621–44.

    Article  PubMed  Google Scholar 

  3. Portincasa P, Ciaula AD, Bonfrate L, Wang DQ. Therapy of gallstone disease: what it was, what it is, what it will be. World J Gastrointest Pharmacol Ther. 2012;3:7–20.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Lammert F, Gurusamy K, Ko CW, Miquel JF, Mendez-Sanchez N, Portincasa P, van Erpecum KJ, et al. Gallstones. Nat Rev Dis Primers. 2016;2:16024.

    Article  PubMed  Google Scholar 

  5. Portincasa P, Moschetta A, Palasciano G. Cholesterol gallstone disease. Lancet. 2006;368:230–9.

    Article  CAS  PubMed  Google Scholar 

  6. Di Ciaula A, Wang DQ, Portincasa P. An update on the pathogenesis of cholesterol gallstone disease. Curr Opin Gastroenterol. 2018;34:71–80.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Wang DQ, Cohen DE, Carey MC. Biliary lipids and cholesterol gallstone disease. J Lipid Res. 2009;50:S406-411.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Wang HH, Portincasa P, Afdhal NH, Wang DQ. Lith genes and genetic analysis of cholesterol gallstone formation. Gastroenterol Clin North Am. 2010;39:185–207.

    Article  CAS  PubMed  Google Scholar 

  9. Wang HH, Li T, Portincasa P, Ford DA, Neuschwander-Tetri BA, Tso P, Wang DQ. New insights into the role of Lith genes in the formation of cholesterol-supersaturated bile. Liver Res. 2017;1:42–53.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Krawczyk M, Wang DQ, Portincasa P, Lammert F. Dissecting the genetic heterogeneity of gallbladder stone formation. Semin Liver Dis. 2011;31:157–72.

    Article  CAS  PubMed  Google Scholar 

  11. Portincasa P, Moschetta A, Di Ciaula A, Pontrelli D, Sasso RC, Wang HH, Wang DQ. Pathophysiology and cholesterol gallstone disease. In: Borzellino G, Cordiano C, editors. Biliary lithiasis: basic science, current diagnosis and management. 1st ed. Milano: Springer Italia S.r.l; 2008. p. 19–49.

    Chapter  Google Scholar 

  12. Wang DQ, Portincasa P, Wang HH. Bile formation and pathophysiology of gallstones. In: Kuipers EJ, (ed). Encyclopedia of gastroenterology, vol 1. 2nd edn. Oxford: Academic Press, 2020; 287–306.

  13. Wang HH, Portincasa P, de Bari O, Liu KJ, Garruti G, Neuschwander-Tetri BA, Wang DQ. Prevention of cholesterol gallstones by inhibiting hepatic biosynthesis and intestinal absorption of cholesterol. Eur J Clin Invest. 2013;43:413–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hofmann AF. Bile acids and the enterohepatic circulation. In: Arias IM, Alter HJ, Boyer JL, Cohen DE, Fausto N, Shafritz DA, Wolkoff AW, editors. The liver: biology and pathobiology. 5th ed. West Sussex: Wiley-Blackwell; 2009. p. 290–304.

    Google Scholar 

  15. Hussaini SH, Pereira SP, Murphy GM, Dowling RH. Deoxycholic acid influences cholesterol solubilization and microcrystal nucleation time in gallbladder bile. Hepatology. 1995;22:1735–44.

    CAS  PubMed  Google Scholar 

  16. Thomas LA, Veysey MJ, Murphy GM, Russell-Jones D, French GL, Wass JA, Dowling RH. Octreotide induced prolongation of colonic transit increases faecal anaerobic bacteria, bile acid metabolising enzymes, and serum deoxycholic acid in patients with acromegaly. Gut. 2005;54:630–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Marcus SN, Heaton KW. Intestinal transit, deoxycholic acid and the cholesterol saturation of bile–three inter-related factors. Gut. 1986;27:550–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wang DQ, Tazuma S, Cohen DE, Carey MC. Feeding natural hydrophilic bile acids inhibits intestinal cholesterol absorption: studies in the gallstone-susceptible mouse. Am J Physiol Gastrointest Liver Physiol. 2003;285:G494-502.

    Article  CAS  PubMed  Google Scholar 

  19. Hofmann AF. Pharmacology of ursodeoxycholic acid, an enterohepatic drug. Scand J Gastroenterol. 1994;204:1–15.

    Article  CAS  Google Scholar 

  20. Hofmann AF. Medical dissolution of gallstones by oral bile acid therapy. Am J Surg. 1989;158:198–204.

    Article  CAS  PubMed  Google Scholar 

  21. Konikoff FM, Chung DS, Donovan JM, Small DM, Carey MC. Filamentous, helical, and tubular microstructures during cholesterol crystallization from bile. Evidence that cholesterol does not nucleate classic monohydrate plates. J Clin Invest. 1992;90:1155–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wang DQ, Carey MC. Complete mapping of crystallization pathways during cholesterol precipitation from model bile: influence of physical-chemical variables of pathophysiologic relevance and identification of a stable liquid crystalline state in cold, dilute and hydrophilic bile salt-containing systems. J Lipid Res. 1996;37:606–30.

    Article  CAS  PubMed  Google Scholar 

  23. Wang DQ, Paigen B, Carey MC. Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: physical-chemistry of gallbladder bile. J Lipid Res. 1997;38:1395–411.

    Article  CAS  PubMed  Google Scholar 

  24. Wang DQ, Carey MC. Characterization of crystallization pathways during cholesterol precipitation from human gallbladder biles: identical pathways to corresponding model biles with three predominating sequences. J Lipid Res. 1996;37:2539–49.

    Article  CAS  PubMed  Google Scholar 

  25. Landi K, Sinard J, Crawford JM, Topazian M. Cholesterol crystal morphology in acalculous gallbladder disease. J Clin Gastroenterol. 2003;36:364–6.

    Article  PubMed  Google Scholar 

  26. Neoptolemos JP, Davidson BR, Winder AF, Vallance D. Role of duodenal bile crystal analysis in the investigation of “idiopathic” pancreatitis. Br J Surg. 1988;75:450–3.

    Article  CAS  PubMed  Google Scholar 

  27. Rosmorduc O, Hermelin B, Poupon R. MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis. Gastroenterology. 2001;120:1459–67.

    Article  CAS  PubMed  Google Scholar 

  28. Smit JJ, Schinkel AH, Oude Elferink RP, Groen AK, Wagenaar E, van Deemter L, Mol CA, et al. Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell. 1993;75:451–62.

    Article  CAS  PubMed  Google Scholar 

  29. Poupon R, Rosmorduc O, Boelle PY, Chretien Y, Corpechot C, Chazouilleres O, Housset C, et al. Genotype-phenotype relationships in the low-phospholipid-associated cholelithiasis syndrome: a study of 156 consecutive patients. Hepatology. 2013;58:1105–10.

    Article  CAS  PubMed  Google Scholar 

  30. Wang HH, Portincasa P, Liu M, Wang DQ. Genetic analysis of ABCB4 mutations and variants related to the pathogenesis and pathophysiology of low phospholipid-associated cholelithiasis. Genes (Basel). 2022;13:1047.

    Article  CAS  PubMed  Google Scholar 

  31. Oude Elferink RP, Ottenhoff R, van Wijland M, Smit JJ, Schinkel AH, Groen AK. Regulation of biliary lipid secretion by mdr2 P-glycoprotein in the mouse. J Clin Invest. 1995;95:31–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lammert F, Wang DQ, Hillebrandt S, Geier A, Fickert P, Trauner M, Matern S, et al. Spontaneous cholecysto- and hepatolithiasis in Mdr2-/- mice: a model for low phospholipid-associated cholelithiasis. Hepatology. 2004;39:117–28.

    Article  PubMed  Google Scholar 

  33. Hay DW, Cahalane MJ, Timofeyeva N, Carey MC. Molecular species of lecithins in human gallbladder bile. J Lipid Res. 1993;34:759–68.

    Article  CAS  PubMed  Google Scholar 

  34. Robins SJ, Brunengraber H. Origin of biliary cholesterol and lecithin in the rat: contribution of new synthesis and preformed hepatic stores. J Lipid Res. 1982;23:604–8.

    Article  CAS  PubMed  Google Scholar 

  35. Cronholm T, Curstedt T, Sjovall J. Origin of biliary phosphatidylcholines studied by coenzyme labelling with [1,1–2H2]ethanol. Biochim Biophys Acta. 1983;753:276–9.

    Article  CAS  PubMed  Google Scholar 

  36. Curstedt T. Biosynthesis of molecular species of phosphatidylcholines in bile, liver and plasma of rats given (1,1–2H2)ethanol. Biochim Biophys Acta. 1974;369:196–208.

    Article  CAS  PubMed  Google Scholar 

  37. Curstedt T, Sjovall J. Biosynthetic pathways and turnover of individual biliary phosphatidylcholines during metabolism of (1,1–2H2)ethanol in the rat. Biochim Biophys Acta. 1974;369:173–95.

    Article  CAS  PubMed  Google Scholar 

  38. Hay DW, Carey MC. Chemical species of lipids in bile. Hepatology. 1990;12:6S-14S (discussion 14S-16S).

    CAS  PubMed  Google Scholar 

  39. Cohen DE. Hepatocellular transport and secretion of biliary phospholipids. Semin Liver Dis. 1996;16:191–200.

    Article  CAS  PubMed  Google Scholar 

  40. Robins SJ, Fasulo JM. High density lipoproteins, but not other lipoproteins, provide a vehicle for sterol transport to bile. J Clin Invest. 1997;99:380–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Alvaro D, Cantafora A, Attili AF, Ginanni Corradini S, De Luca C, Minervini G, Di Biase A, et al. Relationships between bile salts hydrophilicity and phospholipid composition in bile of various animal species. Comp Biochem Physiol B. 1986;83:551–4.

    Article  CAS  PubMed  Google Scholar 

  42. Alvaro D, Angelico M, Cantafora A, Di Biase A, De Santis A, Bracci F, Minervini G, et al. Biliary secretion of phosphatidylcholine and its molecular species in cholecystectomized T-tube patients: effects of bile acid hydrophilicity. Biochem Med Metab Biol. 1986;36:125–35.

    Article  CAS  PubMed  Google Scholar 

  43. Angelico M, Ginanni Corradini 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;15:59–66.

    Article  CAS  PubMed  Google Scholar 

  44. Cohen DE, Carey MC. Physical chemistry of biliary lipids during bile formation. Hepatology. 1990;12:143S-147S (discussion 147S-148S).

    CAS  PubMed  Google Scholar 

  45. Wang DQ. Regulation of intestinal cholesterol absorption. Annu Rev Physiol. 2007;69:221–48.

    Article  CAS  PubMed  Google Scholar 

  46. Wang TY, Liu M, Portincasa P, Wang DQ. New insights into the molecular mechanism of intestinal fatty acid absorption. Eur J Clin Invest. 2013;43:1203–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Ko CW, Qu J, Black DD, Tso P. Regulation of intestinal lipid metabolism: current concepts and relevance to disease. Nat Rev Gastroenterol Hepatol. 2020;17:169–83.

    Article  CAS  PubMed  Google Scholar 

  48. Wang DQ, Afdhal NH. Gallstone disease. In: Feldman M, Friedman LS, Brandt L, Chung RT, Wilcox CM, editors. Sleisenger and Fordtran’s gastrointestinal and liver disease. 11th ed. Philadelphia: Elsevier; 2021. p. 1016–46.

    Google Scholar 

  49. Cohen DE, Leighton LS, Carey MC. Bile salt hydrophobicity controls vesicle secretion rates and transformations in native bile. Am J Physiol. 1992;263:G386-395.

    CAS  PubMed  Google Scholar 

  50. Van Nieuwkerk CM, Elferink RP, Groen AK, Ottenhoff R, Tytgat GN, Dingemans KP, Van Den Bergh Weerman MA, et al. Effects of Ursodeoxycholate and cholate feeding on liver disease in FVB mice with a disrupted mdr2 P-glycoprotein gene. Gastroenterology. 1996;111:165–71.

    Article  PubMed  Google Scholar 

  51. Crawford AR, Smith AJ, Hatch VC, Oude Elferink RP, Borst P, Crawford JM. Hepatic secretion of phospholipid vesicles in the mouse critically depends on mdr2 or MDR3 P-glycoprotein expression. Visualization by electron microscopy. J Clin Invest. 1997;100:2562–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Mazer NA, Carey MC. Quasi-elastic light-scattering studies of aqueous biliary lipid systems Cholesterol solubilization and precipitation in model bile solutions. Biochemistry. 1983;22:426–42.

    Article  CAS  PubMed  Google Scholar 

  53. Crawford JM, Mockel GM, Crawford AR, Hagen SJ, Hatch VC, Barnes S, Godleski JJ, et al. Imaging biliary lipid secretion in the rat: ultrastructural evidence for vesiculation of the hepatocyte canalicular membrane. J Lipid Res. 1995;36:2147–63.

    Article  CAS  PubMed  Google Scholar 

  54. Elferink RP, Groen AK. The mechanism of biliary lipid secretion and its defects. Gastroenterol Clin North Am. 1999;28(59–74):vi.

    PubMed  Google Scholar 

  55. Elferink RP, Tytgat GN, Groen AK. Hepatic canalicular membrane 1: the role of mdr2 P-glycoprotein in hepatobiliary lipid transport. FASEB J. 1997;11:19–28.

    Article  CAS  PubMed  Google Scholar 

  56. Guyot C, Stieger B. Interaction of bile salts with rat canalicular membrane vesicles: evidence for bile salt resistant microdomains. J Hepatol. 2011;55:1368–76.

    Article  CAS  PubMed  Google Scholar 

  57. Mazzone A, Tietz P, Jefferson J, Pagano R, LaRusso NF. Isolation and characterization of lipid microdomains from apical and basolateral plasma membranes of rat hepatocytes. Hepatology. 2006;43:287–96.

    Article  CAS  PubMed  Google Scholar 

  58. Tietz P, Jefferson J, Pagano R, Larusso NF. Membrane microdomains in hepatocytes: potential target areas for proteins involved in canalicular bile secretion. J Lipid Res. 2005;46:1426–32.

    Article  CAS  PubMed  Google Scholar 

  59. Anderson RG, Jacobson K. A role for lipid shells in targeting proteins to caveolae, rafts, and other lipid domains. Science. 2002;296:1821–5.

    Article  CAS  PubMed  Google Scholar 

  60. Simons K, Ikonen E. Functional rafts in cell membranes. Nature. 1997;387:569–72.

    Article  CAS  PubMed  Google Scholar 

  61. Morita SY, Tsuda T, Horikami M, Teraoka R, Kitagawa S, Terada T. Bile salt-stimulated phospholipid efflux mediated by ABCB4 localized in nonraft membranes. J Lipid Res. 2013;54:1221–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Morita SY, Terada T. Molecular mechanisms for biliary phospholipid and drug efflux mediated by ABCB4 and bile salts. Biomed Res Int. 2014;2014: 954781.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Morita SY, Ikeda Y, Tsuji T, Terada T. Molecular mechanisms for protection of hepatocytes against bile salt cytotoxicity. Chem Pharm Bull (Tokyo). 2019;67:333–40.

    Article  CAS  PubMed  Google Scholar 

  64. Eckstein J, Holzhutter HG, Berndt N. The importance of membrane microdomains for bile salt-dependent biliary lipid secretion. J Cell Sci. 2018;131:jcs211524.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Rosmorduc O, Hermelin B, Boelle PY, Parc R, Taboury J, Poupon R. ABCB4 gene mutation-associated cholelithiasis in adults. Gastroenterology. 2003;125:452–9.

    Article  PubMed  Google Scholar 

  66. Nosol K, Bang-Sorensen R, Irobalieva RN, Erramilli SK, Stieger B, Kossiakoff AA, Locher KP. Structures of ABCB4 provide insight into phosphatidylcholine translocation. Proc Natl Acad Sci USA 2021;118:e2106702118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Heuman DM, Bajaj RS, Lin Q. Adsorption of mixtures of bile salt taurine conjugates to lecithin-cholesterol membranes: implications for bile salt toxicity and cytoprotection. J Lipid Res. 1996;37:562–73.

    Article  CAS  PubMed  Google Scholar 

  68. Heuman DM, Mills AS, McCall J, Hylemon PB, Pandak WM, Vlahcevic ZR. Conjugates of ursodeoxycholate protect against cholestasis and hepatocellular necrosis caused by more hydrophobic bile salts. In vivo studies in the rat. Gastroenterology. 1991;100:203–11.

    Article  CAS  PubMed  Google Scholar 

  69. Heuman DM, Pandak WM, Hylemon PB, Vlahcevic ZR. Conjugates of ursodeoxycholate protect against cytotoxicity of more hydrophobic bile salts: in vitro studies in rat hepatocytes and human erythrocytes. Hepatology. 1991;14:920–6.

    Article  CAS  PubMed  Google Scholar 

  70. Heuman DM, Bajaj R. Ursodeoxycholate conjugates protect against disruption of cholesterol-rich membranes by bile salts. Gastroenterology. 1994;106:1333–41.

    Article  CAS  PubMed  Google Scholar 

  71. Gonzales E, Davit-Spraul A, Baussan C, Buffet C, Maurice M, Jacquemin E. Liver diseases related to MDR3 (ABCB4) gene deficiency. Front Biosci. 2009;14:4242–56.

    Article  CAS  Google Scholar 

  72. Gotthardt D, Runz H, Keitel V, Fischer C, Flechtenmacher C, Wirtenberger M, Weiss KH, et al. A mutation in the canalicular phospholipid transporter gene, ABCB4, is associated with cholestasis, ductopenia, and cirrhosis in adults. Hepatology. 2008;48:1157–66.

    Article  CAS  PubMed  Google Scholar 

  73. Ikeda Y, Morita SY, Terada T. Cholesterol attenuates cytoprotective effects of phosphatidylcholine against bile salts. Sci Rep. 2017;7:306.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Carey MC, Small DM. The physical chemistry of cholesterol solubility in bile. Relationship to gallstone formation and dissolution in man. J Clin Invest. 1978;61:998–1026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Holzbach RT, Marsh M, Olszewski M, Holan K. Cholesterol solubility in bile. Evidence that supersaturated bile is frequent in healthy man. J Clin Invest. 1973;52:1467–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Sedaghat A, Grundy SM. Cholesterol crystals and the formation of cholesterol gallstones. N Engl J Med. 1980;302:1274–7.

    Article  CAS  PubMed  Google Scholar 

  77. Holan KR, Holzbach RT, Hermann RE, Cooperman AM, Claffey WJ. Nucleation time: a key factor in the pathogenesis of cholesterol gallstone disease. Gastroenterology. 1979;77:611–7.

    Article  CAS  PubMed  Google Scholar 

  78. Holzbach RT. Newer pathogenetic concepts in cholesterol gallstone formation: a unitary hypothesis. Digestion. 1997;58(S1):29–32.

    Article  PubMed  Google Scholar 

  79. Bojesen ED, Iversen BB. The chemistry of nucleation. CrystEngComm. 2016;18:8332–53.

    Article  Google Scholar 

  80. Holzbach RT, Busch N. Nucleation and growth of cholesterol crystals. Kinetic determinants in supersaturated native bile. Gastroenterol Clin North Am. 1991;20:67–84.

    Article  CAS  PubMed  Google Scholar 

  81. Halpern Z, Dudley MA, Lynn MP, Nader JM, Breuer AC, Holzbach RT. Vesicle aggregation in model systems of supersaturated bile: relation to crystal nucleation and lipid composition of the vesicular phase. J Lipid Res. 1986;27:295–306.

    Article  CAS  PubMed  Google Scholar 

  82. Halpern Z, Dudley MA, Kibe A, Lynn MP, Breuer AC, Holzbach RT. Rapid vesicle formation and aggregation in abnormal human biles. A time-lapse video-enhanced contrast microscopy study. Gastroenterology. 1986;90:875–85.

    Article  CAS  PubMed  Google Scholar 

  83. Afdhal NH, Smith BF. Cholesterol crystal nucleation: a decade-long search for the missing link in gallstone pathogenesis. Hepatology. 1990;11:699–702.

    Article  CAS  PubMed  Google Scholar 

  84. Olszewski MF, Holzbach RT, Saupe A, Brown GH. Liquid crystals in human bile. Nature. 1973;242:336–7.

    Article  CAS  PubMed  Google Scholar 

  85. Holzbach RT, Corbusier C. Liquid crystals and cholesterol nucleation during equilibration in supersaturated bile analogs. Biochim Biophys Acta. 1978;528:436–44.

    Article  CAS  PubMed  Google Scholar 

  86. Konikoff FM, Danino D, Weihs D, Rubin M, Talmon Y. Microstructural evolution of lipid aggregates in nucleating model and human biles visualized by cryogenic transmission electron microscopy. Hepatology. 2000;31:261–8.

    Article  CAS  PubMed  Google Scholar 

  87. Carey MC, Montet JC, Phillips MC, Armstrong MJ, Mazer NA. Thermodynamic and molecular basis for dissimilar cholesterol-solubilizing capacities by micellar solutions of bile salts: cases of sodium chenodeoxycholate and sodium ursodeoxycholate and their glycine and taurine conjugates. Biochemistry. 1981;20:3637–48.

    Article  CAS  PubMed  Google Scholar 

  88. Rubin M, Pakula R, Konikoff FM. Microstructural analysis of bile: relevance to cholesterol gallstone pathogenesis. Histol Histopathol. 2000;15:761–70.

    CAS  PubMed  Google Scholar 

  89. Liu XY. Heterogeneous nucleation or homogeneous nucleation? J Chem Phys. 2000;112:9949–55.

    Article  CAS  Google Scholar 

  90. Liu XY. A new kinetic model for three-dimesional heterogeneous nucleation. J Chem Phys. 1999;111:1628–35.

    Article  CAS  Google Scholar 

  91. Espinosa JR, Sanz E, Valeriani C, Vega C. Homogeneous ice nucleation evaluated for several water models. J Chem Phys. 2014;141:18C529.

    Article  CAS  PubMed  Google Scholar 

  92. Lee SP, LaMont JT, Carey MC. Role of gallbladder mucus hypersecretion in the evolution of cholesterol gallstones. J Clin Invest. 1981;67:1712–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Levy PF, Smith BF, LaMont JT. Human gallbladder mucin accelerates nucleation of cholesterol in artificial bile. Gastroenterology. 1984;87:270–5.

    Article  CAS  PubMed  Google Scholar 

  94. LaMont JT, Smith BF, Moore JR. Role of gallbladder mucin in pathophysiology of gallstones. Hepatology. 1984;4:51S-56S.

    Article  CAS  PubMed  Google Scholar 

  95. Wang DQ, Cohen DE, Lammert F, Carey MC. No pathophysiologic relationship of soluble biliary proteins to cholesterol crystallization in human bile. J Lipid Res. 1999;40:415–25.

    Article  CAS  PubMed  Google Scholar 

  96. Wang HH, Portincasa P, Wang DQ. Molecular pathophysiology and physical chemistry of cholesterol gallstones. Front Biosci. 2008;13:401–23.

    Article  CAS  PubMed  Google Scholar 

  97. Craven BM. Crystal structure of cholesterol monohydrate. Nature. 1976;260:727–9.

    Article  CAS  PubMed  Google Scholar 

  98. Loomis CR, Shipley GG, Small DM. The phase behavior of hydrated cholesterol. J Lipid Res. 1979;20:525–35.

    Article  CAS  PubMed  Google Scholar 

  99. Hsu LY, Nordman CE. Phase transition and crystal structure of the 37 degrees C form of cholesterol. Science. 1983;220:604–6.

    Article  CAS  PubMed  Google Scholar 

  100. Renshaw PF, Janoff AS, Miller KW. On the nature of dilute aqueous cholesterol suspensions. J Lipid Res. 1983;24:47–51.

    Article  CAS  PubMed  Google Scholar 

  101. Shieh HS, Hoard LG, Nordman CE. Crystal structure of anhydrous cholesterol. Nature. 1977;267:287–9.

    Article  PubMed  Google Scholar 

  102. Garti N, Karpuj L, Sarig S. Correlation between crystal habit and the composition of solvated and nonsolvated cholesterol crystals. J Lipid Res. 1981;22:785–91.

    Article  CAS  PubMed  Google Scholar 

  103. Chung DS, Benedek GB, Konikoff FM, Donovan JM. Elastic free energy of anisotropic helical ribbons as metastable intermediates in the crystallization of cholesterol. Proc Natl Acad Sci USA. 1993;90:11341–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Holzbach RT. Recent progress in understanding cholesterol crystal nucleation as a precursor to human gallstone formation. Hepatology. 1986;6:1403–6.

    Article  CAS  PubMed  Google Scholar 

  105. Wang HH, Portincasa P, Liu M, Tso P, Samuelson LC, Wang DQ. Effect of gallbladder hypomotility on cholesterol crystallization and growth in CCK-deficient mice. Biochim Biophys Acta. 2010;1801:138–46.

    Article  CAS  PubMed  Google Scholar 

  106. Wang HH, Liu M, Portincasa P, Tso P, Wang DQ. Lack of endogenous cholecystokinin promotes cholelithogenesis in mice. Neurogastroenterol Motil. 2016;28:364–75.

    Article  CAS  PubMed  Google Scholar 

  107. Wang HH, Portincasa P, Wang DQ. The cholecystokinin-1 receptor antagonist devazepide increases cholesterol cholelithogenesis in mice. Eur J Clin Invest. 2016;46:158–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Busch N, Tokumo H, Holzbach RT. A sensitive method for determination of cholesterol growth using model solutions of supersaturated bile. J Lipid Res. 1990;31:1903–9.

    Article  CAS  PubMed  Google Scholar 

  109. Konikoff FM, Cohen DE, Carey MC. Phospholipid molecular species influence crystal habits and transition sequences of metastable intermediates during cholesterol crystallization from bile salt-rich model bile. J Lipid Res. 1994;35:60–70.

    Article  CAS  PubMed  Google Scholar 

  110. Shoda J, Oda K, Suzuki H, Sugiyama Y, Ito K, Cohen DE, Feng L, et al. Etiologic significance of defects in cholesterol, phospholipid, and bile acid metabolism in the liver of patients with intrahepatic calculi. Hepatology. 2001;33:1194–205.

    Article  CAS  PubMed  Google Scholar 

  111. Mazer NA, Schurtenberg P, Carey MC, Preisig R, Weigand K, Kanzig W. Quasi-elastic light scattering studies of native hepatic bile from the dog: comparison with aggregative behavior of model biliary lipid systems. Biochemistry. 1984;23:1994–2005.

    Article  CAS  PubMed  Google Scholar 

  112. Mazer NA, Carey MC, Kwasnick RF, Benedek GB. Quasielastic light scattering studies of aqueous biliary lipid systems. Size, shape, and thermodynamics of bile salt micelles. Biochemistry. 1979;18:3064–75.

    Article  CAS  PubMed  Google Scholar 

  113. Mazer NA, Benedek GB, Carey MC. Quasielastic light-scattering studies of aqueous biliary lipid systems. Mixed micelle formation in bile salt-lecithin solutions. Biochemistry. 1980;19:601–15.

    Article  CAS  PubMed  Google Scholar 

  114. Ko CW, Schulte SJ, Lee SP. Biliary sludge is formed by modification of hepatic bile by the gallbladder mucosa. Clin Gastroenterol Hepatol. 2005;3:672–8.

    Article  CAS  PubMed  Google Scholar 

  115. Ko CW, Sekijima JH, Lee SP. Biliary sludge. Ann Intern Med. 1999;130:301–11.

    Article  CAS  PubMed  Google Scholar 

  116. Lee SP, Maher K, Nicholls JF. Origin and fate of biliary sludge. Gastroenterology. 1988;94:170–6.

    Article  CAS  PubMed  Google Scholar 

  117. Teefey SA, Hollister MS, Lee SP, Jacobson AF, Higano CS, Bianco JA, Colacurcio CJ. Gallbladder sludge formation after bone marrow transplant: sonographic observations. Abdom Imaging. 1994;19:57–60.

    Article  CAS  PubMed  Google Scholar 

  118. Wang DQ, Schmitz F, Kopin AS, Carey MC. Targeted disruption of the murine cholecystokinin-1 receptor promotes intestinal cholesterol absorption and susceptibility to cholesterol cholelithiasis. J Clin Invest. 2004;114:521–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Lee SP, Nicholls JF. Nature and composition of biliary sludge. Gastroenterology. 1986;90:677–86.

    Article  CAS  PubMed  Google Scholar 

  120. Rosmorduc O, Poupon R. Low phospholipid associated cholelithiasis: association with mutation in the MDR3/ABCB4 gene. Orphanet J Rare Dis. 2007;2:29.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Nervi F, Covarrubias C, Bravo P, Velasco N, Ulloa N, Cruz F, Fava M, et al. Influence of legume intake on biliary lipids and cholesterol saturation in young Chilean men. Identification of a dietary risk factor for cholesterol gallstone formation in a highly prevalent area. Gastroenterology. 1989;96:825–30.

    Article  CAS  PubMed  Google Scholar 

  122. Thistle JL, Schoenfield LJ. Lithogenic bile among young Indian women. N Engl J Med. 1971;284:177–81.

    Article  CAS  PubMed  Google Scholar 

  123. Everhart JE, Yeh F, Lee ET, Hill MC, Fabsitz R, Howard BV, Welty TK. Prevalence of gallbladder disease in American Indian populations: findings from the Strong Heart Study. Hepatology. 2002;35:1507–12.

    Article  PubMed  Google Scholar 

  124. Sampliner RE, Bennett PH, Comess LJ, Rose FA, Burch TA. Gallbladder disease in Pima Indians. Demonstration of high prevalence and early onset by cholecystography. N Engl J Med. 1970;283:1358–64.

    Article  CAS  PubMed  Google Scholar 

  125. Kasbo J, Tuchweber B, Perwaiz S, Bouchard G, Lafont H, Domingo N, Chanussot F, et al. Phosphatidylcholine-enriched diet prevents gallstone formation in mice susceptible to cholelithiasis. J Lipid Res. 2003;44:2297–303.

    Article  CAS  PubMed  Google Scholar 

  126. Wei G, Cao J, Huang P, An P, Badlani D, Vaid KA, Zhao S, et al. Synthetic human ABCB4 mRNA therapy rescues severe liver disease phenotype in a BALB/c.Abcb4(-/-) mouse model of PFIC3. J Hepatol. 2021;74:1416–28.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Funding

This work was supported in part by research grants DK106249, DK114516, and DK126369 (to DQ-HW), as well as P30 DK041296 (to Marion Bessin Liver Research Center), all from the National Institutes of Health (US Public Health Service). No funding or sponsorship was received for the publication of this article.

Author Contributions

Conceptualization: Helen H. Wang and David Q.-H. Wang. Original draft preparation and writing: Helen H. Wang and David Q.-H. Wang. Writing, review and editing: Helen H. Wang, Piero Portincasa, Min Liu and David Q.-H. Wang; Funding acquisition: David Q.-H. Wang. All authors have read and agreed to the published version of the manuscript.

Disclosures

Helen H. Wang, Piero Portincasa, Min Liu and David Q.-H. Wang have nothing to disclose.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

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Authors and Affiliations

  1. Division of Gastroenterology and Liver Diseases, Department of Medicine and Genetics, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY, 10461, USA

    Helen H. Wang & David Q.-H. Wang

  2. Department of Biomedical Sciences and Human Oncology, Clinica Medica “A. Murri”, University of Bari Medical School, Bari, Italy

    Piero Portincasa

  3. Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45237, USA

    Min Liu

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  1. Helen H. Wang
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  2. Piero Portincasa
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  3. Min Liu
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  4. David Q.-H. Wang
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Correspondence to David Q.-H. Wang.

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Wang, H.H., Portincasa, P., Liu, M. et al. Effects of Biliary Phospholipids on Cholesterol Crystallization and Growth in Gallstone Formation. Adv Ther 40, 743–768 (2023). https://doi.org/10.1007/s12325-022-02407-8

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