Abstract
Cholesterol in human bile is solubilized in micelles by (relatively hydrophobic) bile salts and phosphatidylcholine (unsaturated acyl chains at sn-2 position). Hydrophilic tauroursodeoxycholate, dipalmitoyl phosphatidylcholine, and sphingomyelin all decrease cholesterol crystal-containing zones in the equilibrium ternary phase diagram (van Erpecum, K. J., and M. C. Carey. 1997. Biochim. Biophys. Acta. 1345: 269–282) and thus could be valuable in gallstone prevention. We have now compared crystallization in cholesterol-supersaturated model systems (3.6 g/dl, 37°C) composed of various bile salts as well as egg yolk phosphatidylcholine (unsaturated acyl chains at sn-2 position), dipalmitoyl phosphatidylcholine, or sphingomyelin throughout the phase diagram. At low phospholipid contents [left two-phase (micelle plus crystal-containing) zone], tauroursodeoxycholate, dipalmitoyl phosphatidylcholine, and sphingomyelin all enhanced crystallization. At pathophysiologically relevant intermediate phospholipid contents [central three-phase (micelle plus vesicle plus crystal-containing) zone], tauroursodeoxycholate inhibited, but dipalmitoyl phosphatidylcholine and sphingomyelin enhanced, crystallization. Also, during 10 days of incubation, there was a strong decrease in vesicular cholesterol contents and vesicular cholesterol-to-phospholipid ratios (~1 on day 10), coinciding with a strong increase in crystal mass. At high phospholipid contents [right two-phase (micelle plus vesicle-containing) zone], vesicles were always unsaturated and crystallization did not occur. Strategies aiming to increase amounts of hydrophilic bile salts may be preferable to increasing saturated phospholipids in bile, because the latter may enhance crystallization. —Moschetta, A., G. P. vanBerge-Henegouwen, P. Portincasa, G. Palasciano, and K. J. van Erpecum. Cholesterol crystallization in model biles: effects of bile salt and phospholipid species composition.
Highlights
Cholesterol in human bile is solubilized in micelles by bile salts and phosphatidylcholine
The phase diagram describes the occurrence of cholesterol crystals, Abbreviations: BS, bile salts; CSI, cholesterol saturation index; DPPC, dipalmitoyl phosphatidylcholine; EYPC, egg yolk phosphatidylcholine; EYSM, egg yolk sphingomyelin; IMC, intermixed micellar/vesicular bile salt concentration; MWCO, molecular weight cutoff; PL, phospholipids; TC, taurocholate; TDC, taurodeoxycholate; TUDC, tauroursodeoxycholate
Aggregated vesicles are first precipitated by short ultracentrifugation, and micelles or small unilamellar vesicles are subsequently isolated from the supernatant with the aid of highly selective ultrafilters and dialysis, taking into account the intermixed micellar/vesicular bile salt concentration
Summary
Cholesterol in human bile is solubilized in micelles by (relatively hydrophobic) bile salts and phosphatidylcholine (unsaturated acyl chains at sn-2 position). Hydrophilic tauroursodeoxycholate, dipalmitoyl phosphatidylcholine, and sphingomyelin all decrease cholesterol crystal-containing zones in the equilibrium ternary phase diagram At low phospholipid contents [left two-phase (micelle plus crystal-containing) zone], tauroursodeoxycholate, dipalmitoyl phosphatidylcholine, and sphingomyelin all enhanced crystallization. At pathophysiologically relevant intermediate phospholipid contents [central three-phase (micelle plus vesicle plus crystal-containing) zone], tauroursodeoxycholate inhibited, but dipalmitoyl phosphatidylcholine and sphingomyelin enhanced, crystallization. The phase diagram describes the occurrence of cholesterol crystals, Abbreviations: BS, bile salts; CSI, cholesterol saturation index; DPPC, dipalmitoyl phosphatidylcholine; EYPC, egg yolk phosphatidylcholine; EYSM, egg yolk sphingomyelin; IMC, intermixed micellar/vesicular bile salt concentration; MWCO, molecular weight cutoff; PL, phospholipids; TC, taurocholate; TDC, taurodeoxycholate; TUDC, tauroursodeoxycholate. Micelles and vesicles may be separated with the aid of gel filtration with bile salts at intermixed micellar/vesicular concentrations in the eluant buffer in order to avoid artifactual shifts of lipids between phases [7,8,9]. Aggregated vesicles are first precipitated by short ultracentrifugation, and micelles or small unilamellar vesicles are subsequently isolated from the supernatant with the aid of highly selective ultrafilters and dialysis, taking into account the intermixed micellar/vesicular bile salt concentration
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