We have recently synthesized
fatty acid bile acid conjugates (FABAC) that were able to reduce and retard
cholesterol crystallization in model and human biles. When given orally, they prevented the formation of
cholesterol crystals in the bile of hamsters. The aim of the present study was to determine whether the FABAC are
cholesterol solubilizers, whether they can dissolve pre-existing crystals, whether they can prevent the formation of
cholesterol gallstones, and to investigate the optimal type of bond between the
fatty acid and
bile acid. The presence of
cholesterol crystals was determined by light microscopy, and the total crystal mass of precipitated crystals was measured by chemical means. Inbred (C57J/L) mice on a lithogenic diet were used to evaluate
cholesterol crystal formation, dissolution, and
gallstone formation in vivo.
Arachidyl amido cholanoic acid (
Aramchol) was the FABAC used in the present experiments. At equimolar amounts, the
cholesterol-solubilizing capacity of
Aramchol was higher than that of
taurocholate and similar to that of
phosphatidylcholine. The addition of
Aramchol dissolved approximately 50% of pre-existing crystals in model bile solutions. The same phenomenon was demonstrated in human bile ex vivo, with a dose-response effect. All inbred mice developed
cholesterol crystals in bile after 10-14 d on the lithogenic diet. Thereafter, supplementation of the diet with
Aramchol progressively reduced the proportion of mice with crystals to 25% after 28 d. On the lithogenic diet, 100% of inbred mice developed
cholesterol gallstones in the gallbladder by day 21. None of the mice whose diet was supplemented with 0.5 mg or 1.0 mg of
Aramchol/d developed stones or crystals. FABAC are a new class of molecules that are
cholesterol solubilizers and which are able to dissolve
cholesterol crystals in bile. Upon
oral administration, they dissolve pre-existing
cholesterol crystals and prevent the formation of
gallstones in
gallstone-susceptible mice.