Arachidyl amido cholanoic acid (Aramchol) is a cholesterol solubilizer andprevents the formation of cholesterol gallstones in inbred mice

We have recently synthesized fatty acid bile acid conjugates (FABAC) that w ere able to reduce and retard cholesterol crystallization in model and huma n biles. When given orally, they prevented the formation of cholesterol cry stals in the bile of hamsters. The aim of the present study was to determin e whether the FABAC are cholesterol solubilizers, whether they can dissolve pre-existing crystals, whether they can prevent the formation of cholester ol gallstones, and to investigate the optimal type of bond between the fatt y acid and bile acid. The presence of cholesterol crystals was determined b y 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-sol ubilizing capacity of Aramchol was higher than that of taurocholate and sim ilar to that of phosphatidylcholine. The addition of Aramchol dissolved app roximately 50% of preexisting crystals in model bile solutions. The same ph enomenon was demonstrated in human bile ex vivo, with a dose-response effec t. 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 gallst ones in the gallbladder by day 21. None of the mice whose diet was suppleme nted with 0.5 mg or 1.0 mg of Aramchol/d developed stones or crystals. FABA C 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.