1. The Fatty Acid–Bile Acid Conjugate Aramchol Reduces Liver Fat Content in Patients With Nonalcoholic Fatty Liver Disease
Safadi R, Konikoff FM, Mahamid M, Zelber-Sagi S, Halpern M, Gilat T, Oren R, and the FLORA Group
Clin Gastroenterol Hepatol. 2014 May 9, pii: S1542-3565(14)00673-9.
BACKGROUND & AIMS: We investigated the effects of the fatty acid-bile acid conjugate 3β-arachidyl-amido, 7α-12α-dihydroxy, 5β-cholan-24-oic acid (Aramchol; Trima Israel Pharmaceutical Products Ltd, Maabarot, Israel) in a phase 2 trial of patients with nonalcoholic fatty liver disease (NAFLD).
METHODS: We performed a randomized, double-blind, placebo-controlled trial of 60 patients with biopsy-confirmed NAFLD (6 with nonalcoholic steatohepatitis) at 10 centers in Israel. Patients were given Aramchol (100 or 300 mg) or placebo once daily for 3 months (n = 20/group). The main end point was the difference between groups in the change in liver fat content according to magnetic resonance spectroscopy. The secondary end points focused on the differences between groups in alterations of liver enzyme levels, levels of adiponectin, homeostasis model assessment scores, and endothelial function.
RESULTS: No serious or drug-related adverse events were observed in the 58 patients who completed the study. Over 3 months, liver fat content decreased by 12.57% ± 22.14% in patients given 300 mg/day Aramchol, but increased by 6.39% ± 36.27% in the placebo group (P = .02 for the difference between groups, adjusted for age, sex, and body mass index). Liver fat content decreased in the 100-mg Aramchol group, by 2.89% ± 28.22%, but this change was nonsignificant (P = .35), indicating a dose-response relationship (P for trend = .01). Groups given Aramchol had nonsignificant improvements over time in endothelial function and levels of alanine aminotransferase and adiponectin, but homeostasis model assessment scores did not change. The appropriateness of a single daily dose was confirmed by pharmacokinetic analysis.
CONCLUSIONS: Three months’ administration of the fatty acid-bile acid conjugate Aramchol is safe, tolerable, and significantly reduces liver fat content in patients with NAFLD. The reduction in liver fat content occurred in a dose-dependent manner and was associated with a trend of metabolic improvements, indicating that Aramchol might be used for the treatment of fatty liver disease. ClinicalTrials.gov number: NCT01094158.
Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.
2. Fatty acid bile acid conjugate inhibits hepatic stearoyl coenzyme A desaturase and is non-atherogenic
Leikin-Frenkel A, Gonen A, Shaish A, Goldiner I, Leikin-Gobbi D, Konikoff FM, Harats D, Gilat T.
Arch Med Res. 2010 Aug;41(6):397-404. Full Text
Minerva Center for Cholesterol Gallstones and Lipid Metabolism in the Liver, Tel-Aviv University, Tel-Aviv, Israel.
BACKGROUND AND AIMS: Suppression of stearoyl-coenzyme A desaturase (SCD) activity leads to reduction of obesity, fatty liver as well as of insulin resistance. It was, however, recently reported to enhance atherogenesis. The aim of the present study was to investigate whether inhibition of SCD by Aramchol, a fatty acid bile conjugate with known hypocholesterolemic effects, will affect atherogenesis and how.
METHODS: Aramchol was tested in vitro in cultured cells and in vivo in rodents.
RESULTS: Aramchol, at very low concentrations, reduced SCD activity in liver microsomes of mice. Aramchol enhanced cholesterol efflux from macrophages more than twofold. In vivo it increased fecal sterol output and decreased markedly plasma cholesterol levels in mice. In ApoE(-/-), LDRL(-/-) and C57Bl6 mice, the effects of Aramchol on atherogenesis were non-atherogenic.
CONCLUSIONS: Aramchol reduces SCD activity and is non-atherogenic. It may offer a means to obtain the desirable hepatic metabolic effects of SCD inhibition without the deleterious atherogenic effect.
Copyright © 2010 IMSS. Published by Elsevier Inc. All rights reserved
Department of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. firstname.lastname@example.org
BACKGROUND: Preoperative chemotherapy for hepatic resection of colorectal liver metastases is associated with the development of chemotherapy-associated steatohepatitis (CASH). This increases the risk of perioperative morbidity and mortality. To the authors’ knowledge, an animal model for CASH has not been described previously. It has been established that fatty acid bile acid conjugates (FABACs) prevent the formation of diet-induced fatty liver. The current study was designed to establish an animal model of CASH and to use that model to study the effect of FABACs on its occurrence.
METHODS: C57BL/6 mice were given different doses of oxaliplatin and irinotecan. Oxaliplatin administered once weekly at a dose of 6 mg/kg for a total dose of 24 mg/kg was tolerated best and was associated most consistently with CASH. Thus, that dose was chosen as the induction model for CASH. Subsequently, mice were divided into a control group (no treatment), an oxaliplatin group, and a CASH-prevention group, which received oxaliplatin and C20-FABAC at a dose of 150 mg/kg daily. The animals were killed after 28 days.
RESULTS: Liver fat content was significantly lower (P < .0001) in the control group (51.63 mg/g) and the prevention group (62.13 mg/g) compared with the oxaliplatin group (95.35 mg/g). This difference was mainly because of the accumulation of liver triglycerides in the oxaliplatin group.
CONCLUSIONS: The current results indicated that C57BL/6 mice receiving weekly oxaliplatin can be used as a model for CASH. Oral FABAC therapy reduced the development of CASH in animals that received oxaliplatin. To the authors’ knowledge, this report is the first description of a model and a potential preventive treatment for CASH.
Copyright 2010 American Cancer Society.
Leikin-Frenkel A, Goldiner I, Leikin-Gobbi D, Rosenberg R, Bonen H, Litvak A, Bernheim J, Konikoff FM, Gilat T.
Eur J Gastroenterol Hepatol. 2008 Dec;20(12):1205-13. Full Text
Minerva Center for Cholesterol Gallstones and Lipid Metabolism in the Liver, Tel-Aviv University, Tel-Aviv, Israel.
BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in industrialized countries. It has no accepted medical therapy. Fatty acid-bile acid conjugates (FABACs) were proven to prevent diet-induced NAFLD in rodents.
AIM: This study was undertaken to test whether oral FABACs are also effective in reducing liver fat in preestablished diet-induced NAFLD.
METHODS: NAFLD was induced in mice and rats by a high-fat diet and maintained by various proportions thereof. The FABACs used were conjugates of cholic acid with either arachidic or stearic acids.
RESULTS: FABAC therapy reduced liver fat in all four series of experiments. The rapidity of the effect was inversely proportional to the concentration of fat in the maintenance diet. In mice on a 25% maintenance diet FABACs decreased total liver lipids by about 30% in 4 weeks (P<0.03). Diglycerides (P<0.003) and triglycerides (P<0.01) were the main neutral liver lipids that decreased during FABAC therapy. Both FABACs tested reduced liver fat in NAFLD at doses of 25 and 150 mg/kg/day. High-fat diet increased, whereas FABAC therapy decreased plasma 16 : 1/(16 : 0+16 : 1) fatty acid ratio – a marker of stearoyl CoA desaturase activity. In HepG2 cells FABACs decreased de-novo fatty acid synthesis dose dependently.
CONCLUSION: Oral FABAC therapy decreased liver fat in preestablished NAFLD in mice and rats. Inhibition of stearoyl CoA desaturase activity and fatty acid synthesis are mechanisms that may contribute to this decrease. FABACs may be potential therapeutic agents for human NAFLD.
[Article in Hebrew]
Keizman D, Goldiner I, Leikin-Frenkel A, Konikoff FM.
Harefuah. 2008 Apr;147(4):344-9, 373, 372.
Department of Gastroenterology, the Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Gallstones and fatty liver are common disorders in the Western world, largely due to dietary and life style factors. Currently, laparoscopic cholecystectomy is the main treatment option for gallbladder stones. Surgery is, however, expensive and may cause morbidity and even mortality. An effective medical treatment would be desirable, especially in patients with mild to moderate symptoms or high surgical risk. Currently, the bile acid UDCA (Ursodeoxycholic acid) is used for oral dissolution treatment and for the prevention of cholelithiasis in selected cases. However, the major limitations of this treatment are its low efficacy, slow action and stone recurrence. Recently, phospholipids rather than bile salts were realized to be the major natural cholesterol solubilizers in bile. They also possess anti-crystallizing activity. The sn-2 fatty acid of the phospholipids molecule was found to be particularly important. This was the background for the development of FABACs (Fatty Acid and Bile Acid Conjugates), which are novel synthetic lipid molecules. These molecules are composed of fatty acids (with chain lengths from C-14 to C-22), that are linked to cholic acid, by an amide bond at position 3. In vitro and in vivo studies (in mice) have shown that FABACs can prevent the formation of cholesterol crystals and dissolve existing ones. C20-FABAC, when given orally, is absorbed and secreted into bile. It was also found to have a series of beneficial effects on cholesterol metabolism. The main treatment for patients with fatty liver consists of lifestyle and diet modifications, which are associated with low compliance. Currently there is no effective medical treatment for this disease. In the FABAC studies on the prevention and dissolution of gallstones in laboratory animals, it was observed that this treatment also prevents the formation of diet induced fatty liver. Further prospective studies found that FABACs indeed prevent/decrease the formation of fatty liver induced by high fat diet. This influence was observed in all the fatty liver parameters (histology as well as chemical analysis), and in different animal strains. Based on these findings, FABACs seem to be good candidates for the medical treatment of hepatobiliary disorders, in particular gallstones and fatty liver disease.
6. Hypocholesterolemic effects of fatty acid bile acid conjugates (FABACs) in mice.
Leikin-Frenkel A, Parini P, Konikoff FM, Benthin L, Leikin-Gobbi D, Goldiner I, Einarsson C, Gilat T.
Arch Biochem Biophys. 2008 Mar 1;471(1):63-71. Full Text
Minerva Center for Cholesterol Gallstones and Lipid Metabolism in the Liver, Tel-Aviv University, Israel.
Fatty acid bile acid conjugates (FABACs) prevent and dissolve cholesterol gallstones and prevent diet induced fatty liver, in mice. The present studies aimed to test their hypocholesterolemic effects in mice. Gallstone susceptible (C57L/J) mice, on high fat (HFD) or regular diet (RD), were treated with the conjugate of cholic acid with arachidic acid (FABAC; Aramchol). FABAC reduced the elevated plasma cholesterol levels induced by the HFD. In C57L/J mice, FABAC reduced plasma cholesterol by 50% (p<0.001). In mice fed HFD, hepatic cholesterol synthesis was reduced, whereas CYP7A1 activity and expression were increased by FABAC. The ratio of fecal bile acids/neutral sterols was increased, as was the total fecal sterol excretion. In conclusion, FABACs markedly reduce elevated plasma cholesterol in mice by reducing the hepatic synthesis of cholesterol, in conjunction with an increase of its catabolism and excretion from the body.
Goldiner I, van der Velde AE, Vandenberghe KE, van Wijland MA, Halpern Z, Gilat T, Konikoff FM, Veldman RJ, Groen AK.
Biochem J. 2006 Jun 15;396(3):529-36 Full Text
AMC Liver Centre, Academic Medical Centre, Amsterdam, The Netherlands. Reproduced with permission, from Authors, © the Biochemical Society.
FABACs (fatty acid-bile acid conjugates) are synthetic molecules that are designed to treat a range of lipid disorders. The compounds prevent cholesterol gallstone formation and diet-induced fatty liver, and increase reverse cholesterol transport in rodents. The aim of the present study was to investigate the effect of FABACs on cholesterol efflux in human cells. Aramchol (3beta-arachidylamido-7alpha,12alpha,5beta-cholan-24-oic acid) increased cholesterol efflux from human skin fibroblasts in a dose-dependent manner in the absence of known efflux mediators such as apoA-I (apolipoprotein A-I), but had little effect on phospholipid efflux. An LXR (liver X receptor) agonist strongly increased Aramchol-induced cholesterol efflux; however, in ABCA1 (ATP-binding cassette transporter A1)-deficient cells from Tangier disease patients, the Aramchol effect was absent, indicating that activity of ABCA1 was required. Aramchol did not affect ABCA1 expression, but plasma membrane levels of the transporter increased 2-fold. Aramchol is the first small molecule that induces ABCA1-dependent cholesterol efflux without affecting transcriptional control. These findings may explain the beneficial effect of the compound on atherosclerosis.
Konikoff FM, Gilat T.
Curr Drug Targets Immune Endocr Metabol Disord. 2005 Jun;5(2):171-5 Full Text
Minerva Center for Cholesterol Gallstones and Lipid Metabolism in the Liver, Sackler Faculty of Medicine, Tel Aviv University, Israel. email@example.com
Fatty acid bile acid conjugates (FABACs) are novel synthetic lipid molecules, which were designed for the treatment of cholesterol gallstones. The rationale was to combine a cholesterol solubilizing moiety (a saturated fatty acid) with a bile acid (cholic acid) as a vehicle to enable secretion into bile and entry into the enterohepatic circulation. An amide bond was used to provide stability against intestinal degradation. Initial in vitro studies showed that FABACs are indeed cholesterol solubilizers, able to prevent biliary cholesterol crystallization. Arachidyl-amido-cholanoic acid (Aramchol) was found to be the most potent FABAC in these studies. Animal studies revealed that Aramchol was absorbed after oral administration and could prevent cholesterol crystallization as well as dissolve preformed crystals in rodents fed a lithogenic diet. In gallstone susceptible mice, Aramchol prevented gallstone formation and dissolved gallstones. FABACs were found to be metabolically active substances, also able to decrease blood cholesterol, atherosclerotic plaques and fat accumulation in the liver in several animal species. The underlying mechanisms of action are under active investigation, and several effects, e.g. on cholesterol and bile salt metabolizing enzymes as well as cholesterol efflux from cells have been discovered. These findings are, however, only the beginning of our understanding of the metabolic actions as well as the potential of use of FABACs as therapeutic agents.
Leikin-Frenkel A, Weinbroum AA, Leikin-Gobbi D, Krupitzky L, Goldiner I, Shafat L, Gilat T, Konikoff FM.
Biochem Soc Trans. 2004 Feb; 32(Pt 1):131-3.
Minerva Center for Cholesterol, Gallstones and Lipid Metabolism in the Liver, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. firstname.lastname@example.org. Reproduced with permission, from Authors, © the Biochemical Society.
Fatty acid-bile acid conjugates (FABACs) were shown recently to have important and multiple effects on cholesterol metabolism. In human fibroblasts, they were found to markedly enhance cholesterol efflux by an ATP-binding cassette transporter A1-dependent pathway. In C57L/J mice, they increased CYP7A1 activity and RNA expression, while decreasing moderately 3-hydroxy-3-methylglutaryl-CoA reductase activity. In C57L/J mice and in hamsters, they also decreased serum cholesterol levels, whereas in other animals, this effect was not seen in short-term experiments. In the present study, we investigated potential mechanisms of action of arachidyl amido cholanoic acid (Aramchol), with particular reference to biliary and faecal sterol outputs in rats. Supplementation with Aramchol at a dose of 150 mg x kg(-1) x day(-1) increased neutral sterol output by approx. 50%, while the faecal outputs of bile salts and total sterols increased by almost 2-fold. Biliary lipid outputs were not significantly different between the control and FABAC-supplemented animals. These findings indicate an overall catabolic effect of FABACs on body cholesterol.
Gilat T, Leikin-Frenkel A, Goldiner I, Juhel C, Lafont H, Gobbi D, Konikoff FM.
Hepatology. 2003 Aug;38(2):436-42 Full Text
Department of Gastroenterology, Tel Aviv Sourasky Medical Center, Israel.
Fatty acid bile acid conjugates (FABACs) are a new family of synthetic molecules designed to solubilize biliary cholesterol. They were shown to prevent and dissolve cholesterol gallstones in inbred C57L/J mice fed a lithogenic, high-fat diet (HFD). In these mice, fatty liver was observed in the controls but not in the FABAC-treated ones. The present study was designed to study the effect of FABAC (arachidyl-amido-cholanoic acid) on diet-induced fatty liver in rats, hamsters, and mice. The fatty liver score (on a scale of 0-4 by light microscopy) was 4.0 in control hamsters and 0.3 in the FABAC-fed hamsters (P <.001). In mice it was 1.5 and 0.4, respectively (P <.01). The lipid/protein ratio in the liver was 1.3 +/- 0.44 (mg lipid/mg protein) in control rats and 0.66 +/- 0.04 in the FABAC group (P =.001) after 14 days. In hamsters it was 1.41 +/- 0.27 and 1.11 +/- 0.20, respectively (P =.03), after 21 days. In Imperial Charles River (ICR) mice the ratio was 0.34 +/- 0.10 and 0.17 +/- 0.07 (P =.03), respectively, after 24 days. Liver fat concentration, measured as mg lipid/g liver tissue, decreased similarly by FABAC feeding. The decrease in liver fat affected mainly the triglyceride levels. FABAC-fed animals gained weight similarly to the controls. Triglyceride absorption was unaffected by FABAC supplementation. In conclusion, oral FABAC therapy prevents/reduces the development of fatty liver in animals consuming a HFD.
Goldiner I, Overmars H, Groen AK, Kulik W.
J Chromatogr B Analyt Technol Biomed Life Sci. 2003 Sep 25 ;795(1):35-40 Full Text
Department of Gastroenterology, Tel Aviv Sourasky Medical Center, 64239 Tel Aviv, Israel.
Fatty acid-bile acid conjugates and especially arachidyl amido cholic acid are synthetic molecules that were shown to prevent cholesterol gallstone formation in mice and hamsters as well as to dissolve pre-existing gallstones in mice. To measure these novel compounds we developed a liquid chromatography electrospray tandem mass spectrometry method based on the analysis of 100 microL of plasma with stearyl amido cholic acid (stamchol, 1.5 microM/L) added as internal standard. Repeatable calibrations between 0 and 50 microM/L exhibited consistent linearity and reproducibility. Inter- and intraassay C.V.s were 5.3-11.4% and 2.6-6.4%, respectively, at targeted concentrations of 0.1, 2.3 and 50 microM/L.
Konikoff FM, Leikin-Frenkel A, Goldiner I, Michowitz M, Brezowski E, Harats D, Gilat T.
Eur J Gastroenterol Hepatol. 2003 Jun;15(6):649-55.
Minerva Centre for Cholesterol Gallstones and Lipid Metabolism in the Liver, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. email@example.com. Full Text
BACKGROUND: Fatty acid bile acid conjugates (FABACs) are novel synthetic molecules that solubilize cholesterol, prevent cholesterol crystal and gallstone formation, and dissolve pre-existing gallstones in mice. They are thus potential agents for gallstone prevention and treatment. The available knowledge concerning their biliary, systemic or possible toxic effects is, however, incomplete.
AIM: To obtain information regarding biliary and systemic effects of FABACs.
METHODS: Hamsters, rats and mice were administered C20-FABAC intragastrically, and serum and bile chemistries, organ histology, animal wellbeing, and survival were monitored.
RESULTS: FABAC feeding (150 mg/kg/day) caused no adverse effects in any of the animal species studied. FABAC did not influence biliary cholesterol, phospholipid, or bile-salt concentrations in mice. In hamsters, biliary cholesterol concentration decreased slightly, but effects on phospholipids and bile salts were inconsistent. In some mouse strains, FABAC supplementation increased transaminases slightly. In hamsters and rats, transaminases were mainly unaffected or even decreased. Serum alkaline phosphatase, creatinine, albumin and glucose were generally unaffected by FABAC feeding. No gross or histopathological differences between controls and FABAC-fed animals were noted in any of the organs investigated.
CONCLUSIONS: C20-FABAC given at a pharmacological dose is safe and devoid of any significant toxic effects in three different animal species.
Gonen A, Shaish A, Leikin-Frenkel A, Gilat T, Harats D.
Pathobiology. 2002-2003;70(4):215-8. Full Text
Institute of Lipid and Atherosclerosis Research, Sheba Medical Center, Tel Hashomer, Israel.
OBJECTIVE: The aim of the current research was to study whether fatty acid bile acid conjugates (FABACs) have a beneficial effect on atherosclerosis progression and blood lipid levels in mice.
METHODS: C57BL/6 female mice, fed a high-fat Paigen diet, were administered an oral dose of FABAC or DDH2O daily. Quantification of atherosclerotic fatty-streak lesions at the aortic sinus was performed.
RESULTS: The FABAC-treated mice showed a significant reduction in the atherosclerotic lesion areas as compared to the control group (p = 0.019). A significant elevation in total cholesterol levels was observed in both the FABAC and control groups. Higher FABAC levels were measured in the high-density lipoprotein fraction as compared to the very-low-density and low-density lipoprotein fractions.
CONCLUSION: Our findings demonstrate that FABACs, given orally, reduce the development of atherosclerosis in mice fed a high-fat high-cholesterol diet, despite a lack of effect on plasma lipid levels.
Copyright 2003 S. Karger AG, Basel
Gilat T, Leikin-Frenkel A, Goldiner I, Halpern Z, Konikoff FM.
Hepatology. 2002 Mar;35(3):597-600 Full Text
Minerva Center for Cholesterol Gallstones and Lipid Metabolism in the Liver, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. firstname.lastname@example.org
Gallstones, mostly cholesterol stones, affect some 15% of the population. Oral bile salts dissolve human cholesterol gallstones, but with low efficacy, and surgery remains the main therapeutic option. Fatty acid bile acid conjugates (FABACs) were shown to prevent formation of cholesterol gallstones in experimental animals. The aim of this study was to test whether these compounds could dissolve preexisting cholesterol gallstones via oral administration. Inbred, gallstone-susceptible C57J/L mice were given a lithogenic diet for 2 months, and the presence of gallstones was ascertained. The mice were then switched to a regular diet while part of them were given in addition C20-FABAC, by gavage, at a dose of 0.5 or 3 mg per animal per day. All mice tested had cholesterol gallstones after 2 months on the lithogenic diet. In study I, after 2 months on the regular diet, 3 of 4 (75%) of the controls had gallstones, whereas none of the 6 FABAC-fed animals (3 mg/d) had stones (P =.033). In study II, evaluating 2 FABAC doses, after 2 months on the regular diet, 8 of 8 (100%) of the controls had gallstones, which were found in 2 of 7 (28%) and 1 of 8 (12%) of the mice supplemented with 0.5 mg/d (P =.007) or 3 mg/d (P =.001) FABAC, respectively. On a molar basis, the dose of 0.5 mg FABAC is equivalent to 14 mg/kg/d of a bile acid. In conclusion, FABACs given orally can dissolve preexisting cholesterol gallstones in mice. This was accomplished with a dose of FABAC equivalent to the dose of bile acids used in human gallstone dissolution.
Gilat T, Leikin-Frenkel A, Goldiner L, Laufer H, Halpern Z, Konikoff FM.
Lipids. 2001 Oct;36(10):1135-40. Full Text
Department of Gastroenterology, Sourasky Tel Aviv Medical Center, and Sackler Faculty of Medicine, Tel Aviv University, Israel. email@example.com
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.
Gilat T, Somjen GJ, Mazur Y, Leikin-Frenkel A, Rosenberg R, Halpern Z, Konikoff F.
Gut. 2001 Jan;48(1):75-9. Full Text
Department of Gastroenterology, Tel-Aviv Sourasky Medical Center, Tel-Aviv 64239, Israel and Tel-Aviv University. firstname.lastname@example.org
Background: Cholesterol gall stones are a frequent disease for which at present surgery is the usual therapy. Despite the importance of bile acids it has become evident that phospholipids are the main cholesterol solubilisers in bile. Even phospholipid components, such as fatty acids, have anticrystallising activity.
Aim: To synthesise fatty acid bile acid conjugates (FABACs) and study their effects on cholesterol crystallisation in bile in vitro and in vivo.
Methods: FABACs were prepared by conjugation of cholic acid at position 3 with saturated fatty acids of variable chain length using an amide bond. Cholesterol crystallisation and its kinetics (crystal observation time, crystal mass) were studied in model bile, pooled enriched human bile, and fresh human bile using FABACs with saturated fatty acids of varying chain length (C-6 to C-22). Absorption of FABACs into blood and bile was tested in hamsters. Prevention of biliary cholesterol crystallisation in vivo was tested in hamsters and inbred mice.
Results: FABACs strongly inhibited cholesterol crystallisation in model as well as native bile. The FABACs with longer acyl chains (C-16 to C-22) were more effective. At a concentration of 5 mM, FABACs almost completely inhibited cholesterol crystallisation in fresh human bile for 21 days. FABACs were absorbed and found in both portal and heart blood of hamsters. Levels in bile were 2-3 times higher than in blood, indicating active secretion. Appreciable levels were found in the systemic circulation 24-48 hours after a single administration. Ingested FABACs completely prevented the formation of cholesterol crystals in the gall bladders of hamsters and mice fed a lithogenic diet.
Conclusions: FABACs are potent inhibitors of cholesterol crystallisation in bile. They are absorbed and secreted into bile and prevent the earliest step of cholesterol gall stone formation in animals. These compounds may be of potential use in cholesterol gall stone disease in humans.
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