Effects of Fatty Acid Bile Acid Conjugates (FABACs) on Biliary Lithogenesis: Potential Consequences for Non-Surgical Treatment of Gallstones

Abstract

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.

Bile acids and nonalcoholic fatty liver disease

“…Aramchol is a novel synthetic lipid molecule obtained by conjugating two natural components, CA and arachidic acid (a saturated FA), through a stable amide bond. This FA/BA conjugate inhibits SCD1 activity and activates cholesterol efflux by stimulating the ABC transporter, A1, a pan cellular cholesterol export pump . In a phase 2 study involving 60 patients with biopsy‐proven NAFLD, treatment with 100 or 300 mg/day of aramchol for 3 months significantly reduced liver fat content in a dose‐dependent manner and was associated with a trend of metabolic improvements .…”

Steroid degradation in Comamonas testosteroni

“…testosteroni is unable to degrade majority of the steroid compounds with a large side chain at C-17 position such as cholesterols and plant sterols [37], but effectively degrades cholic acid and the derivatives. Cholic acid and the derivatives are not only known for physiological activities on animals and anti-bacterial activity as the main integrants of bile acid [50][51][52][53][54][55][56][57][58][59] but also other various functions that are expected to be applied to medicals and their materials. Furthermore, they are reported to induce defensive effects in plants [60,61].…”

Perspectives on Nonalcoholic Fatty Liver Disease: An Overview of Present and Future Therapies

“…Aramchol is a novel synthetic lipid molecule obtained by conjugating cholic acid and arachidic acid that has been shown to reduce hepatic fat content in animals with a high-fat diet 71. It has been shown to inhibit the stearoyl-coenzyme A desaturase 1 activity, thereby decreasing the synthesis and increasing the beta-oxidation of fatty acids in vitro 72.…”