Research & Development
Basic Research and Clinical Data
Mechanism of Action
Aramchol’s mechanism of action has been studied in-vitro and in-vivo. Aramchol has been shown to work by two parallel pathways, leading to synergistic effects:
The SCD1 Pathway
Aramchol partially inhibits the activity of Stearoyl Coenzyme A Desaturase 1 (SCD1) in the liver. This is likely a direct effect since the mRNA of this and other lipogenic genes or the activities of nuclear receptors are not affected. The physiologic effects of SCD1 inhibition include a reduced synthesis of fatty acids, which results in a decrease in storage of triglycerides and other esters of fatty acids. This effect diminishes liver fat (including triglycerides and free fatty acids), and results in an improvement in insulin resistance1. The partial inhibition of the SCD1 enzyme has been confirmed in human liver microsomes2 and in animal studies by showing a reduction of the SCD1 activity marker, the fatty acid ratio 16:1/16:0, following aramchol treatment1. These studies showed that the SCD1 inhibition effect of aramchol is partial (between 70% and 83% inhibition).
Unlike other SCD1 inhibitors, studies have demonstrated that aramchol’s effects are non- atherogenic 1. Currently, there are no known inhibitors of SCD1 with the established safety and efficacy profile comparable to that of aramachol.
Reverse Cholesterol Transport
In addition to the partial inhibition of SCD1, aramchol activates cholesterol efflux by stimulating the ABCA1 transporter by a factor of 2- to 4-fold). ABCA1 is known to be a universal cholesterol export pump present in all cells2,3. In animal models, Galmed established that the down regulation of ABCA1 leads to a significant reduction of blood and body cholesterol and an increase in fecal sterol output, mostly neutral sterols4.
Aramchol induces apolipoprotein-independent reverse cholesterol transport, which enables a more efficient cholesterol clearance from the liver.
Aramchol increases 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 has little effect on phospholipid efflux. Although there is no effect on ABCA1 expression, plasma membrane levels of the transporter increase 2-fold.
Aramchol is the first small molecule that was shown to induce ABCA1-dependent cholesterol efflux without affecting transcriptional control2.
 Leikin-Frenkel A., Goldiner I., et al., “Treatment of preestablished diet-induced fatty liver by oral fatty acid-bile acid conjugates in rodents“, Eur J Gastroenterol Hepatol. 2008 Dec;20(12):1205-13
 Leikin-Frenkel A, Gonen A et al., “Fatty Acid Bile Acid Conjugate Inhibits hepatic Stearoyl Coenzyme A Desaturase and is not –Atherogenic“, Arch Med Res. 2010 Aug;41(6):397-404
 Goldiner I, van der Velde AE et al., “ABCA1-dependent but apoA-I-independent cholesterol efflux mediated by fatty acid-bile acid conjugates (FABACs)“, Biochem J. 2006 Jun 15;396(3):529-36
 Brown J.M.,and Rudel L.L., “Stearoyl-coenzyme A desaturase 1 inhibition and the metabolic syndrome: considerations for future drug discovery“, Curr Opin Lipidol. 2010 Jun;21(3):192-7