FATP-1 Inhibitors

Chemical inhibitors of the fatty acid transport protein 1 (FATP-1) work by indirectly diminishing the protein's ability to transport fatty acids into cells. Perhexiline, Etomoxir, Oxfenicine, and Teglicar are compounds that share a common mechanism of action; they inhibit carnitine palmitoyltransferase 1 (CPT1), an enzyme pivotal to the beta-oxidation pathway of fatty acids within the mitochondria. By targeting CPT1, these inhibitors reduce the cellular uptake of fatty acids for oxidation, which in turn, leads to a decrease in the intracellular concentration of fatty acids. Since FATP-1 is responsible for the uptake and internalization of fatty acids, a reduction in their intracellular levels due to the action of these inhibitors can lead to a functional inhibition of FATP-1.

Other compounds such as Malonyl Coenzyme A and GSK837149A exert an indirect influence on FATP-1 through their effects on metabolic processes upstream of fatty acid oxidation. Malonyl Coenzyme A is an endogenous molecule that naturally inhibits CPT1, thereby influencing the fatty acid oxidation process similarly to the aforementioned chemical inhibitors. GSK837149A inhibits acetyl-CoA carboxylase (ACC), an enzyme involved in the synthesis of malonyl-CoA. This inhibition can lead to an upregulation of fatty acid oxidation due to less malonyl-CoA being available to inhibit CPT1, potentially lowering the availability of fatty acids for FATP-1 to transport. Meanwhile, Triacsin C targets long-chain acyl-CoA synthetase (ACSL), reducing the conversion of free fatty acids into their CoA derivatives and thus indirectly reducing the substrate availability for FATP-1. Atglistatin inhibits adipose triglyceride lipase (ATGL), leading to decreased release of fatty acids from adipose tissue, which results in decreased availability of fatty acids for FATP-1 to transport. Lastly, Lomitapide and Niclosamide affect lipid metabolism and energy production, respectively. Lomitapide disrupts the assembly and secretion of lipoproteins, which can lead to a reduced intracellular lipid pool and consequently less substrate for FATP-1. Niclosamide uncouples mitochondrial oxidative phosphorylation, which can reduce the energy-dependent uptake of fatty acids, thereby indirectly inhibiting FATP-1's role in fatty acid transport.