CROT Inhibitors

Chemical inhibitors of CROT function through diverse mechanisms that impede CROT's ability to participate in fatty acid metabolism. Orlistat, a lipase inhibitor, reduces the gastrointestinal absorption of fats, leading to a decrease in fatty acid availability for the CROT-mediated conversion of octanoyl-CoA and carnitine into octanoylcarnitine. Perhexiline and Oxfenicine, by inhibiting carnitine palmitoyltransferase (CPT), decrease mitochondrial uptake of long-chain fatty acids, thus reducing the substrate pool for CROT. Similarly, Etomoxir's inhibition of CPT1 curtails the transport of fatty acyl chains into mitochondria, constraining the acyl-carnitine substrates necessary for CROT's enzymatic function. Malonyl-CoA, a natural inhibitor of CPT1, also diminishes the pool of fatty acyl-CoAs, indirectly limiting CROT's activity by substrate deprivation.

Trimetazidine and Ranolazine function by inhibiting enzymes in fatty acid oxidation, thereby lowering the availability of acyl-carnitines for CROT. Mildronate inhibits γ-butyrobetaine hydroxylase, thereby decreasing carnitine synthesis and subsequently the substrate availability for CROT. Metformin indirectly influences CROT by activating AMPK, which can lead to reduced acyl-CoA levels and hence, decreased CROT activity. Fenofibrate activates PPARα, leading to increased fatty acid oxidation, which can deplete the fatty acid substrates required for CROT activity. Nicotinic Acid reduces the mobilization of free fatty acids from adipose tissue, which in turn can limit the substrates available for CROT, resulting in the functional inhibition of the protein's fatty acid transferase activity. Each of these chemicals interacts with different facets of fatty acid metabolism, and by doing so, they can suppress the functional activity of CROT through a reduction in substrate availability or competitive inhibition.