LIPN Inhibitors

Chemical inhibitors of LIPN work through various mechanisms to impede its functional role in lipid metabolism. Orlistat is one such inhibitor that directly targets LIPN by binding to the serine residue within its active site. This binding is critical because it obstructs the enzyme's ability to hydrolyze dietary fats into absorbable free fatty acids, thus blocking the biological function of LIPN. Similarly, Ebelactone A and Ebelactone B operate by forming a covalent bond with the serine residue at the LIPN active site. This action effectively renders LIPN inactive, preventing the enzyme from fulfilling its lipid breakdown function. Methyl arachidonyl fluorophosphonate and Palmitoyl trifluoromethyl ketone also act as irreversible inhibitors of LIPN by covalently binding to the same critical serine residue, ensuring the enzyme cannot access lipid substrates for hydrolysis. Lalistat 2 functions in a comparable way, by associating with the enzyme's active site to inhibit LIPN's ability to break down triglycerides.

Moreover, some chemicals use indirect methods to inhibit LIPN's activity. For instance, 5-(Tetradecyloxy)-2-furoic acid (TOFA) inhibits acyl-CoA synthetase, which is essential for the activation of fatty acids. By inhibiting this enzyme, TOFA reduces the substrate availability for LIPN, thus indirectly restricting its activity. RHC 80267's inhibition of diacylglycerol lipase can lead to a decreased production of monoacylglycerol, potentially reducing LIPN activity by limiting available substrates. Cetilistat works similarly to Orlistat by impeding the hydrolysis of triglycerides, directly inhibiting the action of LIPN. Atglistatin, although selectively targeting adipose triglyceride lipase (ATGL), indirectly influences LIPN through its regulatory role in fatty acid mobilization and metabolism, which can impact LIPN's role in these processes. ML 348 and ML 349 are inhibitors of lysophospholipase and can indirectly impinge on LIPN activity by affecting lysophospholipid levels, which could alter the substrate landscape for LIPN, thereby impeding its function in lipid metabolism.