ACOX1 Activators

ACOX1, or acyl-coenzyme A oxidase 1, stands as a pivotal player in peroxisomal fatty acid oxidation, intricately involved in maintaining cellular energy homeostasis and lipid metabolism. The diverse set of chemicals identified as ACOX1 activators underscores the multifaceted nature of the pathways modulating ACOX1 expression. Resveratrol, a polyphenol found in red grapes, emerges as an indirect activator of ACOX1. Its mechanism involves the enhancement of the SIRT1/AMPK pathway. By bolstering SIRT1 activity, resveratrol triggers AMPK activation, subsequently elevating ACOX1 expression through increased levels of PGC-1α. This intricate interplay exemplifies how cellular pathways involved in energy sensing can dynamically regulate ACOX1, highlighting resveratrol as a modulator of this finely tuned system. Clofibrate, a fibrate drug, takes a direct route in activating ACOX1 by binding to PPARα. This binding induces conformational changes in PPARα, facilitating its heterodimerization with RXR. The formed complex then binds to specific regions in the ACOX1 promoter, enhancing transcription and leading to the activation of ACOX1.

The chemical palette expands with C75, an inhibitor of fatty acid synthase (FAS), indirectly activating ACOX1 by redirecting cellular metabolism towards fatty acid oxidation. Inhibition of FAS by C75 diminishes endogenous fatty acid synthesis, pushing cells to rely more on fatty acid catabolism, consequently upregulating ACOX1 expression.The versatility continues with a set of PPAR agonists-GW7647, Bezafibrate, GW501516, and Wy-14643-each directly activating ACOX1 through the binding of PPARs and subsequent transcriptional initiation. Intriguingly, the AICAR and A769662 chemicals, both AMPK activators, indirectly activate ACOX1 by enhancing cellular energy status. Through AMPK-mediated phosphorylation and activation of PGC-1α, these compounds augment ACOX1 transcription, providing a link between cellular energy sensing and ACOX1 regulation. Although the exact mechanism remains under investigation, the observed increase in ACOX1 levels suggests a role for PFOA in influencing peroxisomal fatty acid oxidation through PPARα-mediated pathways.