Malonyl-CoA and carnitine palmitoyltransferase I: an expanding partnership.

Inhibition of mitochondrial carnitine palmitoyltransferase I (CPT I) by malonyl-CoA, the product of the acetyl-CoA carboxylase reaction, was first recognized in 1977 during the course of studies on hepatic ketogenesis and its regulation [ l ] . What emerged from that work was that with carbohydrate feeding (high insulin/low glucagon) the liver is actively engaged in fatty acid biosynthesis, the tissue malonyl-CoA content is high and the capacity for long-chain-fatty-acid oxidation (and thus ketogenesis) is depressed. Conversely, in starvation or uncontrolled diabetes (low insulin/high glucagon) malonyl-CoA levels fall, hepatic fatty acid synthesis is attenuated, and fatty acids reaching the liver from fat depots are efficiently oxidized, with accelerated production of ketone bodies [2]. It was subsequently established that transition back and forth between normal and ketotic states is accompanied not only by changes in the malonyl-CoA content of liver, but also by marked shifts in the sensitivity of CPT I to the inhibitor, a feature that allows for appropriate alterations in the direction of both fatty acid and glucose carbon flux under such conditions (reviewed in [3,4]). What has also become clear during the past two decades is that the suppressive effect of malonyl-CoA on CPT I is not a phenomenon restricted to liver. Indeed, there is mounting evidence that this same interaction is also at work as