Statin therapy inhibits fatty acid synthase via dynamic protein modifications

Statins are a class of drugs widely prescribed to prevent cardiovascular disease, with pleiotropic cellular effects. Statins inhibit HMG-CoA reductase (HMGCR), which converts the metabolite HMG-CoA into mevalonate. Recent discoveries revealed HMG-CoA is a reactive metabolite that can non-enzymatically modify proteins and impact their activity. Therefore, we predicted that inhibition of HMGCR by statins might increase HMG-CoA levels and protein modifications. We observed a substantial increase in HMG-CoA levels upon statin treatment, and only a single protein was modified. Mass spectrometry revealed fatty acid synthase (FAS) was modified on active site residues, and surprisingly, the modification is located on non-lysine side-chains. The dynamic modifications occur only on a sub-pool of FAS near HMGCR and alter cellular signaling around the ER and Golgi. These results uncover communication between cholesterol and lipid biosynthesis by the substrate of one pathway inhibiting another in a rapid and reversible manner.