Statins are among the most widely prescribed drugs in the world because of their effective prevention of cardiovascular disease; however, the mechanism and effects of statins are incompletely understood. Recent work in our lab has identified a novel post-translational modification in response to statin treatment on fatty acid synthase (FASN). The long-term goal is to understand changes in cellular metabolism that occur during statin therapy and how they contribute to the drug?s pleiotropic effects. The objective of this proposal is to determine how the novel protein modification affects FASN. The central hypothesis is that statin-induced modification of fatty acid synthase modulates fatty acid metabolism during statin therapy. This is based on preliminary data that suggests that active site residues of fatty acid synthase are modified and can inhibit FASN. The rational for the proposed research is that understanding statin effects on fatty acid metabolism may provide a mechanistic explanation for statin therapy side effects that may be manipulated to improve treatment and patient health. Based on preliminary data, the central hypothesis will be tested by pursuing two specific aims: 1) identify the site(s) of the statin-induced modification on fatty acid synthase, and 2) Determine the effects of statins on fatty acid synthase activity. In the first aim, mass spectrometry will accurately identify sites of modification on FASN labeled in vitro, as well as FASN extracted from statin treated cells. In the second aim, in vitro activity assays will be conducted on purified FASN, to examine how activity changes in the presence of the modification. Additionally, labeled carbon tracing studies in cells will be used to measure changes in fatty acid production in the context of statin treatment. The results are expected to have a significant impact by elucidating the effects of a previously unknown modification caused by statin therapy. This will improve the ability to understand and manage the side effects caused by statin therapy, furthering the mission of the NHLBI to ?promote the prevention and treatment of heart, lung, and blood diseases and enhance the health of all individuals so that they can live longer and more fulfilling lives.?
Identifying a mechanism of statin toxicity is relevant to public health because it could lead to more effective and/or more personalized therapies for cardiovascular disease. Furthermore, the research will reveal a new mode of communication between cholesterol and fatty acid metabolism. Thus, the proposed research is relevant to the mission of the NIH by better understanding mechanisms of disease prevention and treatment.
| Trub, Alec G; Hirschey, Matthew D (2018) Reactive Acyl-CoA Species Modify Proteins and Induce Carbon Stress. Trends Biochem Sci 43:369-379 |
