The Effects of a Novel Statin-Induced Protein Modification on Fatty Acid Synthase

他汀类药物是世界上最广泛使用的处方药之一，因为它们有效 预防心血管疾病；然而，他汀类药物的机制和作用是 不完全理解。我们实验室最近的工作发现了一种新的后翻译 他汀类药物对脂肪酸合成酶(FASN)的修饰。长期目标 是为了了解他汀类药物治疗期间细胞代谢的变化，以及它们是如何 有助于药物的多效性作用。这项提案的目标是确定如何 新的蛋白质修饰影响FASN。中心假设是他汀类药物诱导的 在他汀类药物治疗中，脂肪酸合成酶的修饰调节脂肪酸代谢。这是 根据初步数据显示，脂肪酸合成酶的活性部位残基是 经修饰后可抑制FASN。提出这项研究的理由是，理解 他汀类药物对脂肪酸代谢的影响可能为他汀类药物的治疗提供机制上的解释 可被操纵以改善治疗和患者健康的副作用。基于 初步数据，将通过追求两个具体目标来检验中心假设：1)确定 他汀类药物诱导的脂肪酸合成酶修饰的位点(S)，以及2)决定其影响 他汀类药物对脂肪酸合成酶活性的影响。在第一个目标中，质谱学将准确地 鉴定体外标记的FASN的修饰部位以及从他汀类药物中提取的FASN 处理过的细胞。在第二个目标中，将对纯化的FASN进行体外活性分析，以 检查在存在修改的情况下活动如何更改。此外，标记的碳 细胞中的示踪研究将被用来测量在以下情况下脂肪酸产生的变化 他汀类药物治疗。通过阐明这些影响，预计研究结果将产生重大影响 一种以前未知的由他汀类药物引起的改变。这将提高我们的能力 了解和管理他汀类药物治疗引起的副作用，进一步履行 NHLBI将“促进心肺和血液疾病的预防和治疗” 增强所有个人的健康，使他们能够活得更长、更有成就感。

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.”