Forman B M, Chen J, Evans R M
The Salk Institute for Biological Studies, Gene Expression Laboratory, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4312-7. doi: 10.1073/pnas.94.9.4312.
Fatty acids (FAs) and their derivatives are essential cellular metabolites whose concentrations must be closely regulated. This implies that regulatory circuits exist which can sense changes in FA levels. Indeed, the peroxisome proliferator-activated receptor alpha (PPARalpha) regulates lipid homeostasis and is transcriptionally activated by a variety of lipid-like compounds. It remains unclear as to how these structurally diverse compounds can activate a single receptor. We have developed a novel conformation-based assay that screens activators for their ability to bind to PPARalpha/delta and induce DNA binding. We show here that specific FAs, eicosanoids, and hypolipidemic drugs are ligands for PPARalpha or PPARdelta. Because altered FA levels are associated with obesity, atherosclerosis, hypertension, and diabetes, PPARs may serve as molecular sensors that are central to the development and treatment of these metabolic disorders.
脂肪酸（FAs）及其衍生物是重要的细胞代谢物，其浓度必须受到严格调控。这意味着存在能够感知脂肪酸水平变化的调节回路。事实上，过氧化物酶体增殖物激活受体α（PPARα）调节脂质稳态，并被多种类脂化合物转录激活。目前尚不清楚这些结构多样的化合物如何激活单一受体。我们开发了一种基于构象的新型检测方法，用于筛选激活剂与PPARα/δ结合并诱导DNA结合的能力。我们在此表明，特定的脂肪酸、类花生酸和降血脂药物是PPARα或PPARδ的配体。由于脂肪酸水平的改变与肥胖、动脉粥样硬化、高血压和糖尿病相关，PPARs可能作为分子传感器，在这些代谢紊乱的发生和治疗中起核心作用。
