Gani Osman A B S M
Department of Pharmacology, Institute of Medical Biology, Faculty of Medicine, University of Tromsø, 9037 Tromsø, Norway.
Cardiovasc Diabetol. 2008 Mar 20;7:6. doi: 10.1186/1475-2840-7-6.
Peroxisome proliferator-activated receptors (PPARalpha, PPARgamma, and PPARdelta) are physiological sensors for glucose and lipid homeostasis. They are also the targets of synthetic drugs; such as fibrates as PPARalpha agonists which lower lipid level, and glitazones as PPARgamma agonists which lower glucose level. As diabetes and metabolic diseases are often associated with high blood glucose and lipid levels, drugs that activate both PPARalpha/gamma would be a logical approach. But synthetically developed PPARalpha/gamma dual agonists and glitazones are showing side effects such as weight gain and edema. Therefore, natural compounds and their close derivatives are focused as future drugs against metabolic diseases.
Docosahexaenoic acid and eicosapentaenoic acid, which are the fatty acids abundant in fish oil, are traditionally used against metabolic diseases. These fatty acids act as PPAR agonists that transcript the genes involved in glucose and lipid homeostasis. Present hypothesis suggests that the derivatives of these fatty acids are stronger PPAR agonists than the parent compounds. X-ray structures of PPARs indicate that alpha or beta derivatives of fatty acids would fit into PPARalpha/gamma binding cavity. Therefore, the derivatives will exhibit stronger affinities and activities than the parent compounds.
Ligand binding assays and gene transactivation assays should be performed to test the hypothesis. Fluorescence-based methods are advantageous in binding assays, because they were found more suitable for fatty acid binding assays. In transactivation assays, care should be taken to remove contaminants from recombinant proteins.
Present hypothesis is framed on the basis of molecular structure of natural PPAR agonists. Small structural changes in the molecular structure of fatty acids have a great influence on activating different PPARs. Therefore, this hypothesis bridges the concept of natural PPAR agonists and the use of structural information in designing new drugs against diabetes and metabolic syndrome. The derivatives may also be used as anti-inflammatory and anticancer agents.
过氧化物酶体增殖物激活受体（PPARα、PPARγ和PPARδ）是葡萄糖和脂质稳态的生理传感器。它们也是合成药物的作用靶点；例如贝特类药物作为PPARα激动剂可降低血脂水平，格列酮类药物作为PPARγ激动剂可降低血糖水平。由于糖尿病和代谢性疾病常与高血糖和高血脂水平相关，激活PPARα/γ的药物将是一种合理的治疗方法。但合成开发的PPARα/γ双重激动剂和格列酮类药物正显示出如体重增加和水肿等副作用。因此，天然化合物及其密切衍生物成为未来抗代谢性疾病药物的研究重点。
二十二碳六烯酸和二十碳五烯酸是鱼油中富含的脂肪酸，传统上用于治疗代谢性疾病。这些脂肪酸作为PPAR激动剂，可转录参与葡萄糖和脂质稳态的基因。目前的假说认为，这些脂肪酸的衍生物是比母体化合物更强的PPAR激动剂。PPAR的X射线结构表明，脂肪酸的α或β衍生物可与PPARα/γ结合腔相契合。因此，这些衍生物将表现出比母体化合物更强的亲和力和活性。
应进行配体结合试验和基因反式激活试验以验证该假说。基于荧光的方法在结合试验中具有优势，因为它们被发现更适合脂肪酸结合试验。在反式激活试验中，应注意去除重组蛋白中的污染物。
目前的假说是基于天然PPAR激动剂的分子结构提出的。脂肪酸分子结构的微小变化对激活不同的PPAR有很大影响。因此，该假说将天然PPAR激动剂的概念与利用结构信息设计抗糖尿病和代谢综合征新药联系起来。这些衍生物也可用作抗炎和抗癌药物。
