Tenenbaum Alexander, Motro Michael, Fisman Enrique Z
Cardiac Rehabilitation Institute, Sheba Medical Center, 52621 Tel-Hashomer, Israel.
Cardiovasc Diabetol. 2005 Sep 16;4:14. doi: 10.1186/1475-2840-4-14.
There are three peroxisome proliferator-activated receptors (PPARs) subtypes which are commonly designated PPAR alpha, PPAR gamma and PPAR beta/delta. PPAR alpha activation increases high density lipoprotein (HDL) cholesterol synthesis, stimulates "reverse" cholesterol transport and reduces triglycerides. PPAR gamma activation results in insulin sensitization and antidiabetic action. Until recently, the biological role of PPAR beta/delta remained unclear. However, treatment of obese animals by specific PPAR delta agonists results in normalization of metabolic parameters and reduction of adiposity. Combined treatments with PPAR gamma and alpha agonists may potentially improve insulin resistance and alleviate atherogenic dyslipidemia, whereas PPAR delta properties may prevent the development of overweight which typically accompanies "pure" PPAR gamma ligands. The new generation of dual-action PPARs--the glitazars, which target PPAR-gamma and PPAR-alpha (like muraglitazar and tesaglitazar) are on deck in late-stage clinical trials and may be effective in reducing cardiovascular risk, but their long-term clinical effects are still unknown. A number of glitazars have presented problems at a late stage of clinical trials because of serious side-effects (including ragaglitazar and farglitazar). The old and well known lipid-lowering fibric acid derivative bezafibrate is the first clinically tested pan--(alpha, beta/delta, gamma) PPAR activator. It is the only pan-PPAR activator with more than a quarter of a century of therapeutic experience with a good safety profile. Therefore, bezafibrate could be considered (indeed, as a "post hoc" understanding) as an "archetype" of a clinically tested pan-PPAR ligand. Bezafibrate leads to considerable raising of HDL cholesterol and reduces triglycerides, improves insulin sensitivity and reduces blood glucose level, significantly lowering the incidence of cardiovascular events and new diabetes in patients with features of metabolic syndrome. Clinical evidences obtained from bezafibrate-based studies strongly support the concept of pan-PPAR therapeutic approach to conditions which comprise the metabolic syndrome. However, from a biochemical point of view, bezafibrate is a PPAR ligand with a relatively low potency. More powerful new compounds with pan-PPAR activity and proven long-term safety should be highly effective in a clinical setting of patients with coexisting relevant lipid and glucose metabolism disorders.
过氧化物酶体增殖物激活受体（PPAR）有三种亚型，通常称为PPARα、PPARγ和PPARβ/δ。激活PPARα可增加高密度脂蛋白（HDL）胆固醇的合成，刺激“逆向”胆固醇转运并降低甘油三酯。激活PPARγ可导致胰岛素增敏和抗糖尿病作用。直到最近，PPARβ/δ的生物学作用仍不清楚。然而，用特异性PPARδ激动剂治疗肥胖动物可使代谢参数正常化并减少肥胖。联合使用PPARγ和α激动剂可能会改善胰岛素抵抗并减轻致动脉粥样硬化性血脂异常，而PPARδ的特性可能会阻止通常伴随“纯”PPARγ配体出现的超重情况的发生。新一代双作用PPAR——格列扎类药物，靶向PPAR-γ和PPAR-α（如muraglitazar和tesaglitazar），正处于后期临床试验阶段，可能在降低心血管风险方面有效，但其长期临床效果仍未知。一些格列扎类药物由于严重的副作用（包括ragaglitazar和farglitazar）在临床试验后期出现了问题。古老且广为人知的降脂纤维酸衍生物苯扎贝特是首个经过临床测试的泛（α、β/δ、γ）PPAR激活剂。它是唯一一种有超过四分之一个世纪治疗经验且安全性良好的泛PPAR激活剂。因此，苯扎贝特可以被认为（实际上，作为一种“事后”的理解）是经过临床测试的泛PPAR配体的“原型”。苯扎贝特可使HDL胆固醇显著升高，降低甘油三酯，改善胰岛素敏感性并降低血糖水平，显著降低代谢综合征患者心血管事件和新发糖尿病的发生率。从基于苯扎贝特的研究中获得的临床证据有力地支持了针对包括代谢综合征在内的疾病采用泛PPAR治疗方法的概念。然而，从生化角度来看，苯扎贝特是一种效力相对较低的PPAR配体。具有泛PPAR活性且已证实长期安全性的更强效新化合物在同时存在相关脂质和葡萄糖代谢紊乱的患者临床环境中应该会非常有效。
