PPAR家族及其与代谢综合征的关系

过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptors,PPARs)是配体激活的转录因子核受体超家族成员之一。目前已知有三种亚型：PPARα、-β／δ和-γ。它们在脂肪生成、脂质代谢、胰岛素敏感性、炎症和血压调节中起着关键作用,因而近年来倍受关注。越来越多的研究表明,PPARs与代谢综合征,包括胰岛素抵抗、糖耐量受损、2型糖尿病、肥胖、高脂血症、高血压病、动脉粥样硬化和蛋白尿之间存在因果关系。重要的是,PPARα的激动剂如贝丁酸类降脂药(Fibrate)和PPARγ的激动剂如噻唑烷二酮(Thiazolidinedione,TZD)均已被证实有改善代谢综合征的作用。此外,三种PPAR亚型在2型糖尿病及糖尿病肾病的发展中均有重要作用。不断增加的证据提示,PPARs有可能成为代谢综合征及其相关并发症的潜在治疗靶点。本文将就PPARs的生物学活性、配体选择性和生理学功能作一综述,并对其在代谢综合征发病机制中的作用和PPAR配体对2型糖尿病的治疗效用进行重点讨论。     

PPARs and angiogenesis

The PPAR (peroxisome-proliferator-activated receptor) family consists of three ligand-activated nuclear receptors: PPARα, PPARβ/δ and PPARγ. These PPARs have important roles in the regulation of glucose and fatty acid metabolism, cell differentiation and immune function, but were also found to be expressed in endothelial cells in the late 1990s. The early endothelial focus of PPARs was PPARγ, the molecular target for the insulin-sensitizing thiazolidinedione/glitazone class of drugs. Activation of PPARγ was shown to inhibit angiogenesis in vitro and in models of retinopathy and cancer, whereas more recent data point to a critical role in the development of the vasculature in the placenta. Similarly, PPARα, the molecular target for the fibrate class of drugs, also has anti-angiogenic properties in experimental models. In contrast, unlike PPARα or PPARγ, activation of PPARβ/δ induces angiogenesis, in vitro and in vivo, and has been suggested to be a critical component of the angiogenic switch in pancreatic cancer. Moreover, PPARβ/δ is an exercise mimetic and appears to contribute to the angiogenic remodelling of cardiac and skeletal muscle induced by exercise. This evidence and the emerging mechanisms by which PPARs act in endothelial cells are discussed in more detail.     

Discovery of N-(1-(3-(4-phenoxyphenyl)-1,2,4-oxadiazol-5-yl)ethyl)acetamides as novel acetyl-CoA carboxylase 2 (ACC2) inhibitors with peroxisome proliferator-activated receptor α/δ (PPARα/δ) dual agonistic activity

Acetyl-CoA carboxylases (ACCs) catalyze a critical step in de novo lipogenesis, and are considered as promising targets for treatment of obesity, dyslipidemia and type 2 diabetes mellitus. On the other hand, peroxisome proliferator-activated receptors (PPARs) are well-established therapeutic targets for these metabolic syndrome-related diseases. Therefore, we considered that dual modulators of ACC and PPARs would be promising candidates as therapeutic agents. Here, we designed a series of acetamides based on the molecular similarity between ACC inhibitors and PPAR agonists. Screening of the synthesized compounds identified N-(1-(3-(4-phenoxyphenyl)-1,2,4-oxadiazol-5-yl)ethyl)acetamides as novel ACC2 inhibitors with PPARα/PPARδ dual agonistic activity. Structure–activity relationship studies and further structural elaboration afforded compounds with distinct activity profiles. Our findings should be helpful for the discovery of candidate agents with an appropriate balance of ACC-inhibitory and PPAR-activating activities for therapeutic lipid control.     

PPAR-γ: Its ligand and its regulation by microRNAs

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily. PPARs are categorized into three subtypes, PPARα, β/δ, and γ, encoded by different genes, expressed in diverse tissues and participate in various biological functions and can be activated by their metabolic derivatives in the body or dietary fatty acids. The PPAR-γ also takes parts in the regulation of energy balance, lipoprotein metabolism, insulin sensitivity, oxidative stress, and inflammatory signaling. It has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis, and cancers. Among various cellular and molecular targets that are able to regulate PPAR-γ and its underlying pathways, microRNAs (miRNAs) appeared as important regulators. Given that the deregulation of these molecules via targeting PPAR-γ could affect initiation and progression of various diseases, identification of miRNAs that affects PPAR-γ could contribute to the better understanding of roles of PPAR-γ in various biological and pathological conditions. Here, we have summarized the function and various ligands of PPAR-γ and have highlighted various miRNAs involved in the regulation of PPAR-γ.     

A pan-PPAR ligand induces hepatic fatty acid oxidation in PPARα−/− mice possibly through PGC-1 mediated PPARδ coactivation

Tetradecylthioacetic acid (TTA) is a hypolipidemic modified fatty acid and a peroxisome proliferator-activated receptor (PPAR) ligand. The mechanisms of TTA-mediated effects seem to involve the PPARs, but the effects have not been assigned to any specific PPAR subtype. PPARα−/− mice were employed to study the role of PPARα after TTA treatment. We also performed in vitro transfection assays to obtain mechanistic knowledge of how TTA affected PPAR activation in the presence of PPARγ coactivator (PGC)-1 and steroid receptor coactivators (SRC)-1 and SRC-2, which are associated with energy balance and mitochondrial biogenesis. We show that TTA increases hepatic fatty acid β-oxidation in PPARα−/− mice. TTA acts as a pan-PPAR ligand in vitro, and PGC-1, SRC-1 and SRC-2 have cell type and PPAR-specific effects together with TTA. In the absence of exogenous ligands, SRC-1 did not induce PPAR activity, while PGC-1 was the most potent PPAR coactivator. When the coactivators were overexpressed, pronounced effects of TTA were observed especially for PPARδ and PPARγ. We conclude that PPARα is involved in, but not required for, the hypolipidemic mechanisms of TTA. It appears that the activity of PPARδ, with substantial contribution of nuclear receptor coactivators, PGC-1 in special, is conducive to TTA's mechanism of action.     

Switching subtype-selectivity: Fragment replacement strategy affords novel class of peroxisome proliferator-activated receptor α/δ (PPARα/δ) dual agonists

Peroxisome proliferator-activated receptors (PPARs) are important drug targets for treatment of dyslipidemia, type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, and great efforts have been made to develop novel PPAR ligands. However, most existing PPAR ligands contain a carboxylic acid (CA) or thiazolidinedione (TZD) structure (acidic head group) that is essential for activity. We recently discovered non-CA/TZD class PPARα/δ partial agonists, which contain an acetamide moiety and adjacent methyl group, linked to a 1,2,4-oxadiazole ring (“fragment a”). We hypothesized that the acetamide structure might interact with the CA/TZD-binding pocket. To test this idea, we firstly replaced fragment a in one of our compounds with the α-alkoxy-CA structure often found in PPAR agonists. Secondly, we replaced the α-alkoxy-CA head group of several reported PPAR agonists with our acetamide-based fragment a. The agonistic activities of the synthesized hybrid compounds toward PPARs (PPARα, PPARγ and PPARδ) were evaluated by means of cell-based reporter gene assays. All the hybrid molecules showed PPAR-agonistic activities, but replacement of the α-alkoxy-CA head group altered the maximum efficacy and the subtype-specificity. The acetamide-based hybrid molecules showed partial agonism toward PPARα and PPARδ, whereas the α-alkoxy-CA-based molecules were generally selective for PPARα and PPARγ, with relatively high activation efficacies. Thus, the fragment replacement strategy appears promising for the development of novel acetamide-based PPARα/δ dual agonists.