Saha Lekha
Lekha Saha, Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
World J Gastrointest Pharmacol Ther. 2015 Nov 6;6(4):120-6. doi: 10.4292/wjgpt.v6.i4.120.
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. Three subtypes, PPARα, PPARβ/δ, and PPARγ, have been identified so far. PPARα is expressed in the liver, kidney, small intestine, heart, and muscle, where it activates the fatty acid catabolism and control lipoprotein assembly in response to long-chain unsaturated fatty acids, eicosanoids, and hypolipidemic drugs (e.g., fenofibrate). PPARβ/δ is more broadly expressed and is implicated in fatty acid oxidation, keratinocyte differentiation, wound healing, and macrophage response to very low density lipoprotein metabolism. This isoform has been implicated in transcriptional-repression functions and has been shown to repress the activity of PPARα or PPARγ target genes. PPARγ1 and γ2 are generated from a single-gene peroxisome proliferator-activated receptors gamma by differential promoter usage and alternative splicing. PPARγ1 is expressed in colon, immune system (e.g., monocytes and macrophages), and other tissues where it participates in the modulation of inflammation, cell proliferation, and differentiation. PPARs regulate gene expression through distinct mechanisms: Ligand-dependent transactivation, ligand-independent repression, and ligand-dependent transrepression. Studies in animals have demonstrated the gastric antisecretory activity of PPARα agonists like ciprofibrate, bezafibrate and clofibrate. Study by Pathak et al also demonstrated the effect of PPARα agonist, bezafibrate, on gastric secretion and gastric cytoprotection in various gastric ulcer models in rats. The majority of the experimental studies is on pioglitazone and rosiglitazone, which are PPARγ activators. In all the studies, both the PPARγ activators showed protection against the gastric ulcer and also accelerate the ulcer healing in gastric ulcer model in rats. Therefore, PPARα and PPARγ may be a target for gastric ulcer therapy. Finally, more studies are also needed to confirm the involvement of PPARs α and γ in gastric ulcer.
过氧化物酶体增殖物激活受体（PPARs）是属于核激素受体超家族的配体激活转录因子。迄今为止，已鉴定出三种亚型，即PPARα、PPARβ/δ和PPARγ。PPARα在肝脏、肾脏、小肠、心脏和肌肉中表达，在这些部位，它响应长链不饱和脂肪酸、类花生酸和降血脂药物（如非诺贝特）激活脂肪酸分解代谢并控制脂蛋白组装。PPARβ/δ表达更为广泛，参与脂肪酸氧化、角质形成细胞分化、伤口愈合以及巨噬细胞对极低密度脂蛋白代谢的反应。这种亚型与转录抑制功能有关，已被证明可抑制PPARα或PPARγ靶基因的活性。PPARγ1和γ2由单基因过氧化物酶体增殖物激活受体γ通过不同的启动子使用和可变剪接产生。PPARγ1在结肠、免疫系统（如单核细胞和巨噬细胞）及其他组织中表达，在这些组织中它参与炎症、细胞增殖和分化的调节。PPARs通过不同机制调节基因表达：配体依赖性反式激活、配体非依赖性抑制和配体依赖性反式抑制。动物研究已证明PPARα激动剂如环丙贝特、苯扎贝特和氯贝丁酯具有胃抗分泌活性。Pathak等人的研究也证明了PPARα激动剂苯扎贝特对大鼠各种胃溃疡模型中胃分泌和胃细胞保护的作用。大多数实验研究针对的是PPARγ激活剂吡格列酮和罗格列酮。在所有研究中，这两种PPARγ激活剂在大鼠胃溃疡模型中均显示出对胃溃疡的保护作用，并加速溃疡愈合。因此，PPARα和PPARγ可能是胃溃疡治疗的靶点。最后，还需要更多研究来证实PPARα和γ在胃溃疡中的作用。
