Peroksizom Proliferatör ile Etkinleştirilen Reseptörlerin İnsülin Direnci ve Septik Şok Patojenezindeki Rolü

Year 2015, Volume: 5 Issue: 4, 247 - 258, 29.12.2015

Sefika Pinar Senol Bahar Tunctan

https://doi.org/10.5455/musbed.20150715121617

Abstract

Peroksizom proliferatör ile etkinleştirilen reseptörler ligant ile etkin¬leştirilen transkripsiyon faktörleridir ve sınıf II nükleer reseptör ailesine aittirler. Günümüze dek peroksizom proliferatör ile etkinleştirilen resep¬tör (peroxisome proliferator-activated receptor; PPAR) α, PPARβ ve PPARγ olmak üzere 3 alt tür tanımlanmıştır. PPARα başlıca lipit metabolizması ve enflamatuvar sürecin düzenlenmesinde rol oynamaktadır. PPARα ve PPARγ üzerine yapılan çok sayıdaki çalışmaya karşın, PPARβ’nın işlevsel kimliği henüz netlik kazanmamıştır; çünkü neredeyse tüm dokularda eksprese edilmektedir. PPARγ ise glukoz homeostazı ve adipojenezin düzenlenmesinde anahtar rol oynar. İnsülin direnci kandaki normal ya da yüksek insülin düzeyine rağmen, zayıf biyolojik yanıt oluşmasıdır. İnsülin direncinde başta kas, yağ ve karaciğer olmak üzere tüm dokularda insü¬line gerekli ve yeterli yanıt oluşmamaktadır. PPARα lipit metabolizması üzerine etkili genleri düzenleyerek, PPARγ ise çeşitli mekanizmalar ile glukoz homeostazını sağlayarak insülin direnci ortaya çıkmasını engeller. Sepsis, bilinen veya olası bir enfeksiyona karşı verilen sistemik enflama-tuvar yanıt durumu, septik şok ise intravenöz sıvı uygulamasına yanıtsız hipotansiyonun eşlik ettiği şiddetli sepsistir. PPAR agonistleri ile yapılan klinik öncesi çalışmalarda sepsis ve septik şok patojenezinde rol oynayan nükleer faktör κB ve etkinleştirici protein-1 gibi transkripsiyon faktörle-rinin etkinleşmesi inhibe edilerek proenflamatuvar gen ekspresyonunun engellendiği görülmüştür. Bu derlemede, insülin direnci ve septik şok patojenezinde PPAR’ların rolüne değinilerek, PPAR agonistlerinin olası terapötik yararları üzerinde durulmuştur.

Keywords

PPAR, septik şok, insülin direnci, enflamasyon

The Role of Peroxisome Proliferator-Activated Receptors in the Pathogenesis of Insulin Resistance and Septic Shock

Abstract

Peroxisome proliferator-activated receptors are ligand-activated transcription factors and they belong to class II nuclear receptor family. To date, three subspecies have been identified: peroxisome proliferator-activated receptor (PPAR) α, PPARβ and PPARγ. PPARα is mainly involved in the regulation of lipid metabolism and inflammatory processes. Since PPARβ is expressed in almost all tissues, the functional identity of it is not yet clear. PPARγ plays a key role in glucose homeostasis and the regulation of adipogenesis. Insulin resistance is attenuated biological response despite circulating normal or high levels of insulin in blood. In insulin resistance, the response caused by insulin isn’t sufficient or adequate at all tissues particularly in muscle, fat and liver. Development of insulin resistance is prevented by PPARα through regulation of genes affecting lipid metabolism and by PPARγ through provision of glucose homeostasis by different mechanisms. Sepsis is a systemic inflammatory response against a manifest or a potential infection; and septic shock is the severe form of sepsis that is accompanied by hypotension unresponsive to intravenous fluid administration. In preclinical studies proinflammatory gene expression was prevented by the inhibition of activation of transcription factors such as nuclear factor κB and activator protein-1 which are involved in the pathogenesis of sepsis and septic shock by PPAR agonists. This review focuses on the role of PPARs in the pathogenesis of insulin resistance and septic shock and discusses the potential therapeutic benefits of PPAR agonists.

Keywords

PPAR, insulin resistance, septic shock, inflammation

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