Subramanian Saravanan, Pallati Pradeep K, Sharma Poonam, Agrawal Devendra K, Nandipati Kalyana C
Department of Clinical & Translational Science, School of Medicine, Creighton UniversityOmaha, Nebraska, USA.
Department of Surgery, School of Medicine, Creighton UniversityOmaha, Nebraska, USA.
Am J Transl Res. 2017 Jul 15;9(7):3224-3244. eCollection 2017.
Activated cell surface and intracellular receptors lead to insulin resistance in obesity. Among these receptors, triggering receptors expressed on myeloid cells (TREM)-1, toll like receptors (TLRs), and receptors for advanced glycation end products (RAGE) play a significant role in the induction of inflammatory response in innate immunity. TREM-1 potentially amplifies TLRs and RAGE synergistically with DNA-binding high-mobility group box 1 (HMGB-1). The objective of the study was to analyze the association between TREM-1/DAP12 and HMGB-1, RAGE and TLRs in obesity-induced insulin resistance. We examined the mRNA expression by RT-PCR and protein expression by Western blotting and immunofluorescence for TREM-1, TREM-2, DAP-12, HMGB-1, RAGE, TLR-4 and TLR-2 in omentum, subcutaneous and liver biopsy tissues of obese diabetic (n=22) and non-diabetic subjects (n=24) and compared with the non-obese non-diabetic controls (n=5). There was a significantly increased expression of TREM-1, DAP-12, HMGB-1, RAGE, TLR-4 and TLR-2 and decreased expression of TREM-2 in the omentum, subcutaneous and liver biopsy of obese diabetic subjects compared to obese non-diabetics and the non-obese population. Overall, obese diabetic subjects had high expression of TREM-1 in association with HMGB1 (100% vs 58.3%, P=0.003), RAGE (77.3% vs 41.7%, P=0.045), TLR4 (100% vs 58.3%, P=0.003), and TLR2 (100% vs 50%, P=0.003) in liver biopsy samples in comparison to obese non-diabetic subjects. Obese diabetics have significantly increased TREM-1, HMGB1, RAGE, and TLRs compared to obese non-diabetics. Our findings suggest a potential pathophysiological role of TREM-1 in conjunction with HMGB1 and inflammatory cell receptors (RAGE, TLR-4 and TLR-2) in obesity-induced insulin resistance.
活化的细胞表面受体和细胞内受体会导致肥胖中的胰岛素抵抗。在这些受体中，髓样细胞表达的触发受体（TREM）-1、Toll样受体（TLR）以及晚期糖基化终产物受体（RAGE）在先天免疫炎症反应的诱导中起重要作用。TREM-1可能与DNA结合的高迁移率族蛋白盒1（HMGB-1）协同放大TLR和RAGE。本研究的目的是分析肥胖诱导的胰岛素抵抗中TREM-1/DAP12与HMGB-1、RAGE和TLR之间的关联。我们通过逆转录聚合酶链反应（RT-PCR）检测了肥胖糖尿病患者（n=22）和非糖尿病患者（n=24）的网膜、皮下及肝活检组织中TREM-1、TREM-2、DAP-12、HMGB-1、RAGE、TLR-4和TLR-2的mRNA表达，并通过蛋白质印迹法和免疫荧光法检测了其蛋白表达，同时与非肥胖非糖尿病对照组（n=5）进行比较。与肥胖非糖尿病患者和非肥胖人群相比，肥胖糖尿病患者的网膜、皮下及肝活检组织中TREM-1、DAP-12、HMGB-1、RAGE、TLR-4和TLR-2的表达显著增加，而TREM-2的表达降低。总体而言，与肥胖非糖尿病患者相比，肥胖糖尿病患者肝活检样本中TREM-1与HMGB1（100%对58.3%，P=0.003）、RAGE（77.3%对41.7%，P=0.045）、TLR4（100%对58.3%，P=0.003）和TLR2（100%对50%，P=0.003）的共表达较高。与肥胖非糖尿病患者相比，肥胖糖尿病患者的TREM-1、HMGB1、RAGE和TLR显著增加。我们的研究结果表明，TREM-1与HMGB1以及炎症细胞受体（RAGE、TLR-4和TLR-2）共同在肥胖诱导的胰岛素抵抗中具有潜在的病理生理作用。
