PDCD4通过调节内质网应激促进肥胖及相关炎症的作用及机制研究

Obesity，inflammation，and insulin resistance are known as major components of the "common soil" for type II diabetes and cardiovascular diseases including atherosclerosis, so searching and controlling the causal factors of obesity and inflammation is the key step to treat these obesity-associated disease. As a newly accepted tumor suppressor gene, programmed cell death 4 (PDCD4) has been studied a lot in tumor fields, but little is known about its other function. Recent studies indicate that PDCD4 participates in the development of some inflammatory diseases, however, no reports suggest PDCD4 is involved in obesity-associated inflammation. Our preliminary experiments showed that PDCD4 deficiency inhibited adiposity and adipose tissue inflammation of the mice on high-fat diet，the insulin sensitivity was obviously improved on these mice, whereas the exact effects and mechanisms remained to be further studied. In this project, we plan to use immunological and molecular biological techniques, to study the exact effects of PDCD4 on obesity, inflammation and insulin resistance on animal, cellular and clinical levels; Next,we'll explore its underlying mechanisms based on the recent advance which suggest endoplasmic recticulum stress play a causal and curial role in obesity and obesity-associated inflammation. This study aims to propose that PDCD4 is the key gene to promote diet-induced obesity and obesity associated-inflammation, which will provide not only new ideas for functional studies of PDCD4, but also theoretic and experimental basis for treatment of obesity-related diseases.

肥胖、炎症及胰岛素抵抗是II型糖尿病和动脉粥样硬化等心血管疾病发病的"共同土壤"，寻找并控制肥胖及炎症的致病因素是治疗上述肥胖相关疾病的关键。程序性细胞死亡4（PDCD4）作为新抑癌基因在肿瘤领域已有很多研究，但其他功能却所知甚少。有研究提示PDCD4促进某些炎性疾病的发生，但是否参与肥胖相关炎症的病程，尚无报道。预实验中我们发现PDCD4缺失可显著抑制高脂喂养小鼠的肥胖和脂肪组织炎症，并明显改善其对胰岛素的敏感性，然确切效应和机制仍有待探讨。本项目拟利用免疫和分子生物学技术，分别在动物、细胞和临床等不同层面上探讨PDCD4对肥胖、炎症及胰岛素抵抗的确切作用；并基于"内质网应激在肥胖及炎症中关键作用"的新进展，从内质网应激入手探讨其内在机制。该项目旨在揭示PDCD4是导致饮食诱导肥胖及相关炎症的关键基因，不仅为PDCD4的功能研究提供新思路，更为肥胖相关疾病的预防治疗提供理论和实验依据。

肥胖、炎症及其引发的胰岛素抵抗是糖尿病和动脉粥样硬化等心血管疾病发病的“共同土壤”，因此寻找并控制肥胖及炎症的致病因素是治疗肥胖相关疾病的关键。研究显示抑癌基因PDCD4可参与某些炎性疾病的发生发展，但是否参与肥胖及相关炎症的病程，尚无报道。本项目利用细胞和动物模型，采用代谢、免疫和分子生物学等技术探索了PDCD4对肥胖、炎症及胰岛素抵抗的确切效应及内在机制，研究发现并证实：1) PDCD4具有促进饮食诱导肥胖、脂肪肝、炎症及胰岛素抵抗的效应。PDCD4缺失可显著抵抗高脂饮食诱导的小鼠肥胖及脂肪肝形成，改善高脂饮食小鼠的胰岛素敏感性及血糖、血脂的代谢稳态，抑制其脂肪细胞肥大和白色脂肪组织炎症。2) 机制上，能量消耗降低是PDCD4促进饮食诱导肥胖的直接原因。PDCD4缺失可显著增加高脂饮食小鼠的能量消耗，而并不影响其摄食量和运动量。深入研究发现脂质调节因子LXR-α是高脂环境下PDCD4翻译抑制的新靶点。PDCD4通过选择性抑制LXR-α及其下游靶基因的表达上调，干扰白色脂肪组织的脂质代谢稳态并诱导内质网应激，抑制棕色脂肪组织能量消耗相关PGC-1α的表达，进而导致肥胖、炎症及代谢紊乱的发生。在此基础上，本项目拓展研究了PDCD4对脂肪来源干细胞（ADSC）及细胞内应激颗粒的调控作用，并探讨了PDCD4参与肥胖发病的其它相关机制。研究发现：1) PDCD4通过抑制AKT通路活化而限制ADSC增殖及乳酸产生，进而抑制ADSC向米色脂肪细胞的转分化。由此，PDCD4可阻碍高脂饮食小鼠的白色脂肪米色化并促进饮食诱导肥胖的发生。2) PDCD4是高脂诱导细胞内应激颗粒的关键组分，通过其RNA结合区参与应激颗粒的装配，并通过AKT-eIF2α轴调节应激颗粒的形成，指出PDCD4可作为肥胖相关应激反应的干预靶点。总之，本项目从不同角度揭示了PDCD4作为促进饮食诱导肥胖及相关代谢紊乱的关键分子，有望成为治疗肥胖及相关疾病的潜在新靶点。相关研究成果不仅是对PDCD4功能和肥胖发生机制的全新阐述和补充丰富，更为肥胖相关疾病的预防和治疗提供理论和实验依据。