CRP通过抑制AMPK信号促进代谢综合征发生与发展机制研究

Inflammatory factor CRP is involved in the pathogenesis of a variety of inflammatory diseases, such as atherosclerosis and metabolic syndrome. Whether CRP a marker indicating the the existence of inflammation or a maker participating in the inflammatory process is still inconclusive. Chronic low inflammation exists in the body of metabolic syndrome (MS) and insulin resistance (IR) is recognized as the basis and central link that leads to the occurrence of MS. Studies indicate that CRP could promote the development of MS by acting on IR. However, the exact mechanism is not yet clear. Adenosine-activated protein kinase (AMPK) is an important protein kinase, involving in a variety of metabolic pathways, can improve IR to delay the occurrence and progress of MS. The role of CRP on AMPK has not yet fully studied. Our previous study found that SD rats expressing human CRP showed obesity, high blood pressure and high blood glucose. Does CRP promote the development and progression of MS by inhibiting AMPK activity? In this study, we use to SD rats expressing human CRP as a model to observe the role of CRP in the development of MS. Combined with in vitro experiments, to elucidate whether CRP could promote the progress of MS by inhibiting AMPK and increasing IR. This study will add new evidence to the pathogenesis of MS and provide new ideas for clinical prevention and treatment of inflammatory diseases.

炎症因子CRP参与了多种炎症性疾病的发病过程，如动脉粥样硬化、代谢综合征等。CRP究竟只是提示炎症存在的“Marker”还是参与炎症进程的“Maker”，目前仍无定论。代谢综合征（MS）机体内存在慢性低度炎症，胰岛素抵抗（IR）是公认的导致MS发生的基础和中心环节。CRP可以通过作用于IR影响MS的发展过程，其确切机制尚未明了。腺苷酸活化蛋白激酶（AMPK）是一种重要的蛋白激酶，参与多种代谢途径，可以改善IR从而延缓MS的发生及进展。然而CRP对AMPK的作用如何，目前尚未完全研究清楚。我们的前期实验发现，SD大鼠体内过表达人类CRP后，大鼠表现为肥胖、高血压及高血糖。本研究拟以过表达人类CRP大鼠为模型，观察CRP高表达在MS发生发展中的作用，结合离体实验，明确CRP是否通过抑制AMPK，加重IR，从而促进MS进展。本研究将为阐明MS的发病机制增添新证据，为炎症性疾病的临床防治提供新思路

炎症因子CRP参与多种炎症性疾病的发病过程，代谢综合征（MS）机体内存在慢性低度炎症。胰岛素抵抗（IR）是MS发生的中心环节，腺苷酸活化蛋白激酶（AMPK）可以改善IR从而延缓MS的发生及进展。然而CRP对AMPK的作用如何，目前尚未完全研究清楚。在体研究发现SD大鼠过表达人类CRP后体重、收缩压、血糖、甘油三酯、总胆固醇等代谢综合征相关指标均明显升高；过表达人类CRP大鼠体内炎症因子IL-6及TNF-α表达水平较对照组明显升高，抗炎因子脂联素较对照组表达下降，下调AMPK通路后，IL-6及TNF-α表达水平较假手术组进一步增高，脂联素表达水平较假手术组进一步降低，而上调AMPK通路后，IL-6及TNF-α表达水平较假手术组降低，脂联素表达水平较假手术组升高；SD大鼠过表达人类CRP后，AMPK通路相关因子p-AMPK、p-ACC表达降低，且其上游因子LKB1表达降低，提示CRP可能通过抑制LKB1从而抑制AMPK通路活性加重MS的发生及进展。体外研究发现CRP干预细胞后，细胞上清中血糖水平升高，细胞内脂质相关合成因子SCRBP-1、FAS等表达增加，细胞内炎症因子IL-6及TNF-α表达升高，AMPK通路相关因子LKB1、p-AMPK、p-ACC表达降低；使用AICAR激活AMPK通路后，细胞上清中血糖水平降低，细胞内脂质相关合成因子SCRBP-1、FAS等表达减少，细胞内炎症因子IL-6及TNF-α表达降低，AMPK通路相关因子p-AMPK、p-ACC表达升高；进一步证实CRP通过抑制AMPK上游因子LKB1从而抑制AMPK信号通路，并因此加重MS的发生及进展。