基于PGC-1α促脂肪线粒体生物发生探讨丹酚酸A对2型糖尿病脂代谢紊乱的调控机制

Lipid metabolism disorder caused by adipocyte mitochondrial dysfunction is an important risk factor for the development and progression of type 2 diabetes mellitus. Studies have shown that salvianolic acid A (SAA) has a good effect on type 2 diabetes mellitus after oral administration. However its mechanism is unclear. Our previous work found that SAA showed a good distribution in adipose tissue and exerted lipid metabolism regulation effect in the treatment of type 2 diabetes mellitus. The effect of SAA was positively correlated with the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Based on these, we hypothesize that SAA can target adipose tissue, enhance the expression of PGC-1α in adipocytes, promote mitochondrial biogenesis, regulate lipid metabolism disorders, improve insulin sensitivity, and exert therapeutic effect of type 2 diabetes mellitus. In order to verify this hypothesis, this study intends to investigate the therapeutic effect of SAA on type 2 diabetes mellitus and the regulation of lipid metabolism based on Kkay mice and 3T3-L1 adipocytes. By establishing the relationship between the amount-response of SAA and the expression level of PGC-1α, combined with gene silencing and overexpression techniques, the role of PGC-1α will be explored. The PGC-1α-Nrf1-Tfam signaling pathway will be targeted to inspect the pharmacological mechanism of SAA. Our results will promote the development process of SAA.

脂肪细胞线粒体功能失调引起的脂质代谢紊乱，是诱发2型糖尿病发生、发展的重要危险因素。研究证明丹酚酸A（SAA）口服对治疗2型糖尿病效果良好，然而其作用机制尚不明确。我们前期工作发现，SAA在治疗2型糖尿病时，呈现良好的脂肪组织分布和脂质代谢调控作用，并且与脂肪细胞内线粒体生物发生核心因子过氧化物酶体增生物激活受体γ共激活因子1α（PGC-1α）的表达量呈正相关，提示：SAA可能靶向脂肪组织，通过提高脂肪细胞内PGC-1α的表达，促进线粒体生物发生，改善脂质代谢紊乱，发挥2型糖尿病治疗作用。围绕该设想，本课题拟以Kkay小鼠和3T3-L1脂肪细胞为研究对象，明确SAA的2型糖尿病治疗作用和脂质代谢调节作用；采用体内外实验，结合基因沉默和过表达技术，探讨PGC-1α在SAA药效发挥中的作用；并以PGC-1α-Nrf1-Tfam为目标信号通路，探究SAA的潜在作用机制，以推动SAA的开发和使用。

丹酚酸A（SAA）口服对治疗2型糖尿病效果良好，然而其作用机制尚不明确，是其开发过程中亟待解决的问题。脂肪细胞线粒体功能失调引起的脂质代谢紊乱，是导致胰岛素抵抗，诱发2型糖尿病发生、发展的重要危险因素。本项目在前期工作的基础上，首先从动物水平和细胞水平两个层面出发，通过测定用药后糖脂代谢相关指标的变化，证实SAA具有2型糖尿病治疗作用，并且与脂质代谢调节相关；同时，从基因、蛋白和形态学的角度证明了SAA具有促进脂肪细胞线粒体生物发生、改善线粒体功能的作用，明确SAA的药理作用与促进脂肪细胞线粒体生物发生密切相关；并且验证了SAA可以靶向脂肪细胞PGC-1α，通过调控PGC-1α-Nrf1-Tfam信号通路，促进线粒体生物发生，调节脂质代谢紊乱，进而发挥2型糖尿病治疗作用。本项目研究成果揭示了SAA治疗2型糖尿病的潜在作用机制，为发现新型的、靶向脂肪组织，具有促进线粒体生物发生、改善脂质代谢紊乱作用的2型糖尿病治疗药物提供理论依据。