PI3K/Akt/FoxO1通路对皮脂腺细胞增殖、分化、皮脂分泌调控机制及其在痤疮发病中作用

Insulin-like growth factor-1 (IGF-1) can induce sebaceous lipogenesis via activation of PI3K/Akt pathway and play a key role in acne pathogenesis. FoxO1 is the important transcription factor of PI3K/Akt pathway, but its role in sebocytes is seldom reported. High dose IGF-1 activated the PI3K/Akt/FoxO1 pathway in SZ95 sebocytes, while low dose IGF-1 had no effect. However, we found that low dose IGF-1 upregulated FoxO1 expression through PI3K/Akt pathway in primary cultured human sebocytes, and over-expressed FoxO1 stimulated the expression of lipogenic factors and secretion of sebaceous lipogenesis, but the regulatory mechanism remains unknown. This project intends to validate the modulation of IGF-1/PI3K/Akt signaling on FoxO1 expression and the interaction between them in primary cultured human sebocytes treated with different doses of IGF-1, overexpression of FoxO1, and silencing of FoxO1 and Akt. Our results may unravel the regulatory mechanism of PI3K/Akt/FoxO1 pathway on proliferation, differentiation, and lipid secretion of human sebocytes and its role in acne pathogenesis.

IGF-1激活PI3K/Akt通路引起皮脂分泌，在痤疮发病中起关键作用。FoxO1是PI3K/Akt通路主要转录因子，但其在皮脂腺细胞（SC）中作用研究很少。大剂量IGF-1激活SZ95细胞中PI3K/Akt/FoxO1通路，而小剂量IGF-1无明显影响。我们发现小剂量IGF-1通过PI3K/Akt通路上调原代培养人SC表达FoxO1，过表达FoxO1增加成脂因子表达及皮脂分泌，但调控机制不明。本项目拟用不同剂量IGF-1刺激原代培养SC，FoxO1过表达及Akt、FoxO1基因沉默等方法验证IGF-1/PI3K/Akt通路对FoxO1调控及其交互作用；研究结果将揭示PI3K/Akt/FoxO1通路对SC增殖、分化、皮脂分泌调控机制及其在痤疮发病中作用。

“IGF-1激活PI3K/Akt通路引起FoxO1核外转移是引起痤疮发病关键机制”的假说，是建立在脂质代谢细胞和癌细胞实验基础上，皮脂腺细胞中缺乏确切证据。本项目在皮脂腺细胞中通过IGF-1/PI3K/Akt通路对FoxO1及其下游成脂基因调控进行研究。研究结果显示：①正常皮肤皮脂腺中，FoxO1主要表达于胞核，痤疮皮脂腺中FoxO1胞核表达减少胞质表达增加，p-FoxO1在痤疮皮损中表达增加；痤疮皮脂腺中p-Akt表达增多，而Akt未见阳性表达；②FoxO1过表达可以下调成脂基因SREBP-1、 PPARγ表达，减少皮脂腺细胞分化，减少皮脂分泌，皮脂腺细胞增殖，p-FoxO1表达增多核外转移；③皮脂腺细胞中IGF-1可以激活PI3K/Akt通路，使FoxO1核内表达减少，核外转移，p-FoxO1表达增多，PPARγ、SREBP-1表达增加，皮脂分泌增加，PI3K抑制剂可以阻滞这一过程，此细胞模型可以作为IGF-1诱导皮脂腺细胞的体外致病模型；④FoxO1在痤疮发病的表皮中影响人KC增殖、分化和凋亡有重要作用。以上研究为的痤疮发病机制提供理论依据。