载脂蛋白AI经sortilin负向调节成脂分化的机制探讨

Adipogenesis plays an important role in human obesity. Recently, increasing evidence suggests that apoAI has anti-obesity effects. Nevertheless, the mechanisms remain unclear. Sorting protein sortilin has been demonstrated recently to play an important role in regulating adipogenesis. Overexpression of sortilin significantly inhibited adipogenesis. Ectopically expressed on the plasma membrane of AMSCs, β-ATPase was confirmed a receptor of apoAI. Recent studies suggested β-ATPase may be involved in regulation of sortilin expression and adipogenesis. Our previous in vitro study showed that apoAI inhibited adipogenesis and increased the expression of sortilin. Besides, our preliminary studies showed that inhibitor of ROCK, the effector of β-ATPase mediated signaling reversed the regulatory effect of apoAI. This study will further confirm the regulatory effect of apoAI on adipogenesis both in vivo and in vitro (human AMSCs), explore whether the regulatory effect of apoAI is mediated through β-ATPase and consequently altered expression of sortilin, and investigate the molecular mechanisms by which apoAI regulate sortilin expression and adipogenesis. This study is expected to help us understand the anti-obesity effect of apoAI and provide a potential new strategy for the prevention and treatment of obesity.

研究前体脂肪细胞分化是防治肥胖的新思路。近期研究提示载脂蛋白AI具有减轻小鼠肥胖的作用，但机制不明。分选蛋白sortilin在成脂分化调节中起关键作用，过表达sortilin显著抑制成脂分化。已知AMSCs细胞膜表达apoAI的受体β-ATPase可能调节sortilin表达及成脂分化。申请人发现：apoAI可抑制成脂分化并明显上调sortilin的表达，且apoAI的作用可被β-ATPase下游效应分子抑制剂逆转。故推测：apoAI与AMSCs细胞膜β-ATPase结合，通过上调sortilin的表达抑制成脂分化。申请人拟在体内、体外进一步验证apoAI抑制AMSCs成脂分化；阐明apoAI通过结合β-ATPase调节sortilin表达进而抑制成脂分化的机制。本项目将开拓对apoAI抗肥胖机制的认识，为肥胖的防治提供新的思路。