一种全新的高尔基体胆固醇感应蛋白的鉴定和功能研究

将营养物质的识别、储存和利用与适应性反应的有机结合，限制过量营养物质及代谢中间产物对细胞的损害，不但是最基本的生命需求，对于治疗由营养过剩导致的慢性代谢类疾病以及慢性疾病对特定病原微生物的易感性亦至关重要。本团队前期研究发现了一个全新的、定位于高尔基体上的胆固醇感受器-高尔基体糖蛋白73(GP73)，该分子不但可以与胆固醇结合，其表达水平亦受胆固醇水平的调控。有意思的是，GP73肝脏长期高表达诱发肝脏脂类累积、肝功异常以及糖耐量异常。在此基础上，我们将进一步研究GP73作为胆固醇感受器的分子基础，阐明其调控营养过剩诱发适应性反应的分子机制，揭示其肝脏长期高表达对糖脂代谢紊乱的影响，为针对胆固醇稳态途径的药物开发提供潜在的可能靶点。

Cholesterol homeostasis is vital for proper cellular and systemic functions. Disturbed cholesterol balance underlies not only cardiovascular disease, but also an increasing number of other diseases such as neurodegenerative diseases and cancers. Metabolic adaptations defend cellular, tissue, and systemic homeostasis. Guarding against cholesterol toxicity is necessary to sustain metabolism, however, factors mediating this adaptation are not well understood. Our previous study identified GP73 as a potential candidate involved in adaptive response. By sequence alignment, we found GP73 harbors cholesterol recognition amino acid consensus (CRAC and CARC) domains, particularly interesting to us is excess cholesterol upregulated GP73 expression. Notably, Liver-GP73-high mice developed significantly enlarged liver with visibly yellow appearance, increased liver weight, massive lipid accumulation with indications of hepatocyte ballooning and damage as compared with control mice. Simultaneously, Liver-GP73-high mice also displayed abnormal hepatic function, higher fasting glucose level and severe glucose intolerances. Here in this study, we would like to make a deeper investigation on the function of GP73 in adaptive response defending against cholesterol accumulation as a Golgi cholesterol sensor. Therefore, pharmacological manipulation of GP73 might lead to a new, powerful unifying therapeutic avenue for mitigating the toxic effects of excess cholesterol to treat a multitude of human diseases.