囊泡转运相关蛋白YIPF6在抗肥胖及胰岛素抵抗中的功能及其分子机制研究

FGF21 is able to decrease body weight, plasma glucose, triglyceride and increase the energy expenditure in the obese mice, thus has attracted considerable interest in the field of obesity. FGF21 was exported by COPII vesicles and secreted out of the cells to exert its function as the endocrine hormone in key metabolic tissues including liver and adipose tissues. Up to today, the regulations on FGF21 secretion inside the cells are not clear. The preliminary data demonstrated that YIPF6, a vesicles trafficking-related protein, could significantly regulate FGF21 secretion. With high-fat diet (HFD) feeding, the mice bearing YIPF6 mutation has much higher plasma FGF21 concentration than that in wild type mice. Moreover, the YIPF6 mutation mice effectively prevented obesity. On this basis, we plan to further examine the anti-obese effects in key metabolic tissues of these mutation mice. The detailed molecular mechanism of YIPF6 regulation on FGF21 secretion on the cellular level will also be determined. Meanwhile, the clinical samples will be used to examine the link between YIPF6 expression and obesity. This study will shed new light on the strategy of anti-obesity based on FGF21. It also provides strong theoretical basis for the drug development of anti-obesity based on YIPF6.

成纤维细胞生长因子21 （FGF21）能够降低肥胖小鼠的体重、血糖、血脂并增强其能量消耗，是当前肥胖领域研究的热点。FGF21通过COPII囊泡转运并分泌到胞外以内分泌激素形式作用于肝脏、脂肪等代谢关键组织。迄今，FGF21在细胞内的分泌调控仍不清楚。初步研究显示细胞内囊泡转运相关蛋白YIPF6能够显著地调控FGF21的分泌。高脂食物喂养的YIPF6突变小鼠血清中FGF21的浓度远远高于野生型小鼠血清中的浓度，且该小鼠有效地阻止了肥胖的发生。在此基础上，拟进一步在代谢关键组织中系统考察YIPF6突变小鼠抵抗肥胖的效应；并在细胞水平深入研究YIPF6影响FGF21分泌的分子机制；同时将结合临床样本确定YIPF6表达水平与肥胖的临床相关性，为揭示肥胖发病机制提供新的线索。本项目将为开发基于FGF21的抗肥胖治疗策略提供新的思路，也为基于YIPF6的抗肥胖新型药物研发提供重要的理论基础。

成纤维细胞生长因子21（FGF21）是一种内分泌激素，可调节葡萄糖代谢，脂质代谢和能量稳态，但FGF21的运输和分泌的调控机制尚不明确。我们发现，高脂饮食（HFD）喂养的具有Yipf6基因（KLZ）突变的小鼠与野生型小鼠相比能够抵抗HFD诱导的代谢综合征，表现为脂解作用增强，棕色脂肪组织中能量消耗的增加，产热增多以及体温的升高。与野生型小鼠相比，高脂饮食喂养的KLZ小鼠血浆FGF21水平更高，但肝细胞特异性缺失FGF21的KLZ小鼠不再能抵御饮食诱导的肥胖，证实肝细胞分泌的FGF21是保护小鼠免于肥胖的重要因子。通过对FGF21分泌的机制研究，我们发现YIPF6能够在内质网腔中与FGF21结合，在细胞质中与COPII外壳蛋白的核心成分SEC23A结合，在肥胖发展过程中将FGF21包装入COPII囊泡中，以限制其分泌。在非酒精性脂肪肝疾病（NAFLD）患者的临床样本中肝脏YIPF6蛋白的水平与脂肪变性相关，与血清中的FGF21水平呈负相关。因此，YIPF6是肥胖症发展过程中新发现的FGF21分泌调节剂，可能成为肥胖症和NAFLD的治疗靶标。