Vanin-1活化白色脂肪脂质水解的分子机制研究

The lipolysis process in mammalian white adipose tissues contributes importantly to the lipid homeostasis. It has been shown that activation of lipolysis leads to the elevated levels of reactive oxygen species, while antioxidants inhibit lipolysis in human white adipocytes, suggesting a close relationship between oxidative stress and lipolysis. However, how these two processes are integrated remains unknown. In our preliminary study, we found that the expression levels of lipolysis genes and Vanin-1, a pantetheinase and oxidative stress sensor, were positively correlated in human white adipose tissues. Overexpression of Vanin-1 in mouse primary white adipocytes led to reduced phosphorylation levels of nuclear factor FoxO1. In the present study, we will use whole-body Vanin-1 knockout mice and mouse primary white adipocytes as research tools to elucidate the molecular mechanism through which Vanin-1 activates lipolysis via inhibiting FoxO1 phosphorylation. Our study will strengthen current understandings of Vanin-1 biological functions and will provide new evidence for the development of Vanin-1 as a new drug target for the therapy of metabolic diseases.

哺乳动物白色脂肪脂质水解在维持机体脂质动态平衡过程中扮演着重要角色。研究发现，脂质水解活化伴随着活性氧簇含量升高，而抗氧化剂能够抑制人脂肪细胞的脂质水解过程，提示机体氧化应激水平与脂质水解过程之间存在着密切联系。然而，两者之间的分子连接机制尚不清楚。我们在前期研究中发现，机体氧化应激感受器——泛酰巯基乙胺酶Vanin-1与脂质水解基因的表达在人白色脂肪组织中具有正相关性，且Vanin-1在小鼠原代脂肪细胞中过表达导致核因子FoxO1磷酸化水平下降。在本项目中，我们拟利用Vanin-1全身性敲除小鼠模型和小鼠原代脂肪细胞作为研究工具，结合多种生物学方法，阐明Vanin-1通过抑制FoxO1磷酸化，活化白色脂肪脂质水解过程的分子机制。本项目将进一步加深人们对Vanin-1生物学功能的认识，丰富现有白色脂肪脂质水解调控理论，并且为开发其成为可能的代谢性疾病治疗药物靶点提供全新的理论依据。

哺乳动物白色脂肪脂质水解在维持机体脂质动态平衡过程中扮演着重要角色。研究发现，脂质水解活化伴随着活性氧簇含量升高，而抗氧化剂能够抑制人脂肪细胞的脂质水解过程，提示机体氧化应激水平与脂质水解过程之间存在着密切联系。然而，两者之间的分子连接机制尚不清楚。我们的研究发现机体氧化应激感受器——泛酰巯基乙胺酶Vanin-1与脂质水解基因ATGL和HSL的表达水平在人和小鼠腹部白色脂肪组织中呈正相关性。更重要的是，Vanin-1全身性敲除小鼠白色脂肪细胞脂质水解能力明显受损，导致该细胞内脂质异常堆积。为了特异性地调控白色脂肪Vanin-1的表达，我们基于脂肪组织血管特有的高通透性和滞留效应，利用壳聚糖寡聚乳酸及聚乙二醇作为纳米材料载体，协同脂肪靶向肽P3，实现了Vanin-1 siRNA/mRNA的脂肪精准靶向递送。分子水平上，Vanin-1通过活化PPARγ，进而激活脂肪水解基因ATGL和HSL的转录，实现对白色脂肪脂质水解进程的精细调控，改善糖尿病db/db小鼠的葡萄糖/胰岛素耐受性。综上所述，该研究工作揭示了Vanin-1在调节白色脂肪组织脂质水解和脂肪细胞肥大中的重要作用，并构建了一种有效干预白色脂肪组织中Vanin-1表达的RNA递送系统，为Vanin-1失调引起的代谢性疾病提供新的思路及治疗策略。