CYP1B1通过调控脂代谢抑制肥胖作用的机制研究

The deficiency of CYP1B1 can protect against the high-fat diet (HFD)-induced obesity in mice, however, the mechanism about how the inhibition of CYP1B1 prevents from the obesity and if CYP1B1 can show its effect on the obesity in human remains unclear. The preliminary experiment revealed that the deficiency of CYP1B1 can down-regulate the level of hepatic mRNA of SCD1 and decrease serum lysophosphatidylcholine. Therefore, this study proposes that CYP1B1 might regulate lipid metabolism via SCD1 to protect against obesity. In this study, the transgenic CYP1B1 knockout and CYP1B1-humanized mice models were used to determine the effect of humanized-CYP1B1 on obesity in the human, and the overexpression of virus with SCD1 was used to examine the effect of SCD1 on the anti-obesity by CYP1B1. Using lipidomics technology, the level of lipid will be systematically analyzed. This study will gain insight into the molecular mechanism of the effect of CYP1B1 on lipid metabolism. This study will be helpful to provide the scientific evidences for how the inhibition of CYP1B1 can protect against obesity, and offer some new ideas for the development of the drug to treat obesity in the clinic.

CYP1B1的缺失可以抑制高脂膳食诱导的小鼠肥胖，但CYP1B1抑制肥胖的作用机制尚不明确。本项目申请者的前期研究工作显示，在CYP1B1抑制肥胖时，小鼠肝脏中硬脂酰辅酶A去饱和酶1（SCD1）的水平明显下调，而且血液中溶血磷脂酰胆碱水平显著降低。因此，提出如下假说：CYP1B1可能通过对SCD1的调节来维持体内脂代谢平衡，从而实现抑制肥胖的作用。本项目利用CYP1B1转基因敲除小鼠和人源化的CYP1B1小鼠模型来研究人的CYP1B1是否对肥胖有抑制作用。同时，采用SCD1腺病毒体内过表达模型来评价SCD1在CYP1B1抑制肥胖过程中的作用。该项目也采用脂代谢组学技术研究CYP1B1调节脂代谢的分子机制，明确SCD1在CYP1B1维持体内脂代谢平衡中的关键作用，从而为阐明CYP1B1通过调节脂代谢平衡来抑制肥胖提供科学依据，为开发治疗肥胖的药物提供新思路与新途径。

CYP1B1的缺失可以抑制高脂膳食诱导的小鼠肥胖，但CYP1B1抑制肥胖的作用机制尚不明确。本项目申请者的前期研究工作显示，在CYP1B1抑制肥胖时，小鼠肝脏中硬脂酰辅酶A去饱和酶1（SCD1）的水平明显下调，而且血液中溶血磷脂酰胆碱水平显著降低。因此，提出如下假说：CYP1B1可能通过对SCD1的调节来维持体内脂代谢平衡，从而实现抑制肥胖的作用。本项目利用CYP1B1转基因敲除小鼠和人源化的CYP1B1小鼠模型来研究人的CYP1B1是否对肥胖有抑制作用。同时，采用SCD1腺病毒体内过表达模型来评价SCD1在CYP1B1抑制肥胖过程中的作用。该项目也采用脂代谢组学技术研究CYP1B1调节脂代谢的分子机制，明确SCD1在CYP1B1维持体内脂代谢平衡中的关键作用，从而为阐明CYP1B1通过调节脂代谢平衡来抑制肥胖提供科学依据，为开发治疗肥胖的药物提供新思路与新途径。