PXR介导哺乳期倒千里光碱暴露致成年子代脂肪肝的编程机制

肝毒性中药单体吡咯里西啶生物碱（PAs）可通过乳汁排泄引起婴幼儿暴露。我们近期发现，哺乳期母鼠暴露于一种常见PA—倒千里光碱（RTS）可致子代成年脂肪肝，同时创新性发现RTS原型药物可激活孕烷X受体（PXR）。文献报道PXR激活可增加脂肪酸摄取和/或减少其氧化代谢引起脂肪肝；另脂肪酸代谢产物可调控表遗传修饰酶。据此我们提出，哺乳期RTS暴露可通过激活子代肝PXR，增加脂肪酸摄取/抑制β-氧化途径，脂肪酸氧化中间产物丁酰CoA减少，解除对组蛋白乙酰化酶GCN5/PCAF的阻遏，使PXR的H3K9乙酰化水平增加，PXR持续激活至成年并最终引起成年脂肪肝。本项目拟在整体动物、细胞水平并利用基因敲除鼠确证PXR介导哺乳期RTS暴露所致成年子代脂肪肝发生的编程机制。本项目对于加深对PAs远期毒性效应的认识，阐明PAs所致成年子代脂肪肝的发生机制以及探寻可能的防治靶点，均具有重要意义。

The monomer ingredient of hepatotoxic herbal medicine, pyrrolizidine alkaloids (PAs), may cause toxicity in infants through breast milk and milk products. Our preliminary experiment showed that lactating rats exposed to a common PA-retrorsine (RTS) could cause fatty liver in adulthood offspring. Previous studies have focused on the toxicity of PA metabolites, while our novel finding indicated that the parent drug of RTS is an agonist of the pregnane X receptor (PXR). It has been reported that PXR activation is associated with fatty liver development, resulting in increased fatty acid intake and reduced oxidative metabolism. In addition, metabolites of fatty acid can regulate enzymes involved in epigenetic modification. We propose that RTS exposure during lactation can activate PXR, which increases fatty acid intake and inhibits fatty acid β-oxidation. The reduction of butyryl CoA, an intermediate of fatty acid oxidation, may relieve the repression of histone acetylase GCN5/PCAF, increasing acetylation of H3K9 of PXR and continuing PXR expression in adulthood, and eventually results in fatty liver. This project is intended to demonstrate PXR-mediated programming of fatty liver in offspring exposed to RTS during lactation. The implementation of this project is of great significance for deepening the understanding of the long-term effects of PAs toxicity, clarifying the programming mechanism of fatty liver in the offspring caused by PAs exposure during lactation, and exploring the potential prevention and treatment target.