尿毒症毒素通过激活芳香烃受体促进肾脏脂肪酸合成和纤维化
Uremic toxins promote renal fatty acid synthesis and fibrosis via activating aryl hydrocarbon receptor.
摘要(中文译文)
慢性肾脏病(CKD)影响全球约10%的成年人,血脂异常是其常见特征。肾脏脂质代谢异常与CKD进展密切相关;然而,CKD导致脂质代谢紊乱的机制仍研究不足。本研究表明,在尿毒症毒素蓄积后,肾脏中脂质的合成与沉积以及尿毒症毒素受体芳香烃受体(AhR)均上调。在雄性小鼠中,肾小管特异性敲除AhR可减轻尿毒症毒素诱导的肾脏脂肪酸(FA)合成增加、脂质蓄积和纤维化。免疫沉淀-质谱鉴定出核受体亚家族1 D组成员1(NR1D1)为AhR相互作用蛋白。免疫共沉淀证实AhR与NR1D1相互作用并促进其泛素介导的降解。由于NR1D1是脂肪酸合成抑制因子,其减少可解除对固醇调节元件结合蛋白1(SREBP1)的转录抑制作用,从而增强SREBP1/脂肪酸合酶(FASN)通路活性及脂肪酸合成。总之,尿毒症毒素的蓄积可能通过作用于AhR,经SREBP1/FASN通路介导的脂肪酸合成增加而加速肾纤维化。
Abstract
Chronic kidney disease (CKD) affect about 10% of adults worldwide, with dyslipidemia being a common feature. Abnormalities in renal lipid metabolism have been strongly implicated in CKD progression; however, the mechanisms by which CKD leads to lipid metabolism disturbances remain underexplored. Here we show that following the accumulation of uremic toxins, the synthesis and deposition of lipids, along with the uremic toxin receptor aryl hydrocarbon receptor (AhR), are upregulated in the kidneys. Tubule-specific AhR knockout in male mice alleviates uremic toxin-induced increases in renal fatty acid (FA) synthesis, lipid accumulation and fibrosis. Immunoprecipitation‒mass spectrometry identifies nuclear receptor subfamily 1 group D member 1 (NR1D1) as an AhR-interacting protein. Co-immunoprecipitation confirms that AhR interacts with NR1D1 and promotes its ubiquitin-mediated degradation. As NR1D1 is an FA synthesis suppressor, its reduction relieves the transcriptional repressing effects on sterol regulatory element-binding protein 1 (SREBP1), thereby enhancing SREBP1/fatty acid synthase (FASN) pathway activity and FA synthesis. In summary, by acting on AhR, the accumulation of uremic toxins may accelerate renal fibrosis via the SREBP1/FASN pathway-mediated increase in FA synthesis.
如何引用
AMA
Hongyan Xie, Yitao Zhang, Li Lu, Hengjiang Guo, Xi'ang Sun, Ming Ning, et al. Uremic toxins promote renal fatty acid synthesis and fibrosis via activating aryl hydrocarbon receptor.. Nature communications. 2026; doi:10.1038/s41467-026-75114-5.
APA
Hongyan Xie, Yitao Zhang, Li Lu, Hengjiang Guo, Xi'ang Sun, Ming Ning, et al (2026). Uremic toxins promote renal fatty acid synthesis and fibrosis via activating aryl hydrocarbon receptor.. Nature communications. https://doi.org/10.1038/s41467-026-75114-5
GB/T 7714
Hongyan Xie, Yitao Zhang, Li Lu, Hengjiang Guo, Xi'ang Sun, Ming Ning, et al. Uremic toxins promote renal fatty acid synthesis and fibrosis via activating aryl hydrocarbon receptor.[J]. Nature communications, 2026 doi:10.1038/s41467-026-75114-5.
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