Department of Anorectal Surgery, the Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510799, China.
Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University.
Int J Biol Sci. 2022 Jul 11;18(11):4469-4481. doi: 10.7150/ijbs.72283. eCollection 2022.
Our study is to explore the key molecular of Low-density lipoprotein receptor-related protein 6 (LRP6) and the related Wnt/β-catenin pathway regulated by LRP6 during the intestinal barrier dysfunction. Colorectal protein profile analysis showed that LRP6 expression was decreased in dextran sulfate sodium (DSS)-induced colitis mice, and mice received fecal bacteria transplantation from stroke patients. Mice with intestinal hypoxia and intestinal epithelial cells cultured in hypoxia showed decreased expression of LRP6. Overexpression of LPR6 or its N-terminus rescued the Wnt/β-catenin signaling pathway which was inhibited by hypoxia and endoplasmic reticulum stress. In mice overexpressing of LRP6, the expression of β-catenin and DKK1 increased, Bcl2 decreased, and Bax increased. Mice with LRP6 knockout showed an opposite trend, and the expression of Claudin2, Occludin and ZO-1 decreased. Two drugs, curcumin and auranofin could alleviate intestinal barrier damage in DSS-induced colitis mice by targeting LRP-6. Therefore, gut microbiota dysbiosis and hypoxia can inhibit the LRP6 and Wnt/β-catenin pathway, and drugs targeting LRP6 can protect the intestinal barrier.
我们的研究旨在探索低密度脂蛋白受体相关蛋白 6（LRP6）的关键分子及其相关的 Wnt/β-catenin 通路在肠道屏障功能障碍中的调控作用。结直肠蛋白谱分析显示，LRP6 在葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠和接受中风患者粪便移植的小鼠中表达下调。肠道缺氧的小鼠和在缺氧条件下培养的肠道上皮细胞中 LRP6 的表达减少。LRP6 的过表达或其 N 端可恢复由缺氧和内质网应激抑制的 Wnt/β-catenin 信号通路。在过表达 LRP6 的小鼠中，β-catenin 和 DKK1 的表达增加，Bcl2 减少，Bax 增加。LRP6 敲除的小鼠则表现出相反的趋势，Claudin2、Occludin 和 ZO-1 的表达减少。两种药物，姜黄素和金诺芬，可以通过靶向 LRP-6 来缓解 DSS 诱导的结肠炎小鼠的肠道屏障损伤。因此，肠道微生物失调和缺氧会抑制 LRP6 和 Wnt/β-catenin 通路，而靶向 LRP6 的药物可以保护肠道屏障。
