Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Laboratory of Epigenome Biology, Systems Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Cell. 2024 Feb 15;187(4):914-930.e20. doi: 10.1016/j.cell.2024.01.001. Epub 2024 Jan 26.
The gut and liver are recognized to mutually communicate through the biliary tract, portal vein, and systemic circulation. However, it remains unclear how this gut-liver axis regulates intestinal physiology. Through hepatectomy and transcriptomic and proteomic profiling, we identified pigment epithelium-derived factor (PEDF), a liver-derived soluble Wnt inhibitor, which restrains intestinal stem cell (ISC) hyperproliferation to maintain gut homeostasis by suppressing the Wnt/β-catenin signaling pathway. Furthermore, we found that microbial danger signals resulting from intestinal inflammation can be sensed by the liver, leading to the repression of PEDF production through peroxisome proliferator-activated receptor-α (PPARα). This repression liberates ISC proliferation to accelerate tissue repair in the gut. Additionally, treating mice with fenofibrate, a clinical PPARα agonist used for hypolipidemia, enhances colitis susceptibility due to PEDF activity. Therefore, we have identified a distinct role for PEDF in calibrating ISC expansion for intestinal homeostasis through reciprocal interactions between the gut and liver.
肠道和肝脏被认为通过胆管、门静脉和体循环相互交流。然而，目前尚不清楚这个肠道-肝脏轴如何调节肠道生理学。通过肝切除术和转录组学及蛋白质组学分析，我们鉴定出一种来源于肝脏的可溶性 Wnt 抑制剂——色素上皮衍生因子（PEDF），它通过抑制 Wnt/β-连环蛋白信号通路来抑制肠干细胞（ISC）的过度增殖，从而维持肠道内稳态。此外，我们发现肠道炎症产生的微生物危险信号可以被肝脏感知，导致 PEDF 产生受到过氧化物酶体增殖物激活受体-α（PPARα）的抑制。这种抑制作用释放了 ISC 的增殖，从而加速肠道组织修复。此外，用临床用于降血脂的过氧化物酶体增殖物激活受体-α 激动剂——非诺贝特治疗小鼠会由于 PEDF 活性而增加结肠炎易感性。因此，我们已经确定 PEDF 在通过肠道和肝脏的相互作用来调节 ISC 扩张以维持肠道内稳态方面发挥了独特的作用。
