Lee Sang-Hee, Moon Sung-Je, Woo Seung Hee, Ahn Gwangsook, Kim Won Kon, Lee Chul-Ho, Hwang Jung Hwan
Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseoung-gu, Daejeon, 34141, Korea.
Department of Biology, Daejeon University, 62 Daehak-ro, Dong-gu, Daejeon, 34520, Korea.
Cell Biosci. 2023 Jun 27;13(1):116. doi: 10.1186/s13578-023-01065-9.
Hepatic liver disease, including primary sclerosing cholangitis (PSC), is a serious extraintestinal manifestations of colonic inflammation. Cyclic adenosine monophosphate (cAMP)-responsive element-binding protein H (CrebH) is a transcription factor expressed mostly in the liver and small intestine. However, CrebH's roles in the gut-liver axis remain unknown.
Inflammatory bowel disease (IBD) and PSC disease models were established in wild-type and CrebH mice treated with dextran sulfate sodium, dinitrobenzene sulfonic acid, and diethoxycarbonyl dihydrocollidine diet, respectively. RNA sequencing were conducted to investigate differential gene expression. Exosomes were isolated from plasma and culture media. miRNA expression profiling was performed using the NanoString nCounter Mouse miRNA Panel. Effects of miR-29a-3p on adhesion molecule expression were investigated in bEnd.3 brain endothelial cells.
CrebH mice exhibited accelerated liver injury without substantial differences in the gut after administration of dextran sulfate sodium (DSS), and had similar features to PSC, including enlarged bile ducts, enhanced inflammation, and aberrant MAdCAM-1 expression. Furthermore, RNA-sequencing analysis showed that differentially expressed genes in the liver of CrebH mice after DSS overlapped significantly with genes changed in PSC-liver. Analysis of plasma exosome miRNA isolated from WT and CrebH mice indicates that CrebH can contribute to the exosomal miRNA profile. We also identified miR-29a-3p as an effective mediator for MAdCAM-1 expression. Administration of plasma exosome from CrebH mice led to prominent inflammatory signals in the liver of WT mice with inflammatory bowel disease (IBD).
CrebH deficiency led to increased susceptibility to IBD-induced liver diseases via enhanced expression of adhesion molecules and concomitant infiltration of T lymphocytes. Exosomes can contribute to the progression of IBD-induced liver injury in CrebH mice. These study provide novel insights into the role of CrebH in IBD-induced liver injury.
肝脏疾病，包括原发性硬化性胆管炎（PSC），是结肠炎症的严重肠外表现。环磷酸腺苷（cAMP）反应元件结合蛋白H（CrebH）是一种主要在肝脏和小肠中表达的转录因子。然而，CrebH在肠-肝轴中的作用尚不清楚。
分别用硫酸葡聚糖钠、二硝基苯磺酸和二乙氧基羰基二氢可力丁饮食处理野生型和CrebH小鼠，建立炎症性肠病（IBD）和PSC疾病模型。进行RNA测序以研究差异基因表达。从血浆和培养基中分离外泌体。使用NanoString nCounter小鼠miRNA Panel进行miRNA表达谱分析。在bEnd.3脑内皮细胞中研究miR-29a-3p对黏附分子表达的影响。
给予硫酸葡聚糖钠（DSS）后，CrebH小鼠表现出加速的肝损伤，而肠道无明显差异，且具有与PSC相似的特征，包括胆管扩张、炎症增强和异常的黏膜地址素细胞黏附分子-1（MAdCAM-1）表达。此外，RNA测序分析表明，DSS处理后CrebH小鼠肝脏中差异表达的基因与PSC肝脏中变化的基因有显著重叠。对从野生型和CrebH小鼠分离的血浆外泌体miRNA的分析表明，CrebH可影响外泌体miRNA谱。我们还确定miR-29a-3p是MAdCAM-1表达的有效调节因子。给予CrebH小鼠的血浆外泌体导致患有炎症性肠病（IBD）的野生型小鼠肝脏中出现明显的炎症信号。
CrebH缺陷通过增强黏附分子表达和伴随的T淋巴细胞浸润，导致对IBD诱导的肝脏疾病易感性增加。外泌体可促进CrebH小鼠中IBD诱导的肝损伤进展。这些研究为CrebH在IBD诱导的肝损伤中的作用提供了新的见解。
