C/EBP homologous protein–induced loss of intestinal epithelial stemness contributes to bile duct ligation–induced cholestatic liver injury in mice
| العنوان: | C/EBP homologous protein–induced loss of intestinal epithelial stemness contributes to bile duct ligation–induced cholestatic liver injury in mice |
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| المؤلفون: | Arun J. Sanyal, Phillip B. Hylemon, Bhagyalaxmi Sukka Ganesh, Huiping Zhou, Guanhua Lai, Derrick Zhao, William M. Pandak, Zhiming Huang, Jasmohan S. Bajaj, Xiaojiaoyang Li, Runping Liu |
| المصدر: | Hepatology. 67:1441-1457 |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, medicine.medical_specialty, Pathology, CD14, Cell Culture Techniques, Apoptosis, Inflammation, Biology, Stem cell marker, digestive system, Primary sclerosing cholangitis, Mice, 03 medical and health sciences, Cholestasis, Internal medicine, medicine, Animals, Humans, Intestinal Mucosa, Ligation, Liver injury, Hepatology, Liver Diseases, Stem Cells, Endoplasmic Reticulum Stress, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Liver, Hepatocytes, Unfolded protein response, Female, Bile Ducts, Stem cell, medicine.symptom, Transcription Factor CHOP |
| الوصف: | Impaired intestinal barrier function promotes the progression of various liver diseases including cholestatic liver disease. The close association of primary sclerosing cholangitis (PSC) with inflammatory bowel disease highlights the importance of the gut-liver axis. It has been reported that bile duct ligation (BDL)-induced liver fibrosis is significantly reduced in C/EBP homologous protein knock out (CHOP-/-) mice. However, the underlying mechanisms remain unclear. In the current study, we demonstrate that BDL induces striking and acute hepatic ER stress responses after 1 day, which return to normal after 3 days. No significant hepatocyte apoptosis is detected 7 to 14 days following BDL. However, the inflammatory response is significantly increased after 7 days, which is similar to what we found in human PSC liver samples. BDL-induced loss of stemness in intestinal stem cells (ISCs), disruption of intestinal barrier function, bacterial translocation, activation of hepatic inflammation and M2 macrophage polarization and liver fibrosis are significantly reduced in CHOP-/- mice. In addition, intestinal organoids derived from CHOP-/- mice contain more and longer crypt structures than those from WT mice, which is consistent with the upregulation of stem cell markers (Lgr5, Olfm4 and Sox9) and in vivo findings that CHOP-/- mice have longer villi and crypts as compared to WT mice. Similarly, the mRNA levels of CD14, IL-1β, TNF-α and MCP-1 are increased and stem cell proliferation is suppressed in the duodenum of cirrhotic patients. Conclusion: Activation of ER stress and subsequent loss of stemness of ISCs plays a critical role in BDL-induced systemic inflammation and cholestatic liver injury. Modulation of the ER stress response represents a potential therapeutic strategy for cholestatic liver diseases as well as other inflammatory diseases This article is protected by copyright. All rights reserved. |
| تدمد: | 1527-3350 0270-9139 |
| DOI: | 10.1002/hep.29540 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fe7fd14c4fda23c80f29f9fe0e6676f0 https://doi.org/10.1002/hep.29540 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....fe7fd14c4fda23c80f29f9fe0e6676f0 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15273350 02709139 |
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| DOI: | 10.1002/hep.29540 |