التفاصيل البيبلوغرافية
| العنوان: |
Myeloid-specific deletion of chitinase-3-like 1 protein ameliorates murine diet-induced steatohepatitis progression |
| المؤلفون: |
Kim, Andrea D, Kui, Lin, Kaufmann, Benedikt, Kim, Sung Eun, Leszczynska, Aleksandra, Feldstein, Ariel E |
| المصدر: |
Journal of Molecular Medicine, vol 101, iss 7 |
| بيانات النشر: |
eScholarship, University of California |
| سنة النشر: |
2023 |
| المجموعة: |
University of California: eScholarship |
| مصطلحات موضوعية: |
Nutrition, Liver Disease, Digestive Diseases, Hepatitis, Chronic Liver Disease and Cirrhosis, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Oral and gastrointestinal, Mice, Humans, Animals, Non-alcoholic Fatty Liver Disease, Chitinases, Interleukin-13 Receptor alpha2 Subunit, Liver, Liver Cirrhosis, Diet, High-Fat, Knockout, Inbred C57BL, Disease Models, Animal, Chitinase-like proteins, Hepatic stellate cells, Infiltrating macrophages, Medicinal and Biomolecular Chemistry, Immunology |
| جغرافية الموضوع: |
813 - 828 |
| الوصف: |
Chitinase-3-like 1 protein (CHI3L1) is a secreted glycoprotein, strongly correlated with fibrosis severity in chronic liver diseases including non-alcoholic steatohepatitis (NASH). However, the mechanisms by which CHI3L1 contributes to fibrogenesis remain undefined. Here, we showed that infiltrating monocyte-derived liver macrophages represent the main source of CHI3L1 in murine NASH. We developed a floxed CHI3L1 knock-out (KO) mouse to further study the cell-specific role of CHI3L1 ablation. Wildtype (WT) and myeloid cell-specific CHI3L1 KO mice (CreLyz) were challenged with a highly inflammatory and fibrotic dietary model of NASH by administering choline-deficient high-fat diet for 10weeks. Macrophage accumulation and inflammatory cell recruitment were significantly ameliorated in the CreLyz group compared to WT (F4/80 IHC p < 0.0001, CD11b IHC p < 0.0001). Additionally, hepatic stellate cell (HSC) activation and fibrosis were strongly decreased in this group (α-SMA IHC p < 0.0001, picrosirius red staining p < 0.0001). In vitro studies were performed stimulating bone marrow derived macrophages, THP-1 (human monocytes) and LX2 (human HSCs) cells with recombinant CHI3L1 to dissect its relationship with fibrosis development. Results showed an important role of CHI3L1 regulating fibrosis-promoting factors by macrophages (TGFB1 p < 0.05, CTGF p < 0.01) while directly activating HSCs (ACTA2 p < 0.01, COL1A1 p < 0.01), involving IL13Rα2 as the potential mediator. Our findings uncovered a novel role of CHI3L1 derived from liver macrophages in NASH progression and identifies this protein as a potential anti-fibrotic therapeutic target. KEY MESSAGES: We showed that CHI3L1 expression is increased in murine CDAA-HFAT diet NASH model, and that infiltrating macrophages are a key source of CHI3L1 production. Myeloid cell-specific CreLyz CHI3L1 knock-out in mice fed with CDAA-HFAT diet improved the NASH phenotype, with significantly reduced accumulation of pro-inflammatory macrophages and neutrophils ... |
| نوع الوثيقة: |
article in journal/newspaper |
| وصف الملف: |
application/pdf |
| اللغة: |
unknown |
| العلاقة: |
qt76f4374g; https://escholarship.org/uc/item/76f4374gTest |
| الإتاحة: |
https://escholarship.org/uc/item/76f4374gTest |
| حقوق: |
CC-BY |
| رقم الانضمام: |
edsbas.4707FDB8 |
| قاعدة البيانات: |
BASE |
