CHI3L1 in the pathophysiology and diagnosis of liver diseases

Wang, Shuwei; Hu, Ming‐Liang; Qian, Yun-Song; Jiang, Zhibing; Song, Lili; Fu, Liyun; Hu, Yaoren

doi:10.1016/j.biopha.2020.110680

Cited by 32 publications

(28 citation statements)

References 63 publications

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“…The copyright holder for this preprint (which this version posted April 9, 2021. ; https://doi.org/10.1101/2021.04.08.439034 doi: bioRxiv preprint Chi3l1 is upregulated and plays a critical role in AILI. Although elevated serum levels of Chi3l1 has been observed in chronic liver diseases, [13,[17][18][19] modulations of Chi3l1 levels during acute liver injury have not been reported. Our data demonstrated, for the first time, that compared with healthy individuals, patients with AILI displayed higher levels of Chi3l1 in the liver and serum (Figures 1A, B).…”

Section: Resultsmentioning

confidence: 97%

“…The elevation of serum levels of Chi3l1 has been observed in various liver diseases, [13,[17][18][19] but studies of its involvement in liver diseases have only begun to emerge. There are several reports describing a role of Chi3l1 in models of chronic liver injuries caused by alcohol, CCl4 or .…”

Section: Discussionmentioning

confidence: 99%

“…[16] Elevated serum levels of Chi3l1 have been observed in various liver diseases, such as hepatic fibrosis, non-alcoholic fatty liver, alcoholic liver disease, and hepatocellular carcinoma. [13,[17][18][19] However, the biological function of Chi3l1 in liver disease is not clear.…”

Section: Introductionmentioning

confidence: 99%

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Chitinase 3-like-1 Contributes to Acetaminophen-induced Liver Injury by Promoting Hepatic Platelet Recruitment

Shan

Atkins

et al. 2021

Preprint

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Hepatic platelet accumulation contributes to acetaminophen (APAP)-induced liver injury (AILI). However, little is known about the molecular pathways involved in platelet recruitment to the liver and whether targeting such pathways could attenuate AILI. The present study unveiled a critical role of chitinase 3-like-1 (Chi3l1) in hepatic platelet recruitment during AILI. Increased Chi3l1 and platelets in the liver were observed in patients and mice overdosed with APAP. Compared to wild-type (WT) mice, Chi3l1-/- mice developed attenuated AILI with markedly reduced hepatic platelet accumulation. Mechanistic studies revealed that Chi3l1 signaled through CD44 on macrophages to induce podoplanin expression, which mediated platelet recruitment through C-type lectin-like receptor 2. Moreover, APAP treatment of CD44-/- mice resulted in much lower numbers of hepatic platelets and liver injury than WT mice, a phenotype similar to that in Chi3l1-/- mice. Recombinant Chi3l1 could restore hepatic platelet accumulation and AILI in Chi3l1-/- mice, but not in CD44-/- mice. Importantly, we generated anti-Chi3l1 monoclonal antibodies and demonstrated that they could effectively inhibit hepatic platelet accumulation and AILI. Overall, we uncovered the Chi3l1/CD44 axis as a critical pathway mediating APAP-induced hepatic platelet recruitment and tissue injury. We demonstrated the feasibility and potential of targeting Chi3l1 to treat AILI.

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Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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Chitinase 3-like-1 Contributes to Acetaminophen-induced Liver Injury by Promoting Hepatic Platelet Recruitment

Shan

Atkins

et al. 2021

Preprint

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“…Some functions of CHI3L1 are the regulation of cell proliferation, differentiation, apoptosis, and cancer metastasis. It is also related to in ammation and infection [62]. Many studies reported that CHI3L1 is a useful liver brosis marker in NAFLD and hepatitis B virus infection [63,64,62].…”

Section: Discussionmentioning

confidence: 99%

“…It is also related to in ammation and infection [62]. Many studies reported that CHI3L1 is a useful liver brosis marker in NAFLD and hepatitis B virus infection [63,64,62]. Liver brosis may be produced by accumulation and activation of liver macrophages [65].…”

Section: Discussionmentioning

confidence: 99%

Identification of Shared Gene Signatures in Different Stages of Non-Alcoholic Fatty Liver Disease Using Integrated Microarray Dataset

Gh¹,

Arabfard²

2020

Preprint

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Purpose: Non-alcoholic fatty liver disease (NAFLD) is the most preventable type of chronic liver disease worldwide and a risk factor for developing cirrhosis or hepatocellular carcinoma (HCC) if untreated. Although experts have performed lots of efforts to find the underlying mechanisms of NAFLD, it remains a challenge to recognize them. The aim of this study is to distinguish common gene signature and pathways in the human liver during NAFLD progression through the systems biology method.Methods: In this study, the three microarray datasets, GSE48452, GSE63067 and GSE89632, were selected from the NCBI GEO database to explore differentially expressed genes (DEGs) among healthy controls, simple steatosis and non-alcoholic steatohepatitis (NASH) patients. Furthermore, protein-protein interaction (PPI) networks and pathway enrichment analysis were used to detect common genes and biological pathways in different stages of NAFLD.Results: The current study was included 47 healthy subjects, 36 patients with simple steatosis and 46 NASH patients. Common high degree genes among all three sets were CHI3L1, GFBP2, NRG1, PEG10 and FADS2. The top five genes in the hepatic PPI networks of three datasets were STAT3, JUN, CANX, FN1 and MYC. Signal transduction, immune response, and anti-apoptosis were the most important biological pathways between healthy vs. NASH, while cell communication, signal transduction and immune response were three top biological pathways between healthy vs. simple steatosis. Also, the most eminent biological pathways between NASH vs. simple steatosis were metabolism and energy pathways. Conclusion: The present study represented the unique and shared key genes and pathways between different stages of NAFLD, which may facilitate the understanding of the NAFLD mechanism and identify potential therapeutic targets in this disease.

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Myeloid-specific deletion of chitinase-3-like 1 protein ameliorates murine diet-induced steatohepatitis progression

et al. 2023

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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 10 weeks. 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 compared with WT group. DEG and qPCR analysis of genes in CreLyz CHI3L1 knock-out mouse liver showed the mechanistic role of CHI3L1 in cellular chemotaxis. HSC is directly activated by CHI3L1 via receptor IL13Rα2, leading to upregulation of collagen deposition and pro-fibrotic gene, TIMP-1 and TIMP-2 release in whole liver. Direct stimulation of macrophages with CHI3L1 leads to upregulated expression of HSC-activation factors, suggesting its role in modulating macrophage-HSC crosstalk.

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CHI3L1 in the pathophysiology and diagnosis of liver diseases

Cited by 32 publications

References 63 publications

Chitinase 3-like-1 Contributes to Acetaminophen-induced Liver Injury by Promoting Hepatic Platelet Recruitment

Chitinase 3-like-1 Contributes to Acetaminophen-induced Liver Injury by Promoting Hepatic Platelet Recruitment

Identification of Shared Gene Signatures in Different Stages of Non-Alcoholic Fatty Liver Disease Using Integrated Microarray Dataset

Myeloid-specific deletion of chitinase-3-like 1 protein ameliorates murine diet-induced steatohepatitis progression

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