Aortic carboxypeptidase–like protein, a WNT ligand, exacerbates nonalcoholic steatohepatitis

Teratani, Toshiaki; Tomita, Kengo; Suzuki, Takahiro; Furuhashi, Hirotaka; Irie, Rie; Nishikawa, Makoto; Yamamoto, Junji; Hibi, Toshifumi; Miura, Soichiro; Minamino, Tohru; Oike, Yuichi; Hokari, Ryota; Kanai, Takanori

doi:10.1172/jci92863

Cited by 39 publications

(54 citation statements)

References 45 publications

(63 reference statements)

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“…C57BL/6 ES cells with homologous recombination were selected as previously described and injected into BALB/c‐derived blastocysts to obtain chimeric mice. Crosses between these chimeric mice and C57BL/6 J mice were carried out to obtain the F1 generation with germline transmission as previously described and further bred to generate C57BL/6 J‐background Chi3l1 −/− mice as noted in a previous study …”

Section: Methodsmentioning

confidence: 99%

“…Hematoxylin–eosin (HE) and Masson‐trichrome staining were undertaken using paraffin‐embedded liver sections as previously described . For immunohistochemistry, the specimens were deparaffinized, autoclaved in 10 mM citric acid solution (pH 6.0), incubated in a 3% hydrogen peroxide solution, and blocked using Blocking I (Nacalai Tesque, Kyoto, Japan), as previously described . The sections were incubated with primary antibody at 4°C for 16 h, washed with phosphate‐buffered saline, and then incubated with peroxidase‐labeled secondary antibody at room temperature for 30 min.…”

Section: Methodsmentioning

confidence: 99%

“…For immunofluorescence double staining, the sections were reacted with fluorescently labeled secondary antibodies at room temperature for 2 h. Fluorescently stained specimens were observed using a confocal laser scanning microscope (A1R+; Nikon, Tokyo, Japan). Positively immunostained cells in more than 10 high‐power fields (magnification, ×200) were counted and analyzed using ImageJ (NIH) as previously described …”

Section: Methodsmentioning

confidence: 99%

“…The mRNA was isolated and purified from liver tissues using an RNeasy Mini Kit (Qiagen, Dusseldorf, Germany). Reverse transcription was carried out with a High‐Capacity cDNA Reverse Transcription Kit (Thermo Fisher Scientific), and real‐time polymerase chain reaction amplification was undertaken using a Thermal Cycler Dice Real Time System (Takara Bio), as previously described …”

Section: Methodsmentioning

confidence: 99%

“…14 For immunohistochemistry, the specimens were deparaffinized, autoclaved in 10 mM citric acid solution (pH 6.0), incubated in a 3% hydrogen peroxide solution, and blocked using Blocking I (Nacalai Tesque, Kyoto, Japan), as previously described. 14 The sections were incubated with primary antibody at 4°C for 16 h, washed with phosphate-buffered saline, and then incubated with peroxidase-labeled secondary antibody at room temperature for 30 min. After color development using 3,3′-diaminobenzidine-4HCl, counterstaining was undertaken with Mayer's hematoxylin solution (FUJIFILM Wako Chemicals).…”

Section: +B:histology and Immunohistochemistrymentioning

confidence: 99%

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Chitinase 3‐like 1 deficiency ameliorates liver fibrosis by promoting hepatic macrophage apoptosis

Higashiyama

Tomita

Sugihara

et al. 2019

Hepatology Research

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Aim Chitinase 3‐like 1 (CHI3L1), an 18‐glycosyl hydrolase‐related molecule, is a member of the enzymatically inactive chitinase‐like protein family. Serum levels of CHI3L1 are strongly correlated with hepatic fibrosis progression during many liver diseases. Therefore, this protein could be involved in the development of hepatic fibrosis pathology; however, its role has not been elucidated. We aimed to elucidate its role in the pathophysiology of liver fibrosis. Methods Chitinase 3‐like 1‐deficient (Chi3l1−/−) mice were given carbon tetrachloride twice per week for 4 weeks or fed a methionine choline‐deficient diet for 12 weeks to generate mouse liver fibrosis models. Human fibrotic liver tissues were also examined immunohistochemically. Results In human and mouse fibrotic livers, CHI3L1 expression was mainly localized to hepatic macrophages, and the intrahepatic accumulation of CHI3L1+ macrophages was significantly enhanced compared to that in control livers. In the two mouse models, hepatic fibrosis was significantly ameliorated in Chi3l1−/− mice compared to that in wild‐type mice, which was dependent on hepatic macrophages. The accumulation and activation of hepatic macrophages was also significantly suppressed in Chi3l1−/− mice compared to that in wild‐type mice. Furthermore, apoptotic hepatic macrophages were significantly increased in Chi3l1−/− mice. Chitinase 3‐like 1 was found to inhibit hepatic macrophage apoptosis by suppressing Fas expression and activating Akt signaling in an autocrine manner, which resulted in hepatic macrophage accumulation and activation, exaggerating liver fibrosis. Conclusions Chitinase 3‐like 1 exacerbates liver fibrosis progression by suppressing apoptosis in hepatic macrophages. Therefore, this might be a potential therapeutic target for the treatment of liver fibrosis.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: +B:histology and Immunohistochemistrymentioning

confidence: 99%

See 3 more Smart Citations

Chitinase 3‐like 1 deficiency ameliorates liver fibrosis by promoting hepatic macrophage apoptosis

Higashiyama

Tomita

Sugihara

et al. 2019

Hepatology Research

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Wnt signaling pathway: A comprehensive review

Hayat

Manzoor

Hussain

2022

Cell Biology International

153

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Wnt signaling is an evolutionary cell‐to‐cell coordination mechanism and it is highly critical for a variety of physiological processes of an organism's body, including stem cell regeneration, proliferation, division, migration, polarity of a cell, determining fate of the cell and specification of neural crest, neural symmetry and morphogenesis. Wnts are extracellular secreted glycol proteins, consisted of a family of 19 human proteins that represent the complex nature of the regulatory structure and physiological efficiency of signaling. Moreover, a Wnt/β‐catenin‐dependent pathway and the β‐catenin‐independent pathway that is further classified into the Planar Cell Polarity and Wnt/Ca2+ pathways have been established as key signaling nodes downstream of the frizzled (Fz/Fzd) receptor, and these nodes are extensively analyzed at biochemical and molecular levels. Genetic and epigenetic activities that ultimately characterize the pathway and its subsequent responses contribute to Wnt‐β‐catenin signaling pathway hypo or hyper‐activation and is associated with the variety of human disorders progression most significantly cancers. Recognizing how this mechanism operates is crucial to the advancement of cancer prevention therapies or regenerative medicine methods.

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Lipoprotein Lipase Up‐regulation in Hepatic Stellate Cells Exacerbates Liver Fibrosis in Nonalcoholic Steatohepatitis in Mice

et al. 2019

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Lipoprotein lipase (LPL) plays a central role in incorporating plasma lipids into tissues and regulates lipid metabolism and energy balance in the human body. Conversely, LPL expression is almost absent in normal adult livers. Therefore, its physiological role in the liver remains unknown. We aimed to elucidate the role of LPL in the pathophysiology of nonalcoholic steatohepatitis (NASH), a hepatic manifestation of obesity. Hepatic stellate cell (HSC)–specific LPL‐knockout (LplHSC‐KO) mice, LPL‐floxed (Lplfl/fl) mice, or double‐mutant toll‐like receptor 4–deficient (Tlr4−/−) LplHSC‐KO mice were fed a high‐fat/high‐cholesterol diet for 4 weeks to establish the nonalcoholic fatty liver model or an high‐fat/high‐cholesterol diet for 24 weeks to establish the NASH model. Human samples, derived from patients with nonalcoholic fatty liver disease, were also examined. In human and mouse NASH livers, serum obesity‐related factors, such as free fatty acid, leptin, and interleukin‐6, dramatically increased the expression of LPL, specifically in HSCs through signal transducer and activator of transcription 3 signaling, as opposed to that in hepatocytes or hepatic macrophages. In the NASH mouse model, liver fibrosis was significantly reduced in LplHSC‐KO mice compared with that in Lplfl/fl mice. Nonenzymatic LPL‐mediated cholesterol uptake from serum lipoproteins enhanced the accumulation of free cholesterol in HSCs, which amplified TLR4 signaling, resulting in the activation of HSCs and progression of hepatic fibrosis in NASH. Conclusion: The present study reveals the pathophysiological role of LPL in the liver, and furthermore, clarifies the pathophysiology in which obesity, as a background factor, exacerbates NASH. The LPL‐mediated HSC activation pathway could be a promising therapeutic target for treating liver fibrosis in NASH.

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Aortic carboxypeptidase–like protein, a WNT ligand, exacerbates nonalcoholic steatohepatitis

Cited by 39 publications

References 45 publications

Chitinase 3‐like 1 deficiency ameliorates liver fibrosis by promoting hepatic macrophage apoptosis

Chitinase 3‐like 1 deficiency ameliorates liver fibrosis by promoting hepatic macrophage apoptosis

Wnt signaling pathway: A comprehensive review

Lipoprotein Lipase Up‐regulation in Hepatic Stellate Cells Exacerbates Liver Fibrosis in Nonalcoholic Steatohepatitis in Mice

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