N-Acetylglucosaminyltransferase V regulates TGF-β response in hepatic stellate cells and the progression of steatohepatitis

Kamada, Y.; Mori, Takehiko; Matsumoto, Hitoshi; Kiso, Shinichi; Yoshida, Yasuhiko; Shinzaki, Shinichiro; Hiramatsu, Naoki; Ishii, Midori; Moriwaki, Kazuo; Kawada, Norifumi; Takehara, Tetsuo; Miyoshi, Eiji

doi:10.1093/glycob/cws012

Cited by 26 publications

(33 citation statements)

References 25 publications

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“…Some studies indicate that PGs favor the development of hepatic steatosis, NASH and ultimately fibrosis [15][16][17], whilst others provide evidence that PGE 2 suppresses fibrogenesis and NASH progression since COX-2 inhibition potentiates inflammation and experimental liver fibrosis [14,18,19]. Our previous results indicate that constitutive expression of COX-2 in hepatocytes protects against high fat diet-induced steatosis, inflammation, obesity and insulin resistance [20].…”

Section: Introductionmentioning

confidence: 83%

“…ACCEPTED MANUSCRIPT 19 mice. Furthermore, when Wt hepatocytes were co-treated with TGF-β1 and PGE 2, apoptosis was decreased and, conversely, when hCOX-2-Tg hepatocytes were treated with DFU, a COX-2 selective inhibitor; there was an increase in caspase-3 activity and in the Bax/Bcl-x L ratio, indicating the specificity of COX-2-dependent prostaglandins in the modulation of TGF-β1-induced apoptosis.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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Cyclooxygenase-2 expression in hepatocytes attenuates non-alcoholic steatohepatitis and liver fibrosis in mice

Motiño

Agra

Contreras

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Cyclooxygenase-2 (COX-2) is involved in different liver diseases but little is known about the significance of COX-2 in the development and progression of non-alcoholic steatohepatitis (NASH). This study was designed to elucidate the role of COX-2 expression in hepatocytes in the pathogenesis of steatohepatitis and hepatic fibrosis. In the present work, hepatocyte-specific COX-2 transgenic mice (hCOX-2-Tg) and their wild-type (Wt) littermates were either fed methionine-and-choline deficient (MCD) diet to establish an experimental non-alcoholic steatohepatitis (NASH) model or injected with carbon tetrachloride (CCl4) to induce liver fibrosis. In our animal model, hCOX-2-Tg mice fed MCD diet showed lower grades of steatosis, ballooning and inflammation than Wt mice, in part by reduced recruitment and infiltration of hepatic macrophages, with a corresponding decrease in serum levels of pro-inflammatory cytokines. Furthermore, hCOX-2-Tg mice showed a significant attenuation of the MCD diet-induced increase in oxidative stress and hepatic apoptosis observed in Wt mice. Even more, hCOX-2-Tg mice treated with CCl4 had significantly lower stages of fibrosis and less hepatic content of collagen, hydroxyproline and pro-fibrogenic markers than Wt controls. Collectively, our data indicates that constitutive hepatocyte COX-2 expression ameliorates NASH and liver fibrosis development in mice by reducing inflammation, oxidative stress and apoptosis and by modulating activation of hepatic stellate cells, respectively, suggesting a possible protective role for COX-2 induction in NASH/NAFLD progression.

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Section: Introductionmentioning

confidence: 83%

Section: Accepted Manuscriptmentioning

confidence: 99%

Cyclooxygenase-2 expression in hepatocytes attenuates non-alcoholic steatohepatitis and liver fibrosis in mice

Motiño

Agra

Contreras

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…The suppression of lymphocyte infiltration in the GnT-V Tg mouse liver is thought to be due to a shift towards the Th2 response in their T cells. Accordingly, the levels of Th1-cytokines such as interleukin-6, interferon-γ, and tumor necrosis factor α were dramatically suppressed in GnT-V Tg mouse livers (28). Serum alanine aminotransferase levels are also lower in GnT-V Tg mice compared to wild-type mice.…”

Section: The Role Of Gnt-v In the Development Of Steato-hepatitismentioning

confidence: 93%

“…HFHC treatment is one of the best mouse models for NASH because it induces both inflammation and fibrosis in the mouse liver (27). Because the expression of GnT-V was shown to be elevated in chronic hepatitis (17), we gave the GnT-V Tg mice an HFHC diet as a means of understanding the biological effect of up-regulation of GnT-V in the liver (28). When mice were fed a normal chow (NC) diet, the total body weight, liver weight, and liver to body weight ratio were all significantly higher in GnT-V Tg mice compared to wild-type mice.…”

Section: The Role Of Gnt-v In the Development Of Steato-hepatitismentioning

confidence: 99%

“…The phenotypes that we observed in the skin and livers of GnT-V Tg mice could not be detected under normal conditions. It is believed that certain changes in the micro-and macro-environment can lead to the onset of disease, and we and other groups have performed these kinds of experiments using transgenic glyco-gene knockout mice (10,22,28,32,33). In next era of glycobiology research, such experiments will produce mouse models of diseases that involve oligosaccharide remodeling, and tumor induction in GnT-V Tg mice is one of the most promising studies.…”

Section: Closingmentioning

confidence: 99%

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Physiological roles of N-acetylglucosaminyltransferase V (GnT-V) in mice

Miyoshi¹,

Terao²,

Kamada³

2012

BMB Reports

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Inhibition of N‐glycosylation by glucosamine hydrochloride inhibits TGF‐β1‐induced LOXL2 secretion

Kamiya

Kadowaki

Atobe

et al. 2023

J of Cellular Biochemistry

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Kidney fibrosis is closely associated with the progression of chronic kidney disease (CKD). Furthermore, copper‐containing secretory amine oxidases, such as lysyl oxidase (LOX) and LOX‐like 1–4 (LOXL1–4), play pivotal roles in the regulation of extracellular components and facilitate fibrosis. In this study, we investigated the regulation of LOX enzymes in human tubular epithelial HK2 cells to help clarify the role of LOX enzymes in kidney fibrosis. Among 5 LOX enzymes, LOXL2 expression is abundantly expressed in HK2 cells. LOX enzymes inhibitor, β‐aminopropionitrile, suppressed transforming growth factor‐β1 (TGF‐β1)‐promoted epithelial‐to‐mesenchymal transition processes in HK2 cells, indicating that LOX enzymes are involved in TGF‐β1‐mediated fibrotic processes. Recent studies suggest that LOX enzymes are secreted into the extracellular spaces by exosomes and promote fibrotic processes. Similar to the previous reports, we observed that exosomes secreted from HK2 cells carry LOXL2 into the extracellular spaces. Furthermore, we determined that N‐glycosylation on the asparagine residues plays a key role in LOXL2 secretion. Amino acid mutations in three asparagine residues, which can be glycosylated, suppressed the secretion of mutated LOXL2. Moreover, N‐acetylglucosaminyltransferase 5, an enzyme used for the biosynthesis of β1,6N‐acetylglucosamine‐branched N‐glycans, participated in LOXL2 secretion, and the N‐glycosylation inhibitor, glucosamine hydrochloride (GS), inhibited TGF‐β1‐mediated LOXL2 secretion and fibrotic processes. Overall, TGF‐β1 promotes LOXL2 secretion and may participate in kidney fibrosis. Our results provide novel insight into the antifibrotic properties of GS that contribute to the inhibition of CKD progression.

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N-Acetylglucosaminyltransferase V regulates TGF-β response in hepatic stellate cells and the progression of steatohepatitis

Cited by 26 publications

References 25 publications

Cyclooxygenase-2 expression in hepatocytes attenuates non-alcoholic steatohepatitis and liver fibrosis in mice

Cyclooxygenase-2 expression in hepatocytes attenuates non-alcoholic steatohepatitis and liver fibrosis in mice

Physiological roles of N-acetylglucosaminyltransferase V (GnT-V) in mice

Inhibition of N‐glycosylation by glucosamine hydrochloride inhibits TGF‐β1‐induced LOXL2 secretion

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