Increased Urinary Lipocalin-2 Reflects Matrix Metalloproteinase-9 Activity in Chronic Hepatitis C with Hepatic Fibrosis

Kim, Jin Wook; Lee, Sang Hyub; Jeong, Sook Hyang; Kim, Haeryoung; Ahn, Keun Soo; Cho, Jai Young; Yoon, Yoo Seok; Han, Ho Seong

doi:10.1620/tjem.222.319

Cited by 21 publications

(23 citation statements)

References 58 publications

(80 reference statements)

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“…Some inflammatory liver diseases such as chronic hepatitis C infection are characterized by increased urinary excretion of Lcn2 (32) . Unfortunately, the role of Ron receptor as well as pyrin, in hepatitis or other liver inflammatory diseases in humans is not known and needs further characterization.…”

Section: Discussionmentioning

confidence: 99%

Ron receptor-dependent gene regulation of Kupffer cells during endotoxemia

Kulkarni

Stuart

Waltz

2014

Hepatobiliary & Pancreatic Diseases International

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Background We have previously shown that Ron receptor tyrosine kinase signaling in macrophages, including Kupffer cells and alveolar macrophages, suppresses endotoxin-induced proinflammatory chemokine/cytokine production. Further, we have also identified genes from Ron replete and Ron deplete livers that were differentially expressed during the progression of liver inflammation associated with acute liver failure in mice by microarray analyses. While important genes and signaling pathways have been identified downstream of Ron signaling during progression of inflammation by this approach, the precise role that Ron receptor plays in regulating the transcriptional landscape in macrophages, and particular in isolated Kupffer cells, has still not been investigated. Methods Kupffer cells were isolated from wild-type (TK+/+) and Ron tyrosine kinase (TK−/−) deficient mice. Ex vivo, the cells were treated with lipopolysaccharide (LPS) in the presence or absence of the Ron ligand, Hepatocyte growth factor-like protein (HGFL). Microarray and qRT-PCR analyses were utilized to identify alterations in gene expression between genotypes. Results Microarray analyses identified genes expressed differentially in TK+/+ and TK−/− Kupffer cells basally as well as after HGFL and LPS treatment. Interestingly, our studies identified Mefv, a gene that codes for the anti-inflammatory protein pyrin, as an HGFL-stimulated Ron-dependent gene. Moreover, Lcn2 (Lipocalin 2), a proinflammatory gene, which is induced by LPS, was significantly suppressed by HGFL treatment. Microarray results were validated by qRT-PCR studies on Kupffer cells treated with LPS and HGFL. Conclusions The studies herein suggest a novel mechanism whereby HGFL-induced Ron receptor activation promotes the expression of anti-inflammatory genes while inhibiting genes involved in inflammation with a net effect of diminished inflammation in macrophages.

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Section: Discussionmentioning

confidence: 99%

Ron receptor-dependent gene regulation of Kupffer cells during endotoxemia

Kulkarni

Stuart

Waltz

2014

Hepatobiliary & Pancreatic Diseases International

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“…Hepatocyte-derived LCN2 plays an important role in inhibiting bacterial infection and promoting liver regeneration [63] Mouse Partial hepatectomy Mice were subjected to partial hepatectomy LCN2 expression is dramatically induced in livers and sera of mice after partial hepatectomy, whereas liver LCN2-receptor expression was decreased LCN2, although massively induced in mice after partial hepatectomy, is not relevant in murine hepatic regeneration [64] Mouse Acetaminophen intoxication, Human Hepatitis C-induced fibrosis/cirrhosis 18 patients with mild and 24 patients with severe fibrosis/cirrhosis Urine LCN2 levels (normalized to urine creatinine) were higher in patients with severe fibrosis/ cirrhosis showing a positive correlation with urine MMP-9/ MMP-2 activity ratios Urinary LCN2 is a marker of hepatic fibrosis that correlates to urine MMP-9 activity [68] Human Acute-on-chronic liver failure, acute liver failure, chronic hepatic failure Very small cohort of patients with acute-on-chronic liver failure, acute liver failure (n = 8) and chronic hepatic failure (n = 14)…”

Section: Mousementioning

confidence: 99%

“…Moreover, the demonstration that the application of a single-dose irradiation on liver results in an intense increase of LCN2 in serum within the first 6 h suggests LCN2 as a candidate biomarker suitable for detection of early phase hepatic damage induced by radiation [61]. From the diagnostic site, the previous finding that LCN2 is detectable as a complex with metalloproteinase 9 (MMP-9) in urine of cancer patients and that the urinary LCN2/MMP-9 ratio correlates with the fibrotic stage in HCC patients is extremely interesting [68]. A diagnostic classification of respective patients that is simply based on urinary LCN2 and MMP-9 would be a significant add on to existing noninvasive and invasive tests.…”

Section: Normal Livermentioning

confidence: 99%

“…Monoclonal anti-LCN2 antibody, NBPI-05182, (Novus Biologicals) [61] Liver tissue NBP1-05182 (Acris GmbH) [70] Liver tissue Monoclonal anti-LCN2 (Novus Biologicals) [56] Human Urine MAB1757 (R&D Systems) [68] Immuno(fluorescence) staining Mouse Liver tissue Not commercially available antibody [64] Liver tissue AF1857 (R&D Systems)…”

Section: Western Blot Mousementioning

confidence: 99%

“…Not commercially available antibody [46] Rat Liver tissue AF3508 (R&D Systems) [52] Liver tissue AF350 (R&D Systems) [52] Liver tissue Goat polyclonal anti-LCN2 (R&D Systems) [56] Liver tissue Monoclonal anti-LCN2 antibody, NBPI-5182 (Novus Biologicals) [61] ELISA † Mouse Blood serum Mouse LCN2 ELISA-DuoSet Development Kit (R&D Systems) [64] Blood serum Lipocalin-2/NGAL ELISA kit (BioVendor) [49] Rat Blood serum Lipocalin-2 ELISA Bioporto Diagnostics Kit 046 (Bioporto Diagnostics) [56,70] Blood serum ELISA Kit-046 (BioPorto Diagnostics) [61] Human Urine NGAL ELISA kit (BioPorto Diagnostics) [68] Blood serum Human LCN2 ELISA Kit (R&D Systems) [64] Blood serum Lipocalin-2/NGAL ELISA kit (BioVendor) [49] Blood serum Human Lipocalin-2/NGAL Duoset kit (R&D Systems)…”

Section: Western Blot Mousementioning

confidence: 99%

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Lipocalin 2 in the pathogenesis of fatty liver disease and nonalcoholic steatohepatitis

Asimakopoulou

Weiskirchen

2015

Clinical Lipidology

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Lipocalin‐2 activates hepatic stellate cells and promotes nonalcoholic steatohepatitis in high‐fat diet–fed Ob/Ob mice

et al. 2023

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Background and Aims: In obesity and type 2 diabetes mellitus, leptin promotes insulin resistance and contributes to the progression of NASH via activation of hepatic stellate cells (HSCs). However, the pathogenic mechanisms that trigger HSC activation in leptin-deficient obesity are still unknown. This study aimed to determine how HSC-targeting lipocalin-2 (LCN2) mediates the transition from simple steatosis to NASH.Approach and Results: Male wild-type (WT) and ob/ob mice were fed a high-fat diet (HFD) for 20 weeks to establish an animal model of NASH with fibrosis. Ob/ob mice were subject to caloric restriction or recombinant leptin treatment. Double knockout (DKO) mice lacking both leptin and lcn2 were also fed an HFD for 20 weeks. In addition, HFD-fed ob/ob mice were treated with gadolinium trichloride to deplete Kupffer cells. The LX-2 human HSCs and primary HSCs from ob/ob mice were used to investigate the effects of LCN2 on HSC activation. Serum and hepatic LCN2 expression levels were prominently increased in HFD-fed ob/ob mice compared with normal diet-fed ob/ob mice or HFD-fed WT mice, and these changes were closely linked to liver fibrosis and increased hepatic α-SMA/matrix metalloproteinase 9 (MMP9)/signal transducer and activator of transcription 3 (STAT3) protein levels. HFD-fed DKO mice showed a marked reduction of α-SMA

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Increased Urinary Lipocalin-2 Reflects Matrix Metalloproteinase-9 Activity in Chronic Hepatitis C with Hepatic Fibrosis

Cited by 21 publications

References 58 publications

Ron receptor-dependent gene regulation of Kupffer cells during endotoxemia

Ron receptor-dependent gene regulation of Kupffer cells during endotoxemia

Lipocalin 2 in the pathogenesis of fatty liver disease and nonalcoholic steatohepatitis

Lipocalin‐2 activates hepatic stellate cells and promotes nonalcoholic steatohepatitis in high‐fat diet–fed Ob/Ob mice

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