HCV core protein promotes liver fibrogenesis via up-regulation of CTGF with TGF-β1

Shin, Ju Yeop; Hur, Wonhee; Wang, Jin Sang; Jang, Jeong Won; Kim, Chang Wook; Bae, Si Hyun; Jang, Sung Key; Yang, Se Hwan; Sung, Young Chul; Kwon, Oh Joo; Yoon, Seung Kew

doi:10.1038/emm.2005.19

Cited by 102 publications

(81 citation statements)

References 38 publications

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“…Moreover, expression of HCV nonstructural and core proteins induces stellate cell proliferation, release of inflammatory signals, 202 and CTGF, 203 although interaction of HCV E2 protein stimulates MMP-2 expression. 204 Furthermore, hepatocytes harboring replicating HCV in culture produce fibrogenic stimuli towards stellate cells.…”

Section: Hcv and Hivmentioning

confidence: 99%

Mechanisms of Hepatic Fibrogenesis

2008

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Substantial improvements in the treatment of chronic liver disease have accelerated interest in uncovering the mechanisms underlying hepatic fibrosis and its resolution. Activation of resident hepatic stellate cells into proliferative, contractile, and fibrogenic cells in liver injury remains a dominant theme driving the field. However, several new areas of rapid progress in the past 5-10 years also have taken root, including: (1) identification of different fibrogenic populations apart from resident stellate cells, for example, portal fibroblasts, fibrocytes, and bone-marrow-derived cells, as well as cells derived from epithelial mesenchymal transition; (2) emergence of stellate cells as finely regulated determinants of hepatic inflammation and immunity; (3) elucidation of multiple pathways controlling gene expression during stellate cell activation including transcriptional, posttranscriptional, and epigenetic mechanisms; (4) recognition of disease-specific pathways of fibrogenesis; (5) re-emergence of hepatic macrophages as determinants of matrix degradation in fibrosis resolution and the importance of matrix cross-linking and scar maturation in determining reversibility; and (6) hints that hepatic stellate cells may contribute to hepatic stem cell behavior, cancer, and regeneration. Clinical and translational implications of these advances have become clear, and have begun to impact significantly on the management and outlook of patients with chronic liver disease.The field of hepatic fibrosis is flourishing thanks to continued experimental advances complemented by exciting progress in the treatment of chronic liver disease. 1 Control of chronic hepatitis B and C by antiviral therapies has established that advanced fibrosis can regress in association with improved clinical outcomes, 2-4 thereby intensifying enthusiasm to uncover the mechanistic basis for hepatic fibrogenesis and its attenuation. At the same time, simple paradigms defining the cellular sources of extracellular matrix (ECM), and the roles of cytokines and paracrine interactions among resident liver cells and inflammatory cells have yielded a more nuanced understanding of how the liver responds to injury. These advances have had a collateral benefit towards understanding fibrosis in other organs, particularly the pancreas. 5 Thus, a review of the mechanisms underlying hepatic fibrosis is not only timely, but is more clinically relevant than ever. This article focuses on recent advances in the field, building on established principles from earlier reviews 6,7 while weaving in their clinical relevance, but also emphasizing the molecular subtleties that have emerged through continued progress in the field. General PrinciplesFibrosis, or scarring of the liver, is a wound-healing response that engages a range of cell types and mediators to encapsulate injury. Although even acute injury will activate mechanisms of fibrogenesis, the sustained signals associated with chronic liver disease caused by infection, Cirrhosis, the most advanced stage ...

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Section: Hcv and Hivmentioning

confidence: 99%

Mechanisms of Hepatic Fibrogenesis

2008

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“…However, in other diseases, including arthritis (Manns et al 2006;Tanaka et al 2005) and viral hepatitis (Fukutomi et al 2005;Shin et al 2005), CCN2 and CCN5 are similarly expressed. CCN2 and CCN5 have opposite expression patterns in vascular SMC.…”

Section: Introductionmentioning

confidence: 99%

CCN5 expression in mammals

Jones

Gray

Oliveira

et al. 2007

J. Cell Commun. Signal.

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The six proteins of the CCN family have important roles in development, angiogenesis, cell motility, proliferation, and other fundamental cell processes. To date, CCN5 distribution in developing rodents and humans has not been mapped comprehensively. CCN5 strongly inhibits adult smooth muscle cell proliferation and motility. Its antiproliferative action predicts that CCN5 would not be present in developing tissues until the proliferation phase of tissue morphogenesis is complete. However, estrogen induces CCN5 expression in epithelial and smooth muscle cells, suggesting that CCN5 might be widely expressed in embryonic tissues exposed to high levels of estrogen.9-16 day murine embryos and fetuses and 3-7 month human fetal tissues were analyzed by immunohistochemistry. CCN5 was detected in nearly all developing tissues. CCN5 protein expression was initially present in most tissues, and at later times in development tissue-specific expression differences were observed. CCN5 expression was particularly strong in vascular tissues, cardiac muscle, bronchioles, myotendinous junctions, and intestinal smooth muscle and epithelium. CCN5 expression was initially absent in bone cartilaginous forms but was increasingly expressed during bone endochondral ossification. Widespread CCN5 mRNA expression was detected in GD14.5 mice. Although CCN2 and CCN5 protein expression patterns in some adult pathologic conditions are inversely expressed, this expression pattern was not found in developing mouse and human tissues. The widespread expression pattern of CCN5 in most embryonic and fetal tissues suggests a diverse range of functions for CCN5.

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“…The HCV Core transgenic mice suggested that core protein may play an important role in HCVinduced steatosis and HCC (Moriya et al, 1997;Moriya et al, 1998;Shin et al, 2005). Recently, Lerat et al suggested that the expression of the structural proteins enhances a low background of steatosis in C57BL/6 mice, while the additional low-level expression of the nonstructural proteins increases the risk of cancer (Lerat et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Expression of hepatitis C virus nonstructural 4B in transgenic mice

Wang

Moon²,

Kim³

et al. 2006

Exp Mol Med

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Hepatitis C virus (HCV) is a pathogen that is of great medical significance in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma worldwide. Although the HCV proteins have been intensively investigated over the past decade, the biochemical functions of the NS4B protein are still largely unknown. To investigate NS4B as a potential causative agent of liver disease, transgenic mice expressing the NS4B protein in liver tissue were produced. The transgenic animals were phenotypically similar to their normal littermates for up to 18 months of age. Our results suggest that the HCV NS4B protein is not directly cytopathic or oncogenic in our transgenic mice model.

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HCV core protein promotes liver fibrogenesis via up-regulation of CTGF with TGF-β1

Cited by 102 publications

References 38 publications

Mechanisms of Hepatic Fibrogenesis

Mechanisms of Hepatic Fibrogenesis

CCN5 expression in mammals

Expression of hepatitis C virus nonstructural 4B in transgenic mice

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