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Liver Diseases pp 65–74Cite as

Molecular Basis of Fibrogenesis and Angiogenesis During Chronic Liver Disease: Impact of TGF-β and VEGF on Pathogenic Pathways

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Abstract

Liver cirrhosis (LC) is pathologically characterized by the loss of functional hepatocytes. The defective area of hepatocytes is replaced with myofibroblast-produced extracellular matrix (ECM) proteins, such as collagens. Transforming growth factor-β (TGF-β) plays multiple roles in LC progression during chronic liver disease. Indeed, TGF-β induces apoptosis and epithelial mesenchymal transition in hepatocytes. Furthermore, TGF-β induces myofibroblastic phenotypes in hepatic stellate cells and sinusoidal endothelial cells for the production of ECMs. TGF-β also contributes to local hypoxia, at least in part, through the induction of endothelin-1, a potent vasoconstrictor. Under such a hypoxic condition, vascular endothelial growth factor (VEGF) is upregulated, followed by neovessel formation, edema and perivascular inflammation (i.e., pathogenic angiogenesis). VEGF and oxidant stress activate latent form TGF-β, resulting in the enhancement of LC, suggesting a crosstalk between pathogenic angiogenesis and fibrosis. In this chapter, we would like to focus on the potential linkage of VEGF-based angiogenesis with TGF-β-enhanced fibrogenesis for understanding of LC-associated pathogenic processes. Not only TGF-β antagonism but also anti-angiogenic therapy may be practical for retarding the progression of LC, a common hallmark of chronic liver disease.

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Author information

Authors and Affiliations

  1. Department of Zoology, Faculty of Science, Okayama University of Science, Okayama, Japan

    Shinya Mizuno

  2. Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Suita, Japan

    Shinya Mizuno & Eriko Osaki

Authors
  1. Shinya Mizuno
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  2. Eriko Osaki
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Editor information

Editors and Affiliations

  1. Faculty of Medicine, “Titu Maiorescu” University, Central Military Emergency University Hospital “Dr. Carol Davila”, Bucharest, Romania

    Florentina Radu-Ionita

  2. New Jersey Medical School, Rutgers University New Jersey Medical School, Newark, NJ, USA

    Nikolaos T. Pyrsopoulos

  3. Carol Davila University of Medicine and Pharmacy, Central Military Emergency University Hospital “Dr. Carol Davila”, Bucharest, Romania

    Mariana Jinga

  4. Faculty of Medicine, “Titu Maiorescu” University, Central Military Emergency University Hospital “Dr. Carol Davila”, Bucharest, Romania

    Ion C. Tintoiu

  5. Medical Radiation Sciences, Curtin University, Perth, WA, Australia

    Zhonghua Sun

  6. “Prof. C.C. Iliescu” Emergency Institute for Cardiovascular Diseases, Bucharest, Romania

    Ecaterina Bontas

Self Study

Self Study

1.1 Questions

  1. 1.

    Which statement is true?

    1. (a)

      MicroRNA (miRNA) is a small non-coding RNA and is important for RNA silencing and post-transcriptional regulation.

    2. (b)

      miRNA-122 decreases the transcription of α-SMA. CORRECT.

    3. (c)

      TGF-β increases miRNA-122 levels in HSCs.

    4. (d)

      TGF-β inhibits EMT in hepatocytes to acquire MyoFB-like phenotypes for interstitial ECM production.

  2. 2.

    Which statement is true?

    1. (a)

      Transforming growth factor-β (TGF-β) is one of the most important cytokines for the onset and progression of liver cirrhosis.

    2. (b)

      TGF-β secreted from Kupffer cells (KCs) converts sinusoidal cells, such as hepatic stellate cells (HSCs) and endothelial cells (ECs), to smooth muscle cell (SMC)-like myofibroblasts (MyoFBs).

    3. (c)

      In the injured livers, TGF-β is protective toward hepatocytes.

    4. (d)

      Oncostatin-M induces tissue inhibitor of metalloproteinase-1 (TIMP1) in HSCs, and further stimulates liver cirrhosis regression.

1.2 Answers

  1. 1.

    Which statement is true?

    1. (a)

      MicroRNA (miRNA) is a small non-coding RNA and is important for RNA silencing and post-transcriptional regulation. CORRECT.

    2. (b)

      miRNA-122 decreases the transcription of α-SMA. CORRECT.

    3. (c)

      TGF-β decreases miRNA-122 levels in HSCs.

    4. (d)

      TGF-β can induce EMT in hepatocytes to acquire MyoFB-like phenotypes for interstitial ECM production.

  2. 2.

    Which statement is true?

    1. (a)

      Transforming growth factor-β (TGF-β) is one of the most important cytokines for the onset and progression of liver cirrhosis. CORRECT.

    2. (b)

      TGF-β secreted from Kupffer cells (KCs) converts sinusoidal cells, such as hepatic stellate cells (HSCs) and endothelial cells (ECs), to smooth muscle cell (SMC)-like myofibroblasts (MyoFBs). CORRECT.

    3. (c)

      In the injured livers, TGF-β is apoptotic toward hepatocytes.

    4. (d)

      Oncostatin-M induces tissue inhibitor of metalloproteinase-1 (TIMP1) in HSCs, and further stimulates liver cirrhosis progression.

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Mizuno, S., Osaki, E. (2020). Molecular Basis of Fibrogenesis and Angiogenesis During Chronic Liver Disease: Impact of TGF-β and VEGF on Pathogenic Pathways. In: Radu-Ionita, F., Pyrsopoulos, N., Jinga, M., Tintoiu, I., Sun, Z., Bontas, E. (eds) Liver Diseases. Springer, Cham. https://doi.org/10.1007/978-3-030-24432-3_6

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