Increased 9,13-di-cis-retinoic acid in rat hepatic fibrosis: implication for a potential link between retinoid loss and TGF-β mediated fibrogenesis in vivo

Okuno, Masataka; Satō, Takashi; Kitamoto, Takuya; Imai, Shoko; Kawada, Norifumi; Suzuki, Yasuhiro; Yoshimura, Hidetoshi; Moriwaki, Hisataka; Onuki, Kaori; Masushige, Shoichi; Muto, Yasutoshi; Friedman, Scott L.; Kato, Shigeaki; Kojima, Soichi

doi:10.1016/s0168-8278(99)80262-1

Cited by 81 publications

(53 citation statements)

References 27 publications

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“…Although loss of retinoid is a prominent feature accompanying stellate cell activation both in vivo (421) and in culture (175), it is unknown whether this process is a prerequisite for activation to occur. The reports about effects of retinoids on stellate cells and fibrogenesis are contradictory (115,116,199,236,423,460,461,563,582,583,588). In culture, both retinol and retinoic acid suppress stellate cell proliferation, and retinoic acid (RA) is 1,000 times more potent than retinol (116).…”

Section: Effects Of Retinoids On Stellate Cellsmentioning

confidence: 99%

“…In culture, both retinol and retinoic acid suppress stellate cell proliferation, and retinoic acid (RA) is 1,000 times more potent than retinol (116). In contrast, 9-cis-RA and 9,13-di-cis-RA, two metabolites of RA, promote fibrosis by upregu-lating plasminogen activator, which in turn induces the production and activation of TGF-␤ (460,461). This process is mediated by RA receptor (RAR)-␣.…”

Section: Effects Of Retinoids On Stellate Cellsmentioning

confidence: 99%

“…There are also multiple mechanisms mediating the activation of latent TGF-␤1, including cell surface activation following binding to cell-surface mannose-6-phosphate/IGF-II receptor (117) or binding to a number of proteins secreted by stellate cells (209), such as ␣ 2 -macroglobulin (9), decorin, and biglycan (417). Recent studies suggest the important role of local plasminogen activator (PA)/plasmin in activating latent TGF-␤1 (255,460,461). This mechanism is regulated by metabolites of RA.…”

Section: Production Of Growth Factors and Cytokinesmentioning

confidence: 99%

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Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

Friedman

2008

Physiological Reviews

2,390

2,549

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The hepatic stellate cell has surprised and engaged physiologists, pathologists, and hepatologists for over 130 years, yet clear evidence of its role in hepatic injury and fibrosis only emerged following the refinement of methods for its isolation and characterization. The paradigm in liver injury of activation of quiescent vitamin A-rich stellate cells into proliferative, contractile, and fibrogenic myofibroblasts has launched an era of astonishing progress in understanding the mechanistic basis of hepatic fibrosis progression and regression. But this simple paradigm has now yielded to a remarkably broad appreciation of the cell's functions not only in liver injury, but also in hepatic development, regeneration, xenobiotic responses, intermediary metabolism, and immunoregulation. Among the most exciting prospects is that stellate cells are essential for hepatic progenitor cell amplification and differentiation. Equally intriguing is the remarkable plasticity of stellate cells, not only in their variable intermediate filament phenotype, but also in their functions. Stellate cells can be viewed as the nexus in a complex sinusoidal milieu that requires tightly regulated autocrine and paracrine cross-talk, rapid responses to evolving extracellular matrix content, and exquisite responsiveness to the metabolic needs imposed by liver growth and repair. Moreover, roles vital to systemic homeostasis include their storage and mobilization of retinoids, their emerging capacity for antigen presentation and induction of tolerance, as well as their emerging relationship to bone marrow-derived cells. As interest in this cell type intensifies, more surprises and mysteries are sure to unfold that will ultimately benefit our understanding of liver physiology and the diagnosis and treatment of liver disease.

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Section: Effects Of Retinoids On Stellate Cellsmentioning

confidence: 99%

Section: Effects Of Retinoids On Stellate Cellsmentioning

confidence: 99%

Section: Production Of Growth Factors and Cytokinesmentioning

confidence: 99%

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Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

Friedman

2008

Physiological Reviews

2,390

2,549

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“…Other nuclear receptors regulating stellate cell behavior include pregnane X receptor, 90,91 and retinoid receptors. 92,93 Epigenetic regulation is a tightly controlled pathway that modulates stellate cell activation in part through induction of the molecules CBF1 and MeCP2. 94,95 These proteins repress gene expression of the inhibitory protein inhibitor kappa beta (IκB) by CpG island methylation, thereby unleashing nuclear factor κ B activity, which promotes stellate cell survival and thus increases fibrosis.…”

Section: Pathways Of Stellate Cell Activation: a Moving Target Initiamentioning

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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“…However, its relationship with HSC activation remains unknown. Minor metabolites of retinoic acid (RA), 9-cis RA and 9, 13-di-cis RA can stimulate the activation of latent TGF-β1 implying a direct link to fibrogenesis (68). Activated HSCs have increased expression of cell membrane receptors including integrins and receptor tyrosine kinases (RTKs) (69).…”

Section: Perpetuation Of Hsc Activationmentioning

confidence: 99%

Bioconjugation of Oligonucleotides for Treating Liver Fibrosis

Houssein

Mahato

2007

Oligonucleotides

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Liver fibrosis results from chronic liver injury due to hepatitis B and C, excessive alcohol ingestion, and metal ion overload. Fibrosis culminates in cirrhosis and results in liver failure. Therefore, a potent antifibrotic therapy is in urgent need to reverse scarring and eliminate progression to cirrhosis. Although activated hepatic stellate cells (HSCs) remains the principle cell type responsible for liver fibrosis, perivascular fibroblasts of portal and central veins as well as periductular fibroblasts are other sources of fibrogenic cells. This review will critically discuss various treatment strategies for liver fibrosis, including prevention of liver injury, reduction of inflammation, inhibition of HSC activation, degradation of scar matrix, and inhibition of aberrant collagen synthesis. Oligonucleotides (ODNs) are short, single-stranded nucleic acids, which disrupt expression of target protein by binding to complementary mRNA or forming triplex with genomic DNA. Triplex forming oligonucleotides (TFOs) provide an attractive strategy for treating liver fibrosis. A series of TFOs have been developed for inhibiting the transcription of α1(I) collagen gene, which opens a new area for antifibrotic drugs. There will be in depth discussion on the use of TFOs and how different bioconjugation strategies can be utilized for their site-specific delivery to HSCs or hepatocytes for enhanced antifibrotic activities. Various insights developed in individual strategy and the need for multipronged approaches will also be discussed.

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Increased 9,13-di-cis-retinoic acid in rat hepatic fibrosis: implication for a potential link between retinoid loss and TGF-β mediated fibrogenesis in vivo

Cited by 81 publications

References 27 publications

Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

Mechanisms of Hepatic Fibrogenesis

Bioconjugation of Oligonucleotides for Treating Liver Fibrosis

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