Epigenetics in Liver Fibrosis

Massey, Veronica; Cabezas, Joaquín; Bataller, Ramón

doi:10.1055/s-0037-1605371

Cited by 21 publications

(15 citation statements)

References 168 publications

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“…Unfortunately, HDACIs have been shown to carry side effects such as nausea, vomiting, fever, and headache, which can be easily managed [ 139 ]. However, serious adverse effects, such as hepatotoxicity, have also been observed [ 140 ], including a clinical case of steatohepatitis and hepatocellular carcinoma [ 141 ]. VPA has been associated with dose-dependent elevation of serum aminotransferases [ 142 ].…”

Section: Hdac Inhibitors As Therapeutic Tools To Treat Liver Fibromentioning

confidence: 99%

Epigenetics in Liver Fibrosis: Could HDACs be a Therapeutic Target?

Clavería-Cabello

Colyn

Arechederra

et al. 2020

Cells

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Chronic liver diseases (CLD) represent a worldwide health problem. While CLDs may have diverse etiologies, a common pathogenic denominator is the presence of liver fibrosis. Cirrhosis, the end-stage of CLD, is characterized by extensive fibrosis and is markedly associated with the development of hepatocellular carcinoma. The most important event in hepatic fibrogenesis is the activation of hepatic stellate cells (HSC) following liver injury. Activated HSCs acquire a myofibroblast-like phenotype becoming proliferative, fibrogenic, and contractile cells. While transient activation of HSCs is part of the physiological mechanisms of tissue repair, protracted activation of a wound healing reaction leads to organ fibrosis. The phenotypic changes of activated HSCs involve epigenetic mechanisms mediated by non-coding RNAs (ncRNA) as well as by changes in DNA methylation and histone modifications. During CLD these epigenetic mechanisms become deregulated, with alterations in the expression and activity of epigenetic modulators. Here we provide an overview of the epigenetic alterations involved in fibrogenic HSCs transdifferentiation with particular focus on histones acetylation changes. We also discuss recent studies supporting the promising therapeutic potential of histone deacetylase inhibitors in liver fibrosis.

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Section: Hdac Inhibitors As Therapeutic Tools To Treat Liver Fibromentioning

confidence: 99%

Epigenetics in Liver Fibrosis: Could HDACs be a Therapeutic Target?

Clavería-Cabello

Colyn

Arechederra

et al. 2020

Cells

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“…The distinct anatomical location and proposed role of environmental factors such as excessive alcohol consumption (13), heavy manual labor, and exposure to vibrations (14) suggest epigenetic regulation is likely to be important in the pathogenesis of the disease. Epigenetic mechanisms have been shown to be crucial mediators of fibrotic gene expression in a wide range of fibrotic disorders (15), including cardiac fibrosis (16), liver fibrosis (17), and systemic sclerosis (18), and probably account for the persistence of myofibroblasts in disease (19).…”

mentioning

confidence: 99%

Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300

Williams

McCann

Cabrita

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Fibrotic diseases remain a major cause of morbidity and mortality, yet there are few effective therapies. The underlying pathology of all fibrotic conditions is the activity of myofibroblasts. Using cells from freshly excised disease tissue from patients with Dupuytren’s disease (DD), a localized fibrotic disorder of the palm, we sought to identify new therapeutic targets for fibrotic disease. We hypothesized that the persistent activity of myofibroblasts in fibrotic diseases might involve epigenetic modifications. Using a validated genetics-led target prioritization algorithm (Pi) of genome wide association studies (GWAS) data and a broad screen of epigenetic inhibitors, we found that the acetyltransferase CREBBP/EP300 is a major regulator of contractility and extracellular matrix production via control of H3K27 acetylation at the profibrotic genes, ACTA2 and COL1A1. Genomic analysis revealed that EP300 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, and broad transcriptomic and proteomic profiling of CREBBP/EP300 inhibition by the chemical probe SGC-CBP30 identified collagen VI (Col VI) as a prominent downstream regulator of myofibroblast activity. Targeted Col VI knockdown results in significant decrease in profibrotic functions, including myofibroblast contractile force, extracellular matrix (ECM) production, chemotaxis, and wound healing. Further evidence for Col VI as a major determinant of fibrosis is its abundant expression within Dupuytren’s nodules and also in the fibrotic foci of idiopathic pulmonary fibrosis (IPF). Thus, Col VI may represent a tractable therapeutic target across a range of fibrotic disorders.

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“…Activated HSCs are thought to be major mediators of liver fibrosis, and their generation is maintained during liver fibrogenesis [5]. The epigenetic machinery, including DNA methylation, plays a crucial role in the transition of quiescent HSCs to activated HSCs [6][7][8]. It is expected that epigenetic therapy will be effective in changing the phenotype of HSCs from activated to quiescent and in inhibiting liver fibrogenesis [9,10].…”

Section: Introductionmentioning

confidence: 99%

Hydralazine Sensitizes to the Antifibrotic Effect of 5-Aza-2′-deoxycytidine in Hepatic Stellate Cells

Asada

Kaji

Sato

et al. 2020

Biology

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Background: Hepatic stellate cell (HSC) activation is essential for the development of liver fibrosis. Epigenetic machinery, such as DNA methylation, is largely involved in the regulation of gene expression during HSC activation. Although the pharmacological DNA demethylation of HSC using 5-aza-2′-deoxycytidine (5-aza-dC) yielded an antifibrotic effect, this drug has been reported to induce excessive cytotoxicity at a high dose. Hydralazine (HDZ), an antihypertensive agent, also exhibits non-nucleoside demethylating activity. However, the effect of HDZ on HSC activation remains unclear. In this study, we performed a combined treatment with 5-aza-dC and HDZ to obtain an enhanced antifibrotic effect with lower cytotoxicity. Methods: HSC-T6 cells were used as a rat HSC cell line in this study. The cells were cultivated together with 1 µM 5-Aza-dC and/or 10 µg/mL of HDZ, which were refreshed every 24 h until the 96 h treatment ended. Cell proliferation was measured using the WST-1 assay. The mRNA expression levels of peptidylprolyl isomerase A (Ppia), an internal control gene, collagen type I alpha 1 (Cola1), RAS protein activator like 1 (Rasal1), and phosphatase and tensin homolog deleted from chromosome 10 (Pten) were analyzed using quantitative reverse transcription polymerase chain reaction. Results: The percentage cell viability with 5-aza-dC, HDZ, and combined treatment vs. the vehicle-only control was 101.4 ± 2.5, 95.2 ± 5.7, and 79.2 ± 0.7 (p < 0.01 for 5-aza-dC and p < 0.01 for HDZ), respectively, in the 48 h treatment, and 52.4 ± 5.6, 65.9 ± 3.4, and 29.9 ± 1.3 (p < 0.01 for 5-aza-dC and p < 0.01 for HDZ), respectively, in the 96 h treatment. 5-Aza-dC and the combined treatment markedly decreased Cola1 mRNA levels. Accordingly, the expression levels of Rasal1 and Pten, which are antifibrotic genes, were increased by treatment after the 5-aza-dC and combined treatments. Moreover, single treatment with HDZ did not affect the expression levels of Cola1, Rasal1, or Pten. These results suggest that HDZ sensitizes to the antifibrotic effect of 5-aza-dC in HSC-T6 cells. The molecular mechanism underlying the sensitization to the antifibrotic effect of 5-aza-dC by HDZ remains to be elucidated. The expression levels of rat equilibrative nucleoside transporter genes (rEnt1, rEnt2, and rEnt3) were not affected by HDZ in this study. Conclusions: Further confirmation using primary HSCs and in vivo animal models is desirable, but combined treatment with 5-aza-dC and HDZ may be an effective therapy for liver fibrosis without severe adverse effects.

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Epigenetics in Liver Fibrosis

Cited by 21 publications

References 168 publications

Epigenetics in Liver Fibrosis: Could HDACs be a Therapeutic Target?

Epigenetics in Liver Fibrosis: Could HDACs be a Therapeutic Target?

Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300

Hydralazine Sensitizes to the Antifibrotic Effect of 5-Aza-2′-deoxycytidine in Hepatic Stellate Cells

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