Increased DNA methylation in the livers of patients with alcoholic hepatitis

Shen, Hong; French, Barbara A.; Tillman, Brittany; Li, Jun; French, Samuel W.

doi:10.1016/j.yexmp.2015.08.001

Cited by 11 publications

(10 citation statements)

References 28 publications

(35 reference statements)

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“…According to the liver is the human body's largest metabolism organ, there is increasing evidence that DNA methylation also participated in pathological process of various liver diseases. Both of alcohol abuse and tobacco exposure, two major risk factor for the development of liver related disorders, induced alter in gene methylation status (Mansoori and Jain, 2015;Shen et al, 2015). Moreover, both of in vitro and in vivo studies have demonstrated that some anti-inflammatory factors, such as Apoliprotein A1 (ApoA1) and PPAR-γ, could be suppressed by Hepatitis B/C virus core protein through promoter methylation, resulting in deterioration of hepatitis or eventually progress to cancer (Zhao et al, 2015;Wang et al, 2016b).…”

Section: Discussionmentioning

confidence: 99%

Methylation of Septin9 mediated by DNMT3a enhances hepatic stellate cells activation and liver fibrogenesis

Hou

et al. 2017

Toxicology and Applied Pharmacology

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Liver fibrosis, resulting from chronic and persistent injury to the liver, is a worldwide health problem. Advanced liver fibrosis results in cirrhosis, liver failure and even hepatocellular cancer (HCC), often eventually requiring liver transplantation, poses a huge health burden on the global community. However, the specific pathogenesis of liver fibrosis remains not fully understood. Numerous basic and clinical studies have provided evidence that epigenetic modifications, especially DNA methylation, might contribute to the activation of hepatic stellate cells (HSCs), the pivotal cell type responsible for the fibrous scar in liver. Here, reduced representation bisulfite sequencing (RRBS) and bisulfite pyrosequencing PCR (BSP) analysis identified hypermethylation status of Septin9 (Sept9) gene in liver fibrogenesis. Sept9 protein was dramatically decreased in livers of CCl4-treated mice and immortalized HSC-T6 cells exposed to TGF-β1. Nevertheless, the suppression of Sept9 could be blocked by DNMT3a-siRNA and DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (5-azadC). Overexpressed Sept9 attenuated TGF-β1-induced expression of myofibroblast markers α-SMA and Col1a1, accompanied by up-regulation of cell apoptosis-related proteins. Conversely, RNAi-mediated silencing of Sept9 enhanced accumulation of extracellular matrix. These observations suggested that Sept9 contributed to alleviate liver fibrosis might partially through promoting activated HSCs apoptosis and this anti-fibrogenesis effect might be blocked by DNMT-3a mediated methylation of Sept9. Therefore, pharmacological agents that inhibit Sept9 methylation and increase its expression could be considered as valuable treatments for liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

Methylation of Septin9 mediated by DNMT3a enhances hepatic stellate cells activation and liver fibrogenesis

Hou

et al. 2017

Toxicology and Applied Pharmacology

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“…DNMT3B loss inhibits proliferation, migration, and invasion in hepatocellular carcinoma cell lines (Wang et al, 2015). It has been previously noted that livers of patients with alcoholic hepatitis have increased DNA methylation (Shen et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Expression of proteins upregulated in hepatocellular carcinoma in patients with alcoholic hepatitis (AH) compared to non-alcoholic steatohepatitis (NASH): An immunohistochemical analysis of candidate proteins

Nguyen

Samadzadeh

et al. 2018

Experimental and Molecular Pathology

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Both non-alcoholic steatohepatitis (NASH) and alcoholic hepatitis (AH) can lead to cirrhosis and hepatocellular carcinoma. However, the rate of progression to cirrhosis and tumorigenesis in AH is greater than that in NASH. We asked whether there are differences between the two conditions in the expression levels of proteins involved in the pathogenesis of hepatocellular carcinoma. The proteins tested were presented at the 2017 American Association for the Study of Liver Diseases (AASLD) Liver Meeting as overexpressed in hepatocellular carcinoma: KLF4, SCL19A1, FANCG, HRH-1, DNMT1, DNMT3B, TNFR2, DUSP4, EGFR, Integrin α6, HDACII, PDE3A, BCL-XL, and MTCO2. The expression of these proteins was measured in liver biopsy sections from NASH and AH patients using immunohistochemical staining with fluorescent antibodies and then quantifying the fluorescence intensity morphometrically. In AH patients, levels of all tested proteins except HRH-1 were elevated compared to normal patients. In NASH patients, KLF4, SCL19A1, FANCG, HDACII, BCL-XL levels were increased compared to normal controls while HRH-1, DNMT1 and PDE3A levels were decreased. The relative expression of all proteins studied except BCL-XL was significantly higher in AH compared to NASH. In conclusion, proteins involved in hepatocellular cancer development are more highly expressed in AH compared to NASH and normal liver, which corresponds with the higher rate of tumorigenesis in AH patients compared to NASH patients.

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“…Recently, 5hmC has been suggested to be downregulated in ALD patients compared to normal healthy liver controls (16,23). In both studies, 5hmC was found decreased, but not to any significant extent.…”

Section: Discussionmentioning

confidence: 75%

“…Although it is largely unknown how 5hmC is involved in hepatocyte apoptosis in ALD, knockdown of TET1 has been shown to promote neuronal cell apoptosis by altering DNA methylation through the reduction of 5hmC (22). Interestingly, chronic alcohol consumption inhibits 5hmC levels in the livers of ALD human patients (16,23). In addition, chronic alcohol consumption promotes hepatocyte apoptosis in a rat ALD model (24).…”

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confidence: 99%

Chronic ethanol‐mediated hepatocyte apoptosis links to decreased TET1 and 5‐hydroxymethylcytosine formation

Nonomura

Zou

et al. 2018

FASEB j.

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The 5-hydroxymethylcytosine (5hmc) is a newly identified epigenetic modification thought to be regulated by the TET family of proteins. Little information is available about how ethanol consumption may modulate 5hmC formation and alcoholic liver disease (ALD) progression. A rat ALD model was used to study 5hmC in relationship to hepatocyte apoptosis. Human ALD liver samples were also used to validate these findings. It was found that chronic ethanol feeding significantly reduced 5hmC formation in a rat ALD model. There were no significant changes in TET2 and TET3 between the control- and ethanol-fed animals. In contrast, methylcytosine dioxygenase TET1 (TET1) expression was substantially reduced in the ethanol-fed rats and was accompanied by increased hepatocyte apoptosis. Similarly, knockdown of TET1 in human hepatocyte-like cells also significantly promoted apoptosis. Down-regulation of TET1 resulted in elevated expression of the DNA damage marker, suggesting a role for 5hmc in hepatocyte DNA damage as well. Mechanistic studies revealed that inhibition of TET1 promoted apoptotic gene expression. Similarly, targeting TET1 activity by removing cosubstrate promoted apoptosis and DNA damage. Furthermore, treatment with 5-azacitidine significantly mimics these effects, suggesting that chronic ethanol consumption promotes hepatocyte apoptosis and DNA damage by diminishing TET1-mediated 5hmC formation and DNA methylation. In summary, the current study provides a novel molecular insight that TET1-mediated 5hmC is involved in hepatocyte apoptosis in ALD progression.-Ji, C., Nagaoka, K., Zou, J., Casulli, S., Lu, S., Cao, K. Y., Zhang, H., Iwagami, Y., Carlson, R. I., Brooks, K., Lawrence, J., Mueller, W., Wands, J. R., Huang, C.-K. Chronic ethanol-mediated hepatocyte apoptosis links to decreased TET1 and 5-hydroxymethylcytosine formation.

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Increased DNA methylation in the livers of patients with alcoholic hepatitis

Cited by 11 publications

References 28 publications

Methylation of Septin9 mediated by DNMT3a enhances hepatic stellate cells activation and liver fibrogenesis

Methylation of Septin9 mediated by DNMT3a enhances hepatic stellate cells activation and liver fibrogenesis

Expression of proteins upregulated in hepatocellular carcinoma in patients with alcoholic hepatitis (AH) compared to non-alcoholic steatohepatitis (NASH): An immunohistochemical analysis of candidate proteins

Chronic ethanol‐mediated hepatocyte apoptosis links to decreased TET1 and 5‐hydroxymethylcytosine formation

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