Coupling global methylation and gene expression profiles reveal key pathophysiological events in liver injury induced by a methyl‐deficient diet

Tryndyak, Volodymyr; Han, Tao; Muskhelishvili, Levan; Fuscoe, James C.; Ross, Sharon A.; Beland, Frederick A.; Pogribny, Igor P.

doi:10.1002/mnfr.201000300

Cited by 75 publications

(58 citation statements)

References 44 publications

(48 reference statements)

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“…Choline deficiency has also been characterized as leading to ROS generation, which was followed by the loss of ΔΨm and decreased ATP production in CWSV-1 cells [14,31,32]. Therefore, our study intends to find out whether more choline is needed and how choline intervention can prevent mitochondria from impairment in C3A cells exposed to excessive energy substrates.…”

Section: Discussionmentioning

confidence: 99%

The Effects of Choline on Hepatic Lipid Metabolism, Mitochondrial Function and Antioxidative Status in Human Hepatic C3A Cells Exposed to Excessive Energy Substrates

Zhu

Tang

et al. 2014

Nutrients

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Choline plays a lipotropic role in lipid metabolism as an essential nutrient. In this study, we investigated the effects of choline (5, 35 and 70 μM) on DNA methylation modifications, mRNA expression of the critical genes and their enzyme activities involved in hepatic lipid metabolism, mitochondrial membrane potential (Δψm) and glutathione peroxidase (GSH-Px) in C3A cells exposed to excessive energy substrates (lactate, 10 mM; octanoate, 2 mM and pyruvate, 1 mM; lactate, octanoate and pyruvate-supplemented medium (LOP)). Thirty five micromole or 70 μM choline alone, instead of a low dose (5 μM), reduced hepatocellular triglyceride (TG) accumulation, protected Δψm from decrement and increased GSH-Px activity in C3A cells. The increment of TG accumulation, reactive oxygen species (ROS) production and Δψm disruption were observed under LOP treatment in C3A cells after 72 h of culture, which were counteracted by concomitant treatment of choline (35 μM or 70 μM) partially via reversing the methylation status of the peroxisomal proliferator-activated receptor alpha (PPARα) gene promoter, upregulating PPARα, carnitine palmitoyl transferase-I (CPT-I) and downregulating fatty acid synthase (FAS) gene expression, as well as decreasing FAS activity and increasing CPT-I and GSH-Px activities. These findings provided a novel insight into the lipotropic role of choline as a vital methyl-donor in the intervention of chronic metabolic diseases.

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Section: Discussionmentioning

confidence: 99%

The Effects of Choline on Hepatic Lipid Metabolism, Mitochondrial Function and Antioxidative Status in Human Hepatic C3A Cells Exposed to Excessive Energy Substrates

Zhu

Tang

et al. 2014

Nutrients

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“…Um et al (2011) presented that DNA methyltransferase inhibitors, including 5-azacytidine and 5-aza-20-deoxycytidine, may help to eliminate DNA hypermethylation rate as an epigenetic therapy. A recent study investigated the relationship between a methyl-deficient diet and promoter methylation status of 164 genes which altered multiple vital processes including lipid and glucose metabolism, DNA damage and repair, apoptosis, the development of fibrosis, and liver tissue remodeling (Tryndyak et al 2011). Although there were both increased and decreased changes of CpG island methylation rates, the number of hypomethylated genes was substantially greater than the number of hypermethylated genes.…”

Section: Clinical Application Using Epigenetic Modificationsmentioning

confidence: 99%

“…Although there were both increased and decreased changes of CpG island methylation rates, the number of hypomethylated genes was substantially greater than the number of hypermethylated genes. Moreover, diet may artificially regulate the methylation level (Tryndyak et al 2011). A recent study also provided the advanced step from Necdin-Wnt pathway mechanism to clinical application (Yang et al 2012).…”

Section: Clinical Application Using Epigenetic Modificationsmentioning

confidence: 99%

Epigenetic Modifications in Hepatic Stellate Cells Contribute to Liver Fibrosis

Zhao

Qin

Zhao

et al. 2013

Tohoku J. Exp. Med.

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“…Such observed defects might be caused by both intrinsic factors within the lymphocyte and/or extrinsic factors from other parts of body. For example, from a mouse model, it is known that an MDD can cause liver injury [32]. A defect of early B cell development in MDD may be affected by changes in hormone balance from liver injury.…”

Section: Discussionmentioning

confidence: 99%

A Methyl-Deficient Diet Modifies Early B Cell Development

Kurogi

Inoue²,

Guo³

et al. 2012

Pathobiology

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A functional methyl group donor is essential for the epigenetic regulation of all biological events due to the importance of DNA methylation and histone methylation as an epigenetic marker. However, the epigenetic alterations in the immune system due to methyl donor deficiency are not well known. In this study, we tried to address this question by studying the lymphocyte development and DNA methylation changes caused by a methyl-deficient diet (MDD). We fed one group of C57BL/6J mice with a methyl-sufficient diet (MSD) and the other group with an MDD for 5 months. Flow cytometry analyses of their immune systems showed a decrease in B220+ IgM+ (immature B) cells and an increase in B220+ IgM– (pro/pre-B) cells in the bone marrow of mice fed an MDD. By means of an in vitro OP9 coculture system, we recognized that this B220+ IgM– cell fraction from the MDD has an intrinsic developmental defect. When we quantitatively measured the mRNA expression levels of transcription factors and recombination machinery related to B cell development in the B220+ IgM– cell fraction of their bone marrow, we found that ADA, EBF1, DNTT and Pax5 mRNA expression levels were significantly downregulated in mice fed with an MDD. In addition, there was a drastic decrease in histone methylation profile H3K4me3 in the Pax5 and EBF1 promoters in these B220+ IgM– B cells. However, CpG-DNA methylation profiles had not changed and this revealed that these two promoters are demethylated even under an MSD condition. We also found changed expression levels of the Polycomb group genes (mel18, bmi1, Pc1, Pc2, Ring1A, Ring1B, Ph1) on semi-quantitative RT-PCR. These results indicate that under an MDD condition, early B cell development in bone marrow is easily affected by epigenetic alterations.

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Coupling global methylation and gene expression profiles reveal key pathophysiological events in liver injury induced by a methyl‐deficient diet

Abstract: The results this study demonstrate that pairing methylation profiles with gene expression profiles is a powerful approach to identify dysregulated high-priority fundamental pathophysiological pathways associated with disease development.

Cited by 75 publications

References 44 publications

The Effects of Choline on Hepatic Lipid Metabolism, Mitochondrial Function and Antioxidative Status in Human Hepatic C3A Cells Exposed to Excessive Energy Substrates

The Effects of Choline on Hepatic Lipid Metabolism, Mitochondrial Function and Antioxidative Status in Human Hepatic C3A Cells Exposed to Excessive Energy Substrates

Epigenetic Modifications in Hepatic Stellate Cells Contribute to Liver Fibrosis

A Methyl-Deficient Diet Modifies Early B Cell Development

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