Article

Alcoholic Liver Disease and Methionine Metabolism

Department of Veterans Affairs Medical Center, Research Service, Omaha, Nebraska 68105, USA.
Seminars in Liver Disease (Impact Factor: 5.12). 06/2009; 29(2):155-65. DOI: 10.1055/s-0029-1214371
Source: PubMed

ABSTRACT Alcoholic liver disease is a major health care problem worldwide. Findings have demonstrated that ethanol feeding impairs several of the multiple steps in methionine metabolism that leads to progressive liver injury. Ethanol consumption has been reported to predominantly inhibit the activity of a vital cellular enzyme, methionine synthase, involved in remethylating homocysteine. By way of compensation in some species, ethanol can also increase the activity of the enzyme, betaine homocysteine methyltransferase. This enzyme catalyzes an alternate pathway in methionine metabolism and utilizes hepatic betaine to remethylate homocysteine to form methionine and maintain levels of S-adenosylmethionine, the key methylating agent. Under extended periods of ethanol feeding, however, this alternate pathway cannot be maintained. This results in a decrease in the hepatocyte level of S-adenosylmethionine and increases in two toxic metabolites, S-adenosylhomocysteine and homocysteine. These changes in the various metabolites of methionine metabolism, in turn, result in serious functional consequences. These include decreases in essential methylation reactions by inhibiting various methyltransferases critical to normal functioning of the liver and upregulation of the activation of endoplasmic reticulum-dependent apoptosis and lipid synthetic pathways. The ultimate outcome of these consequences is increased fat deposition, increased apoptosis, accumulation of damaged proteins, and alterations in various signaling pathways, all of which can ultimately result in progressive liver damage. Of all the therapeutic modalities that are presently being used to attenuate ethanol-induced liver injury, betaine has been shown to be the most effective in a variety of experimental models of liver disease. Betaine, by virtue of aiding in the remethylation of homocysteine, removes both toxic metabolites (homocysteine and S-adenosylhomocysteine), restores S-adenosylmethionine level, reverses steatosis, prevents apoptosis and reduces both damaged protein accumulation and oxidative stress. Thus, betaine is a promising therapeutic agent in relieving the methylation and other defects associated with alcoholic abuse.

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Available from: Kusum K Kharbanda, Mar 26, 2015
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    • "Specifically, DMGDH, a flavin-containing enzyme, catalyzes the oxidative demethylation of dimethylglycine to sarcosine, which in turn is converted to glycine by the enzyme sarcosine dehydrogenase. Again, while we do not know whether the increase in 4-HNE modification affected the activity of the enzyme, it is known that chronic ethanol perturbs function of the metabolic cycles critical for one-carbon metabolism and that these derangements contribute to steatosis [35]. Importantly, betaine homocysteine methyltransferase (BHMT) is inhibited by accumulation of its product dimethylglycine [36]. "
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    ABSTRACT: Chronic ethanol-mediated oxidative stress and lipid peroxidation increases the levels of various reactive lipid species including 4-hydroxynonenal (4-HNE), which can subsequently modify proteins in the liver. It has been proposed that 4-HNE modification adversely affects the structure and/or function of mitochondrial proteins, thereby impairing mitochondrial metabolism. To determine whether chronic ethanol consumption increases levels of 4-HNE modified proteins in mitochondria, male rats were fed control and ethanol-containing diets for 5 weeks and mitochondrial samples were analyzed using complementary proteomic methods. Five protein bands (approx. 35, 45, 50, 70, and 90 kDa) showed strong immunoreactivity for 4-HNE modified proteins in liver mitochondria from control and ethanol-fed rats when proteins were separated by standard 1D SDS-PAGE. Using high-resolution proteomic methods (2D IEF/SDS-PAGE and BN-PAGE) we identified several mitochondrial proteins immunoreactive for 4-HNE, which included mitofilin, dimethylglycine dehydrogenase, choline dehydrogenase, electron transfer flavoprotein α, cytochrome c1, enoyl CoA hydratase, and cytochrome c. The electron transfer flavoprotein α consistently showed increased 4-HNE immunoreactivity in mitochondria from ethanol-fed rats as compared to mitochondria from the control group. Increased 4-HNE reactivity was also detected for dimethylglycine dehydrogenase, enoyl CoA hydratase, and cytochrome c in ethanol samples when mitochondria were analyzed by BN-PAGE. In summary, this work identifies new targets of 4-HNE modification in mitochondria and provides useful information needed to better understand the molecular mechanisms underpinning chronic ethanol-induced mitochondrial dysfunction and liver injury.
    10/2014; 2. DOI:10.1016/j.redox.2014.09.006
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    • "Previously , we showed reduced levels of the histone residue H3K9me3 together with up-regulation of several genes involved in the endoplasmic reticulum stress pathway after intragastric EtOH feeding of the CbS heterozygous mouse (Esfandiari et al., 2010). The effects of chronic alcoholism and experimental EtOH exposure on methionine metabolism have been extensively described in humans and in animal models of ASH (Halsted and Medici, 2011; Kharbanda, 2009; Watanabe et al., 1995), whereas a prior study that used the same intragastric EtOH feeding model in wild-type mice demonstrated the reversal of histopathology and gene expressions relevant to the endoplasmic reticulum stress pathway by supplementation with betaine (Ji and Kaplowitz, 2003). Others found that supplemental betaine restored histopathology, the gene expression of nitric oxide synthase (Nos2), and hepatic SAM levels, while reducing SAH and increasing the SAM/SAH methylation ratio in an EtOH-fed rat model of this disease (Kharbanda et al., 2012). "
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    ABSTRACT: Background Alcoholic steatohepatitis (ASH) is caused in part by the effects of ethanol (EtOH) on hepatic methionine metabolism.Methods To investigate the phenotypic and epigenetic consequences of altered methionine metabolism in this disease, we studied the effects of 4-week intragastric EtOH feeding with and without the methyl donor betaine in cystathionine beta synthase (CβS) heterozygous C57BL/6J mice.ResultsThe histopathology of early ASH was induced by EtOH feeding and prevented by betaine supplementation, while EtOH feeding reduced and betaine supplementation maintained the hepatic methylation ratio of the universal methyl donor S-adenosylmethionine (SAM) to the methyltransferase inhibitor S-adenosylhomocysteine (SAH). MethylC-seq genomic sequencing of heterozygous liver samples from each diet group found 2 to 4% reduced methylation in gene bodies, but not promoter regions of all autosomes of EtOH-fed mice, each of which were normalized in samples from mice fed the betaine-supplemented diet. The transcript levels of nitric oxide synthase (Nos2) and DNA methyltransferase 1 (Dnmt1) were increased, while those of peroxisome proliferator receptor-α (Pparα) were reduced in EtOH-fed mice, and each was normalized in mice fed the betaine-supplemented diet. DNA pyrosequencing of CβS heterozygous samples found reduced methylation in a gene body of Nos2 by EtOH feeding that was restored by betaine supplementation and was correlated inversely with its expression and positively with SAM/SAH ratios.Conclusions The present study has demonstrated relationships among EtOH induction of ASH with aberrant methionine metabolism that was associated with gene body DNA hypomethylation in all autosomes and was prevented by betaine supplementation. The data imply that EtOH-induced changes in selected gene transcript levels and hypomethylation in gene bodies during the induction of ASH are a result of altered methionine metabolism that can be reversed through dietary supplementation of methyl donors.
    Alcoholism Clinical and Experimental Research 04/2014; 38(6). DOI:10.1111/acer.12405 · 3.31 Impact Factor
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    • "Since epigenetic alterations leading to modified physiological processes may be reversible, they can serve as targets for potential intervention (Choi and Friso 2010). Although alcohol is a known antagonist to OCM (Giovannucci 2004; Kharbanda 2009), the etiology of OCM disturbance in alcoholism is not entirely understood. "
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    ABSTRACT: Excessive alcohol consumption is a prominent problem and one of the major causes of mortality and morbidity around the world. Long-term, heavy alcohol consumption is associated with a number of deleterious health consequences, such as cancer, heart and liver disease, a variety of neurological, cognitive, and behavioral deficits. Alcohol consumption is also associated with developmental defects. The causes of alcohol-induced toxicity are presently unclear. One of the mechanisms underlying alcohol toxicity has to do with its interaction with folic acid/homocysteine or one-carbon metabolism (OCM). OCM is a major donor of methyl groups for methylation, particularly DNA methylation critical for epigenetic regulation of gene expression, and its disturbance may compromise DNA methylation, thereby affecting gene expression. OCM disturbance mediated by nutrient deficits is a well-known risk factor for various disorders and developmental defects (e.g. neural tube defects). In this review, we summarize the role of OCM disturbance and associated epigenetic aberrations in chronic alcohol-induced toxicity. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 02/2014; 129(5). DOI:10.1111/jnc.12677 · 4.24 Impact Factor
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