Alcoholic Liver Disease: From Pathophysiology to Therapy

Seitz, Helmut K.; Lieber, Charles S.; Stickel, Felix; Salaspuro, Mikko; Schlemmer, H. P.; Horie, Yoshineri

doi:10.1097/01.alc.0000171896.37022.f7

Cited by 27 publications

(24 citation statements)

References 32 publications

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“…FAEEs and phosphatidylethanol (PEt) catalyzed by FAEE synthase and phospholipiase D, respectively, are classical nonoxidative metabolites of ethanol commonly found during chronic alcohol abuse (Laposata and Lange, 1986; Mueller et al, 1988; Kaphalia et al, 2004). Although biological significance of lipid metabolites of ethanol is not well understood, their in vivo and/or in vitro hepatocellular toxicity have been reported by us and others (Aydin et al, 2005; Kaphalia and Ansari, 2001; Seitz et al, 2005; Wu et al, 2006). Therefore, a lipid metabolic approach to identify ethanol-induced lipid fingerprint or signature could be important for understanding the mechanism and also to identify biomarker(s) of ALD.…”

Section: Introductionmentioning

confidence: 79%

“…Formation of FAEEs in such target organs as livers and their accumulation to sublethal concentrations may cause hepatocellular cytotoxicity resulting into alcoholic liver disease (Laposata and Lange, 1986; Kaphalia and Ansari, 2001; Aydin et al, 2005; Seitz et al, 2005; Wu et al, 2006). The levels of FAEEs increase dose-dependently in plasma and pancreas of ADH − deer mice fed ethanol (Bhopale et al, 2006; Kaphalia et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

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Hepatic lipid profiling of deer mice fed ethanol using 1H and 31P NMR spectroscopy: A dose-dependent subchronic study

Fernando¹,

Bhopale²,

Boor³

et al. 2012

Toxicology and Applied Pharmacology

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Chronic alcohol abuse is a 2nd major cause of liver disease resulting in significant morbidity and mortality. Alcoholic liver disease (ALD) is characterized by a wide spectrum of pathologies starting from fat accumulation (steatosis) in early reversible stage to inflammation with or without fibrosis and cirrhosis in later irreversible stages. Previously, we reported significant steatosis in the livers of hepatic alcohol dehydrogenase (ADH)-deficient (ADH−) vs. hepatic ADH-normal (ADH+) deer mice fed 4% ethanol daily for 2 months [Bhopale et al., 2006, Alcohol 39, 179–188]. However, ADH− deer mice fed 4% ethanol also showed a significant mortality. Therefore, a dose-dependent study was conducted to understand the mechanism and identify lipid(s) involved in the development of ethanol-induced fatty liver. ADH− and ADH+ deer mice fed 1, 2 or 3.5% ethanol daily for 2 months and fatty infiltration in the livers were evaluated by histology and by measuring dry weights of extracted lipids. Lipid metabolomic changes in extracted lipids were determined by proton (1H) and 31phosphorus (31P) nuclear magnetic resonance (NMR) spectroscopy. The NMR data was analyzed by hierarchical clustering (HC) and principle component analyses (PCA) for pattern recognition. Extensive vacuolization by histology and significantly increased dry weights of total lipids found only in the livers of ADH− deer mice fed 3.5% ethanol vs. pair-fed controls suggest a dose-dependent formation of fatty liver in ADH− deer mouse model. Analysis of NMR data of ADH− deer mice fed 3.5% ethanol vs. pair-fed controls shows increases for total cholesterol, esterified cholesterol, fatty acid methyl esters (FAMEs), triacylglycerides and unsaturation, and decreases for free cholesterol, phospholipids and allylic and diallylic protons. Certain classes of neutral lipids (cholesterol esters, fatty acyl chain (-COCH2-) and FAMEs) were also mildly increased in ADH− deer mice fed 1 or 2% ethanol. Only small increases were observed for allylic and diallylic protons, FAMEs and unsaturations in ADH+ deer mice fed 3.5% ethanol vs. pair-fed controls. PCA of NMR data showed increased clustering by gradual separation of ethanol-fed ADH− deer mice groups from their respective pair-fed control groups and corresponding ethanol-fed ADH+ deer mice groups. Our data indicate that dose of ethanol and hepatic ADH deficiency are two key factors involved in initiation and progression of alcoholic fatty liver disease. Further studies on characterization of individual lipid entities and associated metabolic pathways altered in our deer mouse model after different durations of ethanol feeding could be important to delineate mechanism(s) and identify potential biomarker candidate(s) of early stage ALD.

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Section: Introductionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Hepatic lipid profiling of deer mice fed ethanol using 1H and 31P NMR spectroscopy: A dose-dependent subchronic study

Fernando¹,

Bhopale²,

Boor³

et al. 2012

Toxicology and Applied Pharmacology

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“…Chronic alcohol consumption induces hepatic oxidative stress due to increased generation of reactive oxygen species and/or reduced antioxidant capacity (Seitz et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

The hepato-protective potentials of Moringa oleifera leaf extract on alcohol-induced hepato-toxicity in wistar rat

Saalu¹,

Ogunlade²

2012

AJBMS

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Alcohol (ethanol) is presently reputed to the most cause of disease development in humans. The liver is the human organ that is most frequently challenged in alcohol abuse by oral route in a process that involves generation of reactive oxygen species. In this study we evaluated the liver histology, liver oxidative stress and the activities of liver biomarker enzymes to investigate the capabilities of polyphenolic antioxidant-rich Moringa oleifera Leaf Extract to ameliorate liver derangement caused by alcohol. Three groups of Wistar rats were constructed for the study; A control group that received peanut oil (the vehicle) 300 mg kg -1 body weight, daily, orally, for 56 days, after saline 5 ml kg -1 body weight daily, orally for 56 days. The Moringa oleifera--alone group that received physiological saline 5 ml kg -1 body weight, daily, per oral for 56 days followed by Moringa oleifera leaf extract 300 mg kg -1 body weight, daily, orally for another 56 days. The alcohol-alone group was given alcohol 5 mg kg -1 body weight, daily, per oral for 56 days followed by saline 5 ml kg -1 body weight, daily per oral for another 56 days. Finally, the alcohol plus Moringa oleifera group which were similarly given alcohol, but had Moringa oleifera 300 mg kg -1 body weight, daily, per oral after alcohol for another 56 days.Our results demonstrated that post-treatment with Moringa oleifera leaf extract attenuated the liver morphological, functional and oxidative status changes mediated by alcohol ingestion.

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“…[91][92][93] Similarly, SAM therapy has also been shown to prevent alcoholic liver injury, which has been a subject of several review articles. [94][95][96][97][98] Recent results demonstrates a new signaling pathway implicated in the proliferation of the hepatocyte, where SAM modulates adenosine monophosphate-activated protein kinase activation and HuR (a RNA-binding protein) translocation induced by Figure 2 Current schematic of our working hypothesis. Increased hepatocellular S-adenosylhomocysteine (SAH) levels generated by chronic ethanol exposure can negatively affect the activities of the four methyltransferases, phosphatidylethanolamine methyltransferase (PEMT), isoprenylcysteine carboxyl methyltransferase (ICMT), protein-isoaspartate methyltransferases (PIMT), and protein arginine methyltransferase (PRMT).…”

Section: Defects In Crucial Methylation Reactionsmentioning

confidence: 99%

Alcoholic Liver Disease and Methionine Metabolism

Kharbanda¹

2009

Semin Liver Dis

102

121

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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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Alcoholic Liver Disease: From Pathophysiology to Therapy

Cited by 27 publications

References 32 publications

Hepatic lipid profiling of deer mice fed ethanol using 1H and 31P NMR spectroscopy: A dose-dependent subchronic study

Hepatic lipid profiling of deer mice fed ethanol using 1H and 31P NMR spectroscopy: A dose-dependent subchronic study

The hepato-protective potentials of Moringa oleifera leaf extract on alcohol-induced hepato-toxicity in wistar rat

Alcoholic Liver Disease and Methionine Metabolism

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