Involvement of histone acetyltransferase (HAT) in ethanol-induced acetylation of histone H3 in hepatocytes: potential mechanism for gene expression

Park, Pil-Hoon; Lim, Robert W.; Shukla, Shivendra D.

doi:10.1152/ajpgi.00091.2005

Cited by 102 publications

(123 citation statements)

References 59 publications

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“…Park et al (2005) found that both MEK and JNK pathways' inhibitors, but not p38, prevented the ethanol-induced increase in histone 3 lysine 9 acetylation. We therefore measured the levels of NFκB p65, p38, pJNK, p-AKT, and pErk1/pErk2 in the nuclear extracts from livers at the peaks and troughs of the UAL cycle.…”

Section: Resultsmentioning

confidence: 90%

“…Figure 3 shows that there was an increase in histone 3 lysine 9 acetylation at the peaks of the UAL cycle after chronic ethanol feeding. It was previously reported that there was an increase in histone 3 lysine 9 acetylation in acute ethanol exposure experiments (Park et al 2003(Park et al , 2005. This indicates that histone acetyltransferase (HAT) activity is increased, and that the histone acetyltransferase p300 may be responsible for this increased activity.…”

Section: Resultsmentioning

confidence: 91%

“…The fact that none of the signal transductio n pathways that interact with p300/CBP were not increased in the nuclear extracts at the peaks, suggests that the change in p300 mediated gene transcription is global and represents an epigenetic phenomenon. Park et al (2005) found an increase in HAT in the acute ethanol model. The inhibitors of MEK, and JNK but not p38, suppressed the increase in H3 acetylation.…”

Section: Discussionmentioning

confidence: 86%

“…One reason for focusing on histone acetylation in this model was that when histone acetyltransferase activity is increased and histone H3 acetylation at lysine 9 is increased when rat liver cells are exposed to an acute dose of ethanol in vitro (100 mM) or in vivo by administrating a 6 g dose of alcohol orally (Park et al, 2005;Park et al, 2003). As predicted, when histone H3 acetylated at lysine 9 was measured by Western blot in nuclear extracts from the livers of rats at the peaks and troughs of the UAL cycle, it was increased at the peaks, but not at the troughs.…”

Section: Introductionmentioning

confidence: 99%

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Histone acetyltransferase p300 modulates gene expression in an epigenetic manner at high blood alcohol levels

Bardag‐Gorce

French

Joyce

et al. 2007

Experimental and Molecular Pathology

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When rats are fed ethanol intragastrically at a constant rate for 1 month, the urinary alcohol level (UAL) cycles over 7-9 day intervals. At the peak UAL, the liver is hypoxic shifting from a redox state to a reduced rate. Microarray analysis done on livers at the UAL peaks shows changes in ~1300 gene expression compared to the pair-fed controls. To determine the mechanism of the gene expression changes, histone acetylation regulation was investigated in liver nuclear extracts at the peaks and troughs of the UAL and their pair-fed controls. No change occurred in SirT-1. P300, a histone acetyltransferase (HAT), which acetylates histone H3 on lysine 9, was increased at the peaks. Histone 3 acetylated at lysine 9 was also increased at the peaks. This indicates that the up regulated genes at the UAL peaks resulted from an increase in p300 transcription regulation, epigenetically. P300 activates transcription of numerous genes in response to signal transcription factors such as H1F 1α, increased in the nucleus at UAL peaks. Signal transduction pathways, such as NFκB, AP-1, ERK, JNK, and p38 were not increased at the peaks. β-catenin was increased in the nuclear extract at the UAL peaks and troughs, where increased gene expression was absent. The increase in gene expression at the peaks was due, in part, to increased acetylation of histone 3 at lysine 9.

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Section: Resultsmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Histone acetyltransferase p300 modulates gene expression in an epigenetic manner at high blood alcohol levels

Bardag‐Gorce

French

Joyce

et al. 2007

Experimental and Molecular Pathology

View full text Add to dashboard Cite

show abstract

“…This effect has been observed in isolated hepatocytes and in rat liver after both acute and chronic ethanol exposure [8,[17][18][19][20][21] . Although histone H3 encodes at least four acetylated lysines (lys 9, 14, 18 and 23), acetylation of lysine 9 is selectively increased after exposure to physiological ethanol concentrations [8] .…”

Section: Histone H3mentioning

confidence: 99%

Alcohol-induced protein hyperacetylation: Mechanisms and consequences

Shepard

Tuma

2009

WJG

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Although the clinical manifestations of alcoholic liver disease are well-described, little is known about the molecular basis of liver injury. Recent studies have indicated that ethanol exposure induces global protein hyperacetylation. This reversible, posttranslational modification on the ε-amino groups of lysine residues has been shown to modulate multiple, diverse cellular processes ranging from transcriptional activation to microtubule stability. Thus, alcoholinduced protein hyperacetylation likely leads to major physiological consequences that contribute to alcohol-induced hepatotoxicity. Lysine acetylation is controlled by the activities of two opposing enzymes, histone acetyltransferases and histone deacetylases. Currently, efforts are aimed at determining which enzymes are responsible for the increased acetylation of specific substrates. However, the greater challenge will be to determine the physiological ramifications of protein hyperacetylation and how they might contribute to the progression of liver disease. In this review, we will first list and discuss the proteins known to be hyperacetylated in the presence of e t h a n o l . We w i l l t h e n d e s c r i b e w h a t i s k n o w n about the mechanisms leading to increased protein acetylation and how hyperacetylation may perturb hepatic function.

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Acetate, the key modulator of inflammatory responses in acute alcoholic hepatitis

et al. 2010

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Acute alcoholic hepatitis is characterized by disproportionate macrophage inflammatory cytokine responses to bacterial lipopolysaccharide. Lack of knowledge of the underlying mechanism has limited progress toward effective therapy. We postulated a novel mechanism by which ethanol increases histone acetylation, increasing proinflammatory gene transcription and cytokine synthesis. Cytokine responses to lipopolysaccharide in a human macrophage cell line cultured in 86 mM ethanol, 1 mM acetate, and normal media were measured by multiplex immunoassay. Changes in histone acetylation were determined by immunofluorescence microscopy and chromatin immunoprecipitation on presentation. The effect of ethanol and acetate on acetyl-coenzyme A (acetyl-coA) synthetases, which convert acetate to acetyl-coA, the substrate for histone acetylation, was determined by quantitative reverse-transcription polymerase chain reaction and immunoblotting. Knockdown of acetyl-coA synthetases by short hairpin RNA (shRNA) was used to determine their role in ethanol's enhancement of the inflammatory cytokine response. Ethanolexposed macrophages developed enhanced interleukin 6 (IL6), IL8, and tumor necrosis factor alpha responses to lipopolysaccharide with time-dependent increases in histone acetylation that could be prevented by inhibition of ethanol metabolism. Chromatin immunoprecipitation confirmed increased histone acetylation at promoter regions of specific cytokine genes. The effect of ethanol was reproduced by incubation with acetate, the principal hepatic metabolite of ethanol, and both ethanol and acetate reduced histone deacetylase activity and up-regulated acetyl-coA synthetases. Knockdown of the acetyl-coA synthetases abrogated the effect of ethanol on cytokine production. Conclusion: Synthesis of metabolically available acetyl-coA from acetate is critical to the increased acetylation of proinflammatory gene histones and consequent enhancement of the inflammatory response in ethanol-exposed macrophages. This mechanism is a potential therapeutic target in acute alcoholic hepatitis. (HEPATOLOGY 2010; 51:1988-1997 A lcoholic liver disease (ALD) is a significant and growing global health problem. Clinical liver failure in ALD can result from chronic hepatocyte injury producing cirrhosis or from rapid, acute hepatocellular dysfunction secondary to inflammation in acute alcoholic hepatitis. AAH This acute inflammatory form of ALD carries a mortality of up to 35% on first presentation, killing patients before they have the opportunity to reap the benefits of appropriate health education and subsequent abstinence from alcohol. 1

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Involvement of histone acetyltransferase (HAT) in ethanol-induced acetylation of histone H3 in hepatocytes: potential mechanism for gene expression

Cited by 102 publications

References 59 publications

Histone acetyltransferase p300 modulates gene expression in an epigenetic manner at high blood alcohol levels

Histone acetyltransferase p300 modulates gene expression in an epigenetic manner at high blood alcohol levels

Alcohol-induced protein hyperacetylation: Mechanisms and consequences

Acetate, the key modulator of inflammatory responses in acute alcoholic hepatitis

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