MAP kinase signaling in diverse effects of ethanol

Aroor, Annayya R.; Shukla, Shivendra D.

doi:10.1016/j.lfs.2003.11.001

Cited by 187 publications

(151 citation statements)

References 163 publications

(197 reference statements)

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“…Continued chronic exposure to ethanol may impair liver function via pathways that are dependent or independent on ethanol metabolism. Ethanol also alters signal transduction pathways that include G protein coupled receptors and protein kinases (e. g. PKC, Src, MAPKs) as well as transcription factors (Peoples et al, 1996;Nagy, 2004;Aroor & Shukla, 2004).…”

Section: Introductionmentioning

confidence: 99%

Distinct methylation patterns in histone H3 at Lys-4 and Lys-9 correlate with up- & down-regulation of genes by ethanol in hepatocytes

et al. 2007

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Ethanol induced liver injury is associated with a global change in gene expression but its mechanisms are not known. We studied whether alcohol induced gene expression are associated with posttranslational methylations of histone H3. Primary culture of rat hepatocytes were treated with ethanol (50 or 100 mM) for 24 hr and the status of methylation of H3 at lys 4 (H3dimeK4) or lys 9 (H3dimeK9) were monitored by western blotting using antibodies to dimethylated histone H3 at lys 4 or lys 9. The cells exposed to ethanol showed strikingly opposing behaviors in methylation patterns; H3dimeK9 methylation was decreased whereas H3dimeK4 increased. Similar results were obtained in the interphase nuclei. Their binding on the metaphase chromosomes exhibit distinct site specific pattern of accumulation. Next, chromatin immuno-precipitation of the ethanol treated samples with antibodies for methylated lys 4 or lys 9 histone H3 followed by amplification of the immunoprecipitated DNA, was used to determine their association with the promoters of genes up-or down regulated by ethanol. Lys4 methylation was associated with ethanol up-regulated genes (Adh, GSTyc2) whereas lys 9 methylation with down regulated genes (Lsdh, cytP4502c11) demonstrating a difference between these two methylations. These results suggest that exposure of hepatocytes to ethanol changes the expression of several susceptible genes which are associated with site specific modification of dimethylated forms of histone H3 amino termini at their regulatory regions.

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Section: Introductionmentioning

confidence: 99%

Distinct methylation patterns in histone H3 at Lys-4 and Lys-9 correlate with up- & down-regulation of genes by ethanol in hepatocytes

et al. 2007

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“…The activation of p-JNK1/2 nor mally occurs in response to growth stimuli and is involved in cell proliferation [17] . This is also related to apoptosis and antiapoptosis, and is activated by cytokines or stress stimuli such as osmotic shock, UV light, and heat [9,18] .…”

Section: Discussionmentioning

confidence: 99%

Effects of ethanol on insulin-like growth factor-I system in primary cultured rat hepatocytes: Implications of JNK1/2 and alcoholdehydrogenase

Kim²,

Kang³

2008

WJG

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AIM:To evaluate the effects of ethanol on the insulinlike growth factor-Ⅰ (IGF-Ⅰ) system involved in c-Jun N-terminal kinase (JNK1/2) and alcoholdehydrogenase (ADH) activity in primary cultured rat hepatocytes. M E T H O D S : H e p a t o c y t e s i s o l a t e d f r o m m a l eSprague-Dawley rats were incubated with various concentrations of ethanol for different durations of time. The cells were pretreated with SP600125 (10 μmol/L) and 4-MP (200 μmol/L), and then treated with ethanol (200 mmol/L). We then measured IGF-Ⅰ secretion, IGF-Ⅰ mRNA expression, cell viability and JNK1/2 activity by radioimmunoassay, RT-PCR, MTT assay and Western blot, respectively (n = 6). RESULTS: Ethanol induced the activity of phospho (p)-JNK1/2, reaching a maximum at 60 min and then decreasing at 180 min. The effects of ethanol on the IGF-Ⅰ system were increased at 60 min (secretion:7.11 ± 0.59 ng/mg protein vs 4.91 ± 0.51 ng/mg, mRNA expression: 150.2% ± 10.2% vs 101.5% ± 11.3%, P = 0.045) and then decreased at 180 min (secretion: 3.89 ± 0.25 ng/mg vs 5.4 ± 0.54 ng/mg protein; mRNA expression: 41.5% ± 10.4% vs 84.7% ± 12.1%, P = 0.04), however cell viability was decreased in a dose-and time-dependent manner. SP600125 blocked the ethanol-induced changes (at 60 min). Additionally, 4-methylpyrazole prevented the ethanol-induced decreases in the IGF-Ⅰ system, cell viability and p-JNK1/2 activity (at 180 min). CONCLUSION: This study suggests that ethanolinduced p-JNK1/2 activation is associated with the IGF-Ⅰ system and cell viability in hepatocytes. Furthermore, alcohol dehydrogenase is involved in the relationship between ethanol-induced inactivation of p-JNK1/2 and the changes of the IGF-Ⅰ system and cell viability. Oh YI, Kim JH, Kang CW. Effects of ethanol on insulin-like growth factor-Ⅰ system in primary cultured rat hepatocytes: Implications of JNK1/2 and alcoholdehydrogenase.

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“…In chronic alcohol treatment, MAP kinase signaling pathways were involved in development of liver injuries [26][27][28]. Based upon the blunting of acute ethanol-induced steatosis by the JNK inhibitor, we evaluated whether JNK was indeed activated, and if so, which JNK isoform, JNK1 or JNK2 or both was activated.…”

Section: Acute Alcohol Treatment Induces Activation Of Jnk Map Kinasementioning

confidence: 99%

Cytochrome P4502E1, Oxidative Stress, JNK, and Autophagy in Acute Alcohol-Induced Fatty Liver

Cederbaum¹

2014

Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging

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Binge alcohol drinking induces hepatic steatosis. Recent studies showed that chronic ethanolinduced fatty liver was, at least in part, CYP2E1 dependent. The mechanism of acute alcohol induced steatosis and whether CYP2E1 plays any role is still unclear. Increasing oxidative stress by alcohol can activate the JNK MAP kinase signaling pathway, suggesting that JNK might be a target for prevention of alcohol induced steatosis. We used CYP2E1 knockout (KO) mice, a JNK inhibitor, and JNK1 or JNK2 knockout mice to test the role of CYP2E1, JNK, and the individual role of JNK1 and JNK2 in acute alcohol-induced steatosis. In wild type (WT) mice, acute alcohol activates CYP2E1 and increases oxidative stress, which reciprocally increases activation of the JNK signaling pathway. Acute alcohol-induced fatty liver and oxidative stress was blunted in CYP2E1 KO mice and by the JNK inhibitor in WT mice. The antioxidant N-acetylcysteine decreased the acute alcohol induced oxidative stress, activation of JNK and the steatosis but not the activation of CYP2E1. Acute alcohol decreased autophagy and increased expression of SREBP, effects blocked by the JNK inhibitor. Acute alcohol-induced fatty liver was the same in either JNK1 or JNK2 KO mice as WT mice, thus either JNK1 or JNK2 per se is sufficient in induction of steatosis by acute alcohol.Conclusion-acute alcohol elevation of CYP2E1, oxidative stress and activation of JNK interact to lower autophagy and increase lipogenic SREBP resulting in fatty liver.

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MAP kinase signaling in diverse effects of ethanol

Cited by 187 publications

References 163 publications

Distinct methylation patterns in histone H3 at Lys-4 and Lys-9 correlate with up- & down-regulation of genes by ethanol in hepatocytes

Distinct methylation patterns in histone H3 at Lys-4 and Lys-9 correlate with up- & down-regulation of genes by ethanol in hepatocytes

Effects of ethanol on insulin-like growth factor-I system in primary cultured rat hepatocytes: Implications of JNK1/2 and alcoholdehydrogenase

Cytochrome P4502E1, Oxidative Stress, JNK, and Autophagy in Acute Alcohol-Induced Fatty Liver

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