Mechanisms of alcohol-induced hepatotoxicity: studies in rats

R.G., R.G. Thurman

doi:10.2741/thurman

Cited by 40 publications

(17 citation statements)

References 10 publications

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“…Moreover, ERK1/2 phosphorylation was higher in KC Ethanol than in KC Control exposed to AA. These results, consistent with previous work by other laboratories, including ours (10,36,38), suggest a role for ROS in activating the pERK1/2 pathway and confirm that ethanol increases the AA-mediated effects on KC-derived TNF␣ production.…”

Section: Discussionsupporting

confidence: 93%

Arachidonic acid stimulates TNFα production in Kupffer cells via a reactive oxygen species-pERK1/2-Egr1-dependent mechanism

Cubero

Nieto

2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Kupffer cells are a key source of mediators of alcohol-induced liver damage such as reactive oxygen species, chemokines, growth factors, and eicosanoids. Since diets rich in polyunsaturated fatty acids are a requirement for the development of alcoholic liver disease, we hypothesized that polyunsaturated fatty acids could synergize with ethanol to promote Kupffer cell activation and TNFα production, hence, contributing to liver injury. Primary Kupffer cells from control and from ethanol-fed rats incubated with arachidonic acid showed similar proliferation rates than nontreated cells; however, arachidonic acid induced phenotypic changes, lipid peroxidation, hydroperoxides, and superoxide radical generation. Similar effects occurred in human Kupffer cells. These events were greater in Kupffer cells from ethanol-fed rats, and antioxidants and inhibitors of arachidonic acid metabolism prevented them. Arachidonic acid treatment increased NADPH oxidase activity. Inhibitors of NADPH oxidase and of arachidonic acid metabolism partially prevented the increase in oxidant stress. Upon arachidonic acid stimulation, there was a rapid and sustained increase in TNFα, which was greater in Kupffer cells from ethanol-fed rats than in Kupffer cells from control rats. Arachidonic acid induced ERK1/2 phosphorylation and nuclear translocation of early growth response-1 (Egr1), and ethanol synergized with arachidonic acid to promote this effect. PD98059, a mitogen extracellular kinase 1/2 inhibitor, and curcumin, an Egr1 inhibitor, blocked the arachidonic acid-mediated upregulation of TNFα in Kupffer cells. This study unveils the mechanism whereby arachidonic acid and ethanol increase TNFα production in Kupffer cells, thus contributing to alcoholic liver disease.

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Section: Discussionsupporting

confidence: 93%

Arachidonic acid stimulates TNFα production in Kupffer cells via a reactive oxygen species-pERK1/2-Egr1-dependent mechanism

Cubero

Nieto

2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Furthermore, the levels of Th17 cells, which are considered to be involved in many human inflammatory diseases, including psoriasis, have increased both in the circulation and in the liver of alcoholics with liver disease [36]. Alcohol metabolism can also lead to hepatocyte necrosis or apoptosis [37,38,39] and intracellular components derived from these cells can act as endogenous ‘danger signals' to activate the inflammatory response [40]. Additionally, the dysregulation of fatty acid metabolism resulting from alcohol metabolism contributes to fatty acid accumulation in hepatocytes inducing IL-8 synthesis, a cytokine which attracts neutrophils [41].…”

Section: Alcohol Liver and Persistent Systemic Inflammationmentioning

confidence: 99%

Alcohol, Liver, Systemic Inflammation and Skin: A Focus on Patients with Psoriasis

Farkas

Kemény

2013

Skin Pharmacol Physiol

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Emerging evidence suggests that excessive alcohol consumption is associated with psoriasis. In alcoholics, antipsoriatic treatments are less efficient, but more toxic and an additional challenge is poor therapeutic compliance. There is a correlation between excess alcohol intake and increased risk of infections, but on the other hand alcohol and its metabolites can trigger a persistent systemic inflammation, mediated by pro-inflammatory cytokines released from activated Kupffer cells in the liver and from monocytes in the circulation. Ethanol and its metabolites can also enhance lymphocyte and keratinocyte activation and proliferation and can increase the mRNA levels of genes characteristic for proliferating keratinocytes. In this review, we discuss the mechanisms by which alcohol contributes to psoriasis development focusing on liver, systemic inflammation and skin.

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“…Chronic ethanol exposure promotes the development of alcoholic liver disease (ALD), but the mechanisms underlying ethanol-induced hepatotoxicity remain poorly understood. 1,2 The effects of ethanol on hepatocyte function are diverse and range from an increased pro-oxidative state and acetaldehyde adduct formation to interference with cellular signaling processes associated with stress defenses. One of the primary sites manifesting damage brought on by ethanol is the mitochondria.…”

mentioning

confidence: 99%

Ethanol potentiates tumor necrosis factor-α cytotoxicity in hepatoma cells and primary rat hepatocytes by promoting induction of the mitochondrial permeability transition

2000

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Mechanisms of alcohol-induced hepatotoxicity: studies in rats

Cited by 40 publications

References 10 publications

Arachidonic acid stimulates TNFα production in Kupffer cells via a reactive oxygen species-pERK1/2-Egr1-dependent mechanism

Arachidonic acid stimulates TNFα production in Kupffer cells via a reactive oxygen species-pERK1/2-Egr1-dependent mechanism

Alcohol, Liver, Systemic Inflammation and Skin: A Focus on Patients with Psoriasis

Ethanol potentiates tumor necrosis factor-α cytotoxicity in hepatoma cells and primary rat hepatocytes by promoting induction of the mitochondrial permeability transition

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