EFFECTS OF ACETALDEHYDE AND TNFα ON THE INHIBITORY KAPPA B- Α PROTEIN AND NUCLEAR FACTOR KAPPA B ACTIVATION IN HEPATIC STELLATE CELLS

Novitskiy, Gennadiy; Ravi, Rajani; Potter, James J.; Rennie-Tankersley, Lynda; Wang, Lan; Mezey, Esteban

doi:10.1093/alcalc/agh116

Cited by 21 publications

(13 citation statements)

References 30 publications

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“…Previous in vitro studies have suggested that acetaldehyde can increase TNFα production in both HepG2 cells and Kupffer cells (Hsiang et al, 2005; Cao et al, 2002). Since significant in vitro data from previous studies suggest a role for acetaldehyde in EtOH-mediated increases in TGFβ and stellate cell activation (Anania et al, 1996; Purohit and Brenner, 2006; Novitsky et al 2005; Zheng et al, 2007), it is surprising that 4MP treatment had no effect in the current study on EtOH-induced TGFβ mRNA or increased expression of SMA. Acetaldehyde has also been reported to inhibit hepatocyte proliferation in vitro (Clemens, 2007).…”

Section: Discussionmentioning

confidence: 59%

The role of ethanol metabolism in development of alcoholic steatohepatitis in the rat

Ronis

Korourian

Blackburn

et al. 2010

Alcohol

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The importance of ethanol (EtOH) metabolism in development of alcoholic liver disease remains controversial. The current study examined the effects of selective inhibition of the cytochrome P450 enzyme CYP2E1 compared to inhibition of overall EtOH metabolism on the development of alcoholic steatohepatitis. Adult male Sprague-Dawley rats were fed via total enteral nutrition for 45 d with or without 10-12 g/kg/d EtOH. Some groups were given 200 mg/kg/d of the CYP2E1 inhibitor diallylsulfide (DAS). Other groups were treated with 164 mg/kg/d of the alcohol dehydrogenase inhibitor 4-methylpyazole (4MP) and dosed at 2-3 g/kg/d EtOH to maintain similar average urine EtOH concentrations. Liver pathology scores and levels of apoptosis were elevated by EtOH (P< 0.05), but did not differ significantly on co-treatment with DAS or 4MP. However, liver triglycerides were lower when EtOH was fed with DAS or 4MP (P< 0.05). Serum alanine aminotransferase (ALT) values were significantly lower in EtOH-fed 4MP-treated rats indicating reduced necrosis. Hepatic oxidative stress and the endoplasmic reticulum (ER) stress marker TRB3 were increased after EtOH (P<0.05); further increased by DAS; but partly attenuated by 4MP. DAS and 4MP both reversed EtOH increases in the cytokine, tumor necrosis factor (TNF)α, and the chemokine CXCL-2 (P<0.05). However, neither inhibitor prevented EtOH suppression of interleukins IL-4 or IL-12. Moreover, neither inhibitor prevented EtOH increases in tumor growth factor (TGF)β mRNA. EtOH and DAS additively induced hepatic hyperplasia (P<0.05). These data suggest that a significant proportion of hepatic injury following EtOH exposure is independent of alcohol metabolism. EtOH metabolism by CYP2E1 may be linked in part to triglyceride accumulation; to induction of TNFα; and to chemokine production. EtOH metabolism by ADH may be linked in part to oxidative and ER stress and necrotic injury. KeywordsAlcohol; Liver; Metabolism; Acetaldehyde; ADH; CYP2E1 The role played by ethanol metabolism in the development of alcohol-induced liver damage (ALD) remains controversial. It has been suggested that oxidative stress, resulting from reactive oxygen species generated during metabolism of ethanol (EtOH) via a cytochrome P450 enzyme (CYP2E1)-dependent pathway, plays a primary role in hepatocellular necrosis and Kupffer cell activation (Lieber and De Carli, 1991;Ronis et al., 1996;Albano et al., 1996;Lu and Cederbaum, 2008, Butura et al., 2009). Similar claims regarding ALD have been made for acetaldehyde, the major product of ethanol metabolism by alcohol dehydrogenase (ADH) and CYP2E1 and for redox changes associated with increased conversion of NAD to NADH during ADH-dependent and subsequent aldehyde dehydrogenase-dependent metabolism of EtOH to acetaldehyde and acetate (Lieber and DeCarli 1991;Lieber 1993;Anania et al. 1996; Cao et al., 2000;Lieber 2004;Purohit and Brenner, 2006). Increased ALD has been described in conditions where CYP2E1 is over-expressed (Korourian et al., 1999;Butura et al., 2009). CYP2...

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Section: Discussionmentioning

confidence: 59%

The role of ethanol metabolism in development of alcoholic steatohepatitis in the rat

Ronis

Korourian

Blackburn

et al. 2010

Alcohol

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“…Acetaldehyde has also been shown to affect NFκB-induced cytokine production in various liver cells. In the presence of acetaldehyde, Kupffer cells, the specialized macrophages in the liver, treated with LPS show decreased NFκB activation (Jokelainen, Thomas et al 1998), while hepatic stellate cells, the major producers of collagen that accumulate during hepatic fibrosis, show enhanced NFκB activation (Novitskiy, Ravi et al 2005). Finally, acetaldehyde disrupts intestinal epithelial barrier function and increases paracellular permeability which plays a crucial role in the pathogenesis of alcoholic liver disease by a tyrosine kinase-dependent mechanism (Sheth, Seth et al 2004).…”

Section: Resultsmentioning

confidence: 99%

Opposing effects of alcohol on the immune system

Barr

Helms

Grant

et al. 2016

Progress in Neuro-Psychopharmacology and Biological Psychiatry

179

121

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Several studies have described a dose-dependent effect of alcohol on human health with light to moderate drinkers having a lower risk of all-cause mortality than abstainers, while heavy drinkers are at the highest risk. In the case of the immune system, moderate alcohol consumption is associated with reduced inflammation and improved responses to vaccination, while chronic heavy drinking is associated with a decreased frequency of lymphocytes and increased risk of both bacterial and viral infections. However, the mechanisms by which alcohol exerts a dose-dependent effect on the immune system remain poorly understood due to a lack of systematic studies that examine the effect of multiple doses and different time courses. This review will summarize our current understanding of the impact of moderate versus excessive alcohol consumption on the innate and adaptive branches of the immune system derived from both in vitro as well as in vivo studies carried out in humans and animal model studies.

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“…SREBP-1c knockout mice fed ethanol had the expected levels of proapoptotic factors, suggesting that CHOP, and the ER stress response, independently of SREBP-1c, play the major role in ethanol-induced apoptosis. Although there are reported correlations between TNF-␣ levels and SAH/SAM ratios after chronic ethanol feeding (43), TNF-␣ receptor (TNFR1) knockout mice were not protected against the ER stress response and responded to betaine administration the same as wild-type mice (32). Thus, homocysteine/ER stress pathways probably play a significant role in ethanol-induced liver disease synergistically with TNF-␣.…”

Section: Homocysteine and The Er Stress Responsementioning

confidence: 97%

Alcohol and lipid metabolism

Sozio

Crabb²

2008

American Journal of Physiology-Endocrinology and Metabolism

184

143

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Many new mechanisms for alcoholic steatosis have been suggested by work reported in the last five years. These include alterations of transcriptional controls of lipid metabolism, better understanding of the effects of abnormal methionine metabolism on the endoplasmic reticulum stress response, unraveling of the basis for sensitization of the Kupffer cell to lipopolysaccharide, a better understanding of the role of cytokines and adipokines in alcoholic liver disease, and implication of the innate immune and complement systems in responses to alcohol. Much of this work has been facilitated by work with knockout mice. Undoubtedly, there are interrelationships among these various pathogenic mechanisms that ultimately will provide a more cohesive picture of how heavy alcohol use deranges hepatic lipid metabolism.

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EFFECTS OF ACETALDEHYDE AND TNFα ON THE INHIBITORY KAPPA B- Α PROTEIN AND NUCLEAR FACTOR KAPPA B ACTIVATION IN HEPATIC STELLATE CELLS

Cited by 21 publications

References 30 publications

The role of ethanol metabolism in development of alcoholic steatohepatitis in the rat

The role of ethanol metabolism in development of alcoholic steatohepatitis in the rat

Opposing effects of alcohol on the immune system

Alcohol and lipid metabolism

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