Inhibition of Proteasome Function Leads to Nf–κB–Independent Il–8 Expression in Human Hepatocytes

Joshi‐Barve, Swati; Barve, Shirish; Butt, Waseem; Klein, Jon B.; McClain, Craig J.

doi:10.1053/jhep.2003.50470

Cited by 78 publications

(76 citation statements)

References 46 publications

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“…TLR4 is also expressed in HSCs and endothelial cells, and regulates alcohol-induced proangiogenic and profibrogenic responses [158] . Kupffer cell activation contributes to intrahepatic recruitment and activation of granulocytes [159][160][161] . Acetaldehyde and LPS [162][163][164] stimulate parenchymal and nonparenchymal cells to produce IL-8, chemokine CXC ligand (CXCL)1 (Gro-α) and IL-17 that directly or indirectly contribute to neutrophil infiltration and severity of AH [165][166][167] .…”

Section: Ethanol Oxidation and Activation Of Innate And Adaptive Immumentioning

confidence: 99%

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Ceni

Mello

Galli

2014

WJG

415

339

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Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). Although the pathogenesis of alcoholic liver disease (ALD) involves complex and still unclear biological processes, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species (ROS) play a preeminent role in the clinical and pathological spectrum of ALD. Ethanol oxidative metabolism influences intracellular signaling pathways and deranges the transcriptional control of several genes, leading to fat accumulation, fibrogenesis and activation of innate and adaptive immunity. Acetaldehyde is known to be toxic to the liver and alters lipid homeostasis, decreasing peroxisome proliferator-activated receptors and increasing sterol regulatory element binding protein activity via an AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK activation by ROS modulates autophagy, which has an important role in removing lipid droplets. Acetaldehyde and aldehydes generated from lipid peroxidation induce collagen synthesis by their ability to form protein adducts that activate transforming-growth-factor-β-dependent and independent profibrogenic pathways in activated hepatic stellate cells (HSCs). Furthermore, activation of innate and adaptive immunity in response to ethanol metabolism plays a key role in the development and progression of ALD. Acetaldehyde alters the intestinal barrier and promote lipopolysaccharide (LPS) translocation by disrupting tight and adherent junctions in human colonic mucosa. Acetaldehyde and LPS induce Kupffer cells to release ROS and proinflammatory cytokines and chemokines that contribute to neutrophils infiltration. In addition, alcohol consumption inhibits natural killer cells that are cytotoxic to HSCs and thus have an important antifibrotic function in the liver. Ethanol metabolism may also interfere with cell-mediated adaptive immunity by impairing proteasome function in macrophages and dendritic cells, and consequently alters allogenic antigen presentation. Finally, acetaldehyde and ROS have a role in alcohol-related carcinogenesis because they can form DNA adducts that are prone to mutagenesis, and they interfere with methylation, synthesis and repair of DNA, thereby increasing HCC susceptibility. Key words: Alcohol metabolism; Acetaldehyde; Reactive oxygen species; Alcoholic liver disease; Protein adducts; Hepatic stellate cells; Liver fibrosis; CYP2E1Core tip: The goal of this article is to review the mechanisms of alcohol-mediated toxicity in parenchymal and non-parenchymal cells of the liver. Specifically, we highlight the effect of oxidative ethanol metabolites such as acetaldehyde and reactive oxygen species in the development of fat accumulation, fibrosis and deranged immune response.Ceni E, Mello T, Galli A. Pathogenesis of alcoholic liver disease: Role of oxidative metabolism.

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Section: Ethanol Oxidation and Activation Of Innate And Adaptive Immumentioning

confidence: 99%

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Ceni

Mello

Galli

2014

WJG

415

339

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“…Known factors which sensitize the liver to TNFα are inhibitors of mRNA or protein synthesis, which likely prevent the synthesis of protective factors, inhibition of NF-κB activation to lower synthesis of such protective factors, depletion of GSH, especially mitochondrial GSH, lowering of s-adenosyl methionine (SAM) coupled to elevation of S-adenosyl homocysteine (SAH) i.e. a decline in the SAM/SAH ratio, or inhibition of the proteasome (203)(204)(205)(206)(207)(208)(209)(210). Of major relevance to this review, is the work by Hoek and collaborators that combined treatment with ethanol plus TNFα is more toxic to hepatocytes and HepG2 E47 cells which express high levels of CYP2E1 than control hepatocytes with lower levels of CYP2E1 or HepG2 C34 cells which do not express CYP2E1 (171).…”

Section: Lps/tnfα-cyp2e1 Interactionsmentioning

confidence: 99%

CYP2E1 and oxidative liver injury by alcohol

Cederbaum

2008

Free Radical Biology and Medicine

662

534

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Ethanol-induced oxidative stress appears to play a major role in mechanisms by which ethanol causes liver injury. Many pathways have been suggested to contribute to the ability of ethanol to induce a state of oxidative stress. One central pathway appears to be the induction of cytochrome P450 2E1 (CYP2E1) by ethanol. CYP2E1 metabolizes and activates many toxicological substrates, including ethanol, to more reactive, toxic products. Levels of CYP2E1 are elevated under a variety of physiological and pathophysiological conditions, and after acute and chronic alcohol treatment. CYP2E1 is also an effective generator of reactive oxygen species such as the superoxide anion radical and hydrogen peroxide, and in the presence of iron catalysts, produces powerful oxidants such as the hydroxyl radical. This Review Article summarizes some of the biochemical and toxicological properties of CYP2E1, and briefly describes the use of cell lines developed to constitutively express CYP2E1 in assessing the actions of CYP2E1. Possible therapeutic implications for treatment of alcoholic liver injury by inhibition of CYP2E1 or CYP2E1-dependent oxidative stress will be discussed, followed by some future directions which may help to understand the actions of CYP2E1 and its role in alcoholic liver injury.

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“…This proteasome pathway is independent of the activation of NF-κB, and may lead to the similar consequences-inflammatory chemokine infiltration such as IL-18, activation of cell differentiation and further damage to liver cells (Joshi-Barve et al 2003).…”

Section: Epigenetic Modifications In Hsc Promote Oxidative Stress Andmentioning

confidence: 99%