Alcohol induced hepatic fibrosis: Role of acetaldehyde

Mello, Tommaso; Ceni, E.; Surrenti, C.; Galli, Andrea

doi:10.1016/j.mam.2007.10.001

Cited by 131 publications

(112 citation statements)

References 39 publications

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“…HSCs are one of the major sources of ECM in the liver and they have been identified as the precursor cell type mainly responsible for the development of liver fibrosis. Following liver injury, HSCs undergo activation that leads to the loss of the typical star-shape, fat-storing phenotype and acquisition of a myofibroblast-like phenotype consisting of increased cell proliferation, enhanced cytokine expression, and synthesis of ECM components [104,105] . Acetaldehyde is one of the main mediators of alcohol-induced fibrogenesis in the liver [106,107] .…”

Section: Mechanism Of Alcohol-induced Fibrogenesismentioning

confidence: 99%

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Ceni

Mello

Galli

2014

WJG

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388

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: Mechanism Of Alcohol-induced Fibrogenesismentioning

confidence: 99%

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Ceni

Mello

Galli

2014

WJG

Self Cite

388

339

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“…With continuing alcohol use, the disease progresses via continuing cellular injury, inflammation, impairment of hepatic regeneration, and increasing fibrogenesis to cirrhosis and its complications [2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Plasma membrane proteome analysis of the early effect of alcohol on liver: implications for alcoholic liver disease

Zhang¹,

Jia²,

Feng³

et al. 2011

ABBS

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In humans, the over-consumption of alcohol can lead to serious liver disease. To examine the early effects of alcohol on liver disease, rats were given sufficient ethanol to develop liver cirrhosis. Rats before the onset of fibrosis were studied in this work. Plasma membranes (PM) of liver were extracted by twice sucrose density gradient centrifugation. The proteome profiles of PM from ethanol-treated rats and the controls were analyzed using two-dimensional gel electrophoresis (2-DE) and isobaric tag for relative and absolute quantitation (iTRAQ) technology. Ethanol treatment altered the amount of 15 different liver proteins: 10 of them were detected by 2-DE and 5 by iTRAQ. Keratin 8 was detected by both methods. Gene ontology analysis of these differentially detected proteins indicated that most of them were involved in important cell functions such as binding activity (including ion, DNA, ATP binding, etc.), cell structure, or enzyme activity. Among these, annexin A2, keratin 8, and keratin 18 were further verified using western blot analysis and annexin A2 was verified by immunohistochemistry. Our results suggested that alcohol has the potential to affect cell structure, adhesion and enzyme activity by altering expression levels of several relevant proteins in the PM. To the best of our knowledge, this is the first time to study the effect of alcohol on the liver PM proteome and it might be helpful for understanding the possible mechanisms of alcohol-induced liver disease.

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“…In this setting, both host and microbial enzymes of the oro-gastrointestinal tract produce ethanol and oxidize it into acetaldehyde in a dose-dependent manner [70,83,[86][87][88][89][90][91]. Interestingly, on the one hand, exposure to ethanol stimulates alcoholdegrading enzymes [67,92], and on the other, it inhibits the catalytic action of aldehyde dehydrogenase (ALDH), thereby contributing to acetaldehyde accumulation [93][94][95][96][97][98]. This, coupled with hepatic firstpass metabolism (FPM) of ethanol may reduce substantially BACs.…”

Section: Oro-gastrointestinal Production Of Ethanol and Acetaldehydementioning

confidence: 99%

Nonalcoholic fatty pancreas disease as an endogenous alcoholic fatty pancreas disease

Medeiros¹,

Lima²

2016

Gastroenterol Hepatol Endosc

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Nonalcoholic fatty pancreas disease (NAFPD) is closely linked to nonalcoholic steatohepatitis (NASH), suggesting that the two conditions share a common etiopathogenetic background. In Addition, growing evidence indicates that endogenous ethanol (EE) plays a fundamental role in NASH pathogenesis. Accordingly, it is intuitively appealing to assume that EE plays also a causative role in NAFPD development. This connection is further supported by the finding that NAFPD shares with alcoholic fatty pancreas disease (AFPD) similar metabolic signaling pathways and histopathological features. However, low blood alcohol concentrations (BAC) along with the alleged inability of gut microbiota to produce toxic amounts of ethanol are the main obstacles to validate the idea of an endogenous alcoholic fatty pancreas disease (EAFPD). Here, we provide a mechanistic explanation reconciling the EAFPD hypothesis with these apparently conflicting observations. The key conclusions of our investigation are as follows. First, ethanol is a prodrug, implicating that under extensive presystemic metabolism BACs can be low and/ or absent. Second, oro-gastrointestinal microbiota may produce higher amounts of ethanol than those required to cause AFPD. Last, livers of NASH/NAFPD individuals overexpress all genes encoding alcohol-metabolizing enzymes identically to livers of patients with alcoholic hepatitis. Even more importantly, the upregulation of these genes is higher in the early steatotic stage of nonalcoholic fatty liver disease than in alcoholic hepatitis. This suggests a greater exposure of the liver, and by extension, of the pancreas, to ethanol in the former than in the latter condition. In summary, this paper provides a mechanistic framework for how NAFPD indeed may be an EAFPD.

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Alcohol induced hepatic fibrosis: Role of acetaldehyde

Cited by 131 publications

References 39 publications

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Plasma membrane proteome analysis of the early effect of alcohol on liver: implications for alcoholic liver disease

Nonalcoholic fatty pancreas disease as an endogenous alcoholic fatty pancreas disease

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