Cytochrome P450 2E1 contributes to ethanol-induced fatty liver in mice

Lu, Yongke; Zhuge, Jian; Wang, Xiaodong; Bai, Jing; Cederbaum, Arthur I.

doi:10.1002/hep.22222

Cited by 266 publications

(242 citation statements)

References 42 publications

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“…Also alcohol is known to induce hepatocellular lipid accumulation in vitro and in vivo [23,41]. Alcohol oxidation leads to acetyl-CoA synthesis from acetate or citrate that constitutes the substrates for lipogenic enzymes, and accordingly, we observed an increased expression of FASN and SCD1 in alcohol stimulated PHH.…”

Section: Discussionsupporting

confidence: 53%

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Identification of cytochrome CYP2E1 as critical mediator of synergistic effects of alcohol and cellular lipid accumulation in hepatocytes in vitro

Mahli

Thasler²,

Patsenker

et al. 2015

Z Gastroenterol

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Clinical studies propose a causative link between the consumption of alcohol and the development and progression of liver disease in obese individuals. However, it is incompletely understood how alcohol and obesity interact and whether the combined effects are additive or synergistic. In this study, we developed an in vitro model to address this question. Lipid accumulation in primary human hepatocytes was induced by incubation with oleic acid. Subsequently, steatotic and control hepatocytes were incubated with up to 50 mM alcohol. This alcohol concentration on its own revealed only minimal effects but significantly enhanced oleate-induced lipogenesis and cellular triglyceride content compared to control cells. Similarly, lipid peroxidation, oxidative stress and pro-inflammatory gene expression as well as CYP2E1 levels and activity were synergistically induced by alcohol and steatosis. CYP2E1 inhibition blunted these synergistic pathological effects. Notably, alcohol and cellular steatosis also induced autophagy in a synergistic manner, and also this was mediated via CYP2E1. Further induction of autophagy ameliorated the joint effects of alcohol and oleic acid on hepatocellular lipid accumulation and inflammatory gene expression while inhibition of autophagy further enhanced the dual pathological effects. Further analyses revealed that the joint synergistic effect of alcohol and steatosis on autophagy was mediated via activation of the JNK-pathway. In summary, our data indicate that alcohol induces not only pathological but also protective mechanisms in steatotic hepatocytes via CYP2E1. These findings may have important implications on the prognosis and treatment of alcoholic liver disease particularly in obese individuals.

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Section: Discussionsupporting

confidence: 53%

“…CYP2E1 activity has been shown to correlate with alcohol-induced liver injury, and inhibition of CYP2E1 prevented the induction of hepatic steatosis and ROS production in models of alcoholic steatohepatitis [23,41,44]. Also in NASH, increased CYP2E1 activity has been described and has been identified as a pathogenic factor [45][46][47].…”

Section: Discussionmentioning

confidence: 99%

Identification of cytochrome CYP2E1 as critical mediator of synergistic effects of alcohol and cellular lipid accumulation in hepatocytes in vitro

Mahli

Thasler²,

Patsenker

et al. 2015

Z Gastroenterol

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“…In mouse models of ALD, treatment with PPARα ligands such as WY14, 643 and clofibrate, restores receptor activity and significantly ameliorates fat accumulation and necroinflammation [63,64] . In addition, ethanol can also inhibit PPARα via upregulation of CYP2E1-derived oxidative stress [65] . Sterol regulatory element-binding proteins (SREBPs) are a family of transcription factors strictly correlated with PPARs and they control a set of enzymes involved in the synthesis of fatty acids and triglycerides.…”

Section: Mechanisms Of Alcoholic Fatty Livermentioning

confidence: 99%

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Ceni

Mello

Galli

2014

WJG

386

297

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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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“…These results indicate the importance of endotoxinactivated TLR4 signaling in the pathogenesis of aggravated steatohepatitis in alcohol-fed NS5A Tg mice. Oxidant damage is a key feature of alcoholic liver damage that can be further potentiated by endotoxin (28,29). Thus, we measured the hepatic content lipid peroxides in WT and NS5A Tg mice fed alcohol or control diet.…”

Section: Ns5amentioning

confidence: 99%

Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog

Machida

Tsukamoto²,

Mkrtchyan³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

207

218

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Alcohol synergistically enhances the progression of liver disease and the risk for liver cancer caused by hepatitis C virus (HCV). However, the molecular mechanism of this synergy remains unclear. Here, we provide the first evidence that Toll-like receptor 4 (TLR4) is induced by hepatocyte-specific transgenic (Tg) expression of the HCV nonstructural protein NS5A, and this induction mediates synergistic liver damage and tumor formation by alcohol-induced endotoxemia. We also identify Nanog, the stem/progenitor cell marker, as a novel downstream gene up-regulated by TLR4 activation and the presence of CD133/Nanog-positive cells in liver tumors of alcohol-fed NS5A Tg mice. Transplantation of p53-deficient hepatic progenitor cells transduced with TLR4 results in liver tumor development in mice following repetitive LPS injection, but concomitant transduction of Nanog shorthairpin RNA abrogates this outcome. Taken together, our study demonstrates a TLR4-dependent mechanism of synergistic liver disease by HCV and alcohol and an obligatory role for Nanog, a TLR4 downstream gene, in HCV-induced liver oncogenesis enhanced by alcohol.

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Cytochrome P450 2E1 contributes to ethanol-induced fatty liver in mice

Cited by 266 publications

References 42 publications

Identification of cytochrome CYP2E1 as critical mediator of synergistic effects of alcohol and cellular lipid accumulation in hepatocytes in vitro

Identification of cytochrome CYP2E1 as critical mediator of synergistic effects of alcohol and cellular lipid accumulation in hepatocytes in vitro

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog

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