Acetaldehyde Inhibits PPARγ via H2O2-Mediated c-Abl Activation in Human Hepatic Stellate Cells

Ceni, E.; Crabb, David W.; Foschi, Marco; Mello, Tommaso; Tarocchi, Mirko; Patussi, Valentino; Moraldi, Luca; Moretti, Renato; Milani, Stefano; Surrenti, C.; Galli, Andrea

doi:10.1053/j.gastro.2006.08.009

Cited by 38 publications

(30 citation statements)

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“…To determine the effect of TZD and GW1929 on PPARc transcriptional activity in HBV transgenic mice, the ability of nuclear proteins extracted from isolated hepatocytes to bind a PPRE probe (ARE-7), that has previously been shown to bind preferentially PPARc over other PPAR isoforms, 15 was tested by EMSA. Nuclear extracts from hepatocytes isolated from control transgenic mice contained proteins that retarded the ARE-7 oligonucleotide (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Nuclear proteins were extracted from isolated hepatocytes based on a micropreparation method. 15 Electrophoretic mobility shift assays (EMSA) were performed by radiolabeling doublestranded oligonucleotides corresponding to the PPAR Response Element (PPRE) ARE7 (5 0 -TGCACATTT CACCCAGAGAGAAGGGATTGA-3 0 ). Transfection of Cultured Hepatocytes.…”

Section: Methodsmentioning

confidence: 99%

“…After 48 hours, the cells were harvested for luciferase and CAT assays. 15 Western Blot. Protein extracts were fractionated by 12% sodium dodecyl sulfate-polyacrylamide gel electrophoresis.…”

Section: Methodsmentioning

confidence: 99%

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Thiazolidinediones inhibit hepatocarcinogenesis in hepatitis B virus–transgenic mice by peroxisome proliferator‐activated receptor γ–independent regulation of nucleophosmin†

et al. 2010

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Antidiabetic thiazolidinediones (TZD) have in vitro antiproliferative effect in epithelial cancers, including hepatocellular carcinoma (HCC). The effective anticancer properties and the underlying molecular mechanisms of these drugs in vivo remain unclear. In addition, the primary biological target of TZD, the ligand-dependent transcription factor peroxisome proliferator-activated receptor c (PPARc), is up-regulated in HCC and seems to provide tumor-promoting responses. The aim of our study was to evaluate whether chronic administration of TZD may affect hepatic carcinogenesis in vivo in relation to PPARc expression and activity. The effect of TZD oral administration for 26 weeks was tested on tumor formation in PPARc-expressing and PPARc-deficient mouse models of hepatic carcinogenesis. Proteomic analysis was performed in freshly isolated hepatocytes by differential in gel electrophoresis and mass spectrometry analysis. Identified TZD targets were confirmed in cultured PPARc-deficient hepatocytes. TZD administration in hepatitis B virus (HBV)-transgenic mice (TgN[Alb1HBV]44Bri) reduced tumor incidence in the liver, inhibiting hepatocyte proliferation and increasing apoptosis. PPARc deletion in hepatocytes of HBV-transgenic mice (Tg[HBV]CreKOc) did not modify hepatic carcinogenesis but increased the TZD antitumorigenic effect. Proteomic analysis identified nucleophosmin (NPM) as a TZD target in PPARc-deficient hepatocytes. TZD inhibited NPM expression at protein and messenger RNA levels and decreased NPM promoter activity. TZD inhibition of NPM was associated with the induction of p53 phosphorylation and p21 expression. Conclusion: These findings suggest that chronic administration of TZD has anticancer activity in the liver via inhibition of NPM expression and indicate that these drugs might be useful for HCC chemoprevention and treatment. (HEPATOLOGY 2010;52:493-505)

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Thiazolidinediones inhibit hepatocarcinogenesis in hepatitis B virus–transgenic mice by peroxisome proliferator‐activated receptor γ–independent regulation of nucleophosmin†

et al. 2010

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“…In addition, acetaldehyde modulates collagen α1(I) expression with a mechanism involving members of the CAAT/enhanced binding protein (C/EBP) family of transcription factors. Acetaldehyde increases DNA binding and transcriptional activity of C/EBPβ [115,116] with a mechanism that requires H2O2 production [117] . Similarly, acetaldehyde exerts its profibrogenic action by inhibition of the PPARγ transcriptional activity in HSCs [118] .…”

Section: Mechanism Of Alcohol-induced Fibrogenesismentioning

confidence: 99%

“…Similarly, acetaldehyde exerts its profibrogenic action by inhibition of the PPARγ transcriptional activity in HSCs [118] . PPARγ is a member of the nuclear receptor superfamily of ligand-dependent transcription factors that is predominantly expressed in adipose tissue, where it has been shown to have a key role in adipogenesis and in regulation of insulin resistance [117] . Acetaldehyde inhibits PPARγ transcriptional activity in H2O2-dependent phosphorylation of the receptor [119][120][121] .…”

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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413

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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Hepatic Stellate Cells

Rojkind

Reyes‐Gordillo

2009

The Liver

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Acetaldehyde Inhibits PPARγ via H2O2-Mediated c-Abl Activation in Human Hepatic Stellate Cells

Cited by 38 publications

References 79 publications

Thiazolidinediones inhibit hepatocarcinogenesis in hepatitis B virus–transgenic mice by peroxisome proliferator‐activated receptor γ–independent regulation of nucleophosmin†

Thiazolidinediones inhibit hepatocarcinogenesis in hepatitis B virus–transgenic mice by peroxisome proliferator‐activated receptor γ–independent regulation of nucleophosmin†

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Hepatic Stellate Cells

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