Effects of acetaldehyde on nuclear protein binding to the nuclear factor I consensus sequence in the α2(I) collagen promoter

Anania, Frank A.; Potter, James J.; Rennie-Tankersley, Lynda; Mezey, Esteban

doi:10.1002/hep.1840210624

Cited by 18 publications

(18 citation statements)

References 31 publications

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“…The regulation of the type I collagens involves various transcription factors binding to proximal TGF-␤-responsive elements. In previous studies, we showed that acetaldehyde enhances the activity of the ␣ 2 (I) collagen promoter in stellate cells and that this effect is mediated by increased binding of nuclear proteins, including nuclear factor I to a region, which is located in the TGF-␤-responsive element (12). The binding of Sp1, by contrast, was not affected by acetaldehyde (14).…”

Section: The Activating Effect Of Acetaldehyde On Enhancing the Activmentioning

confidence: 84%

“…In previous studies, we showed that acetaldehyde enhances the activity of the murine ␣ 2 (I) collagen promoter in stellate cells and that this effect is mediated by increased binding of nuclear proteins including nuclear factor I to region Ϫ315 to Ϫ295 of the promoter (12). Although Sp1 is important in maintaining basal activity of the ␣ 2 (I) collagen promoter, it plays no role in mediating the effects of acetaldehyde (14).…”

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confidence: 94%

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Identification of a Novel NF-κB-binding Site with Regulation of the Murine α2(I) Collagen Promoter

Novitskiy

Potter

Rennie-Tankersley

et al. 2004

Journal of Biological Chemistry

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Hepatic fibrosis is due to the increased synthesis and deposition of type I collagen. Acetaldehyde activates type I collagen promoters. Nuclear factor B (NF-B) was previously shown to inhibit expression of murine ␣ 1 (I) and human ␣ 2 (I) collagen promoters. The present study identifies binding of NF-B, present in nuclear extracts of stellate cells, to a region between ؊553 and ؊537 of the murine ␣ 2 (I) collagen promoter. The NF-B (p65) expression vector inhibited promoter activity. Mutation of the promoter at the NF-B-binding site increased basal promoter activity and abrogated the activating and inhibitory effects of transforming growth factor ␤ and tumor necrosis factor ␣, respectively, on promoter activity. Acetaldehyde increased I B-␣ kinase activity and phosphorylated I B-␣, NF-B nuclear protein, and its binding to the promoter. However, the activating effect of acetaldehyde was not affected by the mutation of the promoter. In conclusion, although acetaldehyde increases the binding of NF-B to the murine ␣ 2 (I) collagen promoter, this binding does not mediate the activating effect of acetaldehyde on promoter activity. The effects of acetaldehyde in increasing the translocation of NF-B to the nucleus with increased DNA binding activity may be important in mediating the effects of acetaldehyde on other genes.

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Section: The Activating Effect Of Acetaldehyde On Enhancing the Activmentioning

confidence: 84%

mentioning

confidence: 94%

Identification of a Novel NF-κB-binding Site with Regulation of the Murine α2(I) Collagen Promoter

Novitskiy

Potter

Rennie-Tankersley

et al. 2004

Journal of Biological Chemistry

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“…However, the transacting factor binding to the AcRE after acetaldehyde was identified as NF-1. 47 This nuclear transcription factor has been shown to play an important role in TGF-␤1-mediated upregulation of the mouse col1a2. 48 However, our studies have failed to demonstrate binding of NF1 to the COL1A2 AcRE, as antibody interference assays with NF1 antibodies had no effect on retarded bands induced by acetaldehyde (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Early response of α2(I) collagen to acetaldehyde in human hepatic stellate cells is TGF-β independent

et al. 2005

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Acetaldehyde is fibrogenic and induces the expression of type I collagen genes in hepatic stellate cells. Some of these acetaldehyde-dependent events are mediated by H 2 O 2 and thus establish a direct connection between oxidative stress and collagen upregulation. We localized to the ؊378 to ؊183 region of the ␣2(I) collagen (COL1A2) promoter an acetaldehyde-responsive element (AcRE) functional in human hepatic stellate cells (HHSCs) and investigated molecular mechanisms whereby acetaldehyde stimulates and modulates its transcriptional activity. Because the AcRE co-localized with a previously described transforming growth factor ␤ (TGF-␤)1-responsive element, and both acetaldehyde and this cytokine induce their effects through H 2 O 2 , we investigated whether all fibrogenic actions of acetaldehyde were mediated by this cytokine. Here we show that acetaldehyde-induced COL1A2 upregulation in HHSCs recognizes two distinct but overlapping early and late stages that last from 1 to 6 hours and from 6 to 24 hours, respectively. We present several lines of evidence to show that early acetaldehyde-mediated events are independent of TGF-␤1. These include significant timecourse differences in the expression of COL1A2 and TGF-␤1 mRNAs and inability of neutralizing antibodies to TGF-␤1 to inhibit acetaldehyde-dependent collagen gene transcription and Smad 3 phosphorylation. We also show that although acetaldehyde-dependent upregulation of collagen was PI3K dependent, that of TGF-␤1 was PI3K independent. In conclusion, acetaldehyde-dependent mechanisms involved in COL1A2 upregulation are similar, but not identical, to those of TGF-␤1. We suggest that early acetaldehyde-dependent events induce the late expression of TGF-␤1 and create an H 2 O 2 -dependent autocrine loop that may sustain and amplify the fibrogenic response of this alcohol metabolite. (HEPATOLOGY 2005;42:343-352.)

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“…Both collagen α1(I) and α2(I) promoters have an acetaldehyde-responsive element (AcRE) that includes binding sites for different transcription factors including AP-1 and specificity protein (SP)-1. AP-1 activation is postulated to be involved in the acetaldehyde-induced expression of the basic transcription element binding protein (BTEB), which is able to transactivate the rat α1(I) collagen promoter [113,114] . 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.…”

Section: Mechanism Of Alcohol-induced Fibrogenesismentioning

confidence: 99%

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Ceni

Mello

Galli

2014

WJG

405

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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Effects of acetaldehyde on nuclear protein binding to the nuclear factor I consensus sequence in the α2(I) collagen promoter

Cited by 18 publications

References 31 publications

Identification of a Novel NF-κB-binding Site with Regulation of the Murine α2(I) Collagen Promoter

Identification of a Novel NF-κB-binding Site with Regulation of the Murine α2(I) Collagen Promoter

Early response of α2(I) collagen to acetaldehyde in human hepatic stellate cells is TGF-β independent

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

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