Malondialdehyde and 4-hydroxynonenal protein adducts in plasma and liver of rats with iron overload.

Houglum, K; Filip, Małgorzata; Witztum, Joseph L.; Chojkier, Mario

doi:10.1172/jci114934

Cited by 240 publications

(155 citation statements)

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“…A large number of studies have suggested that aldehyde- protein adducts may play a role in the regulation of collagen gene expression and in the pathogenesis of liver fibrosis (1,6,12,14,15). Our study adds new evidence supporting the role of these adducts in the mediation of these effects, because pretreatment of HSC with pHMB or P5P abolished the effect of MDA on col1a1 mRNA levels (Fig.…”

Section: Discussionsupporting

confidence: 60%

Sp1 and Sp3 Transcription Factors Mediate Malondialdehyde-induced Collagen α1(I) Gene Expression in Cultured Hepatic Stellate Cells

Garcia‐Ruiz

Torre

Díaz

et al. 2002

Journal of Biological Chemistry

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Malondialdehyde, the end product of lipid peroxidation, has been shown to stimulate collagen ␣1(I) (Col1a1) gene expression. However, mechanisms of this effect are unclear. The purpose of this study was to clarify these mechanisms. Rat hepatic stellate cells were cultured in the presence of 200 M malondialdehyde, and the effects on collagen gene expression and the binding of nuclear proteins to the col1a1 promoter were analyzed. Malondialdehyde treatment induced an increase in the cellular levels of col1a1 mRNA that was abrogated by pretreating cells with cycloheximide, p-hydroxymercuribenzoate, pyridoxal 5-phosphate, and mithramycin. Transient transfections showed that malondialdehyde exerted its effect through regulatory elements located between ؊220 and ؊110 bp of the col1a1 promoter. Gel retardation assays demonstrated that malondialdehyde increased the binding of nuclear proteins to two elements located between ؊161 and ؊110 bp of the col1a1 promoter. These bindings were supershifted with Sp1 and Sp3 antibodies. Finally, malondialdehyde increased cellular levels of the Sp1 and Sp3 proteins and Sp1 mRNA. Our data indicated that treatment of hepatic stellate cells with malondialdehyde stimulated col1a1 gene expression by inducing the synthesis of Sp1 and Sp3 and their binding to two regulatory elements located between ؊161 and ؊110 bp of the col1a1 promoter.Lipid peroxidation by-products, particularly reactive aldehydes, such as malondialdehyde (MDA) 1 and 4-hydroxy-2-nonenal (4HNE), have been incriminated in the pathogenesis of liver fibrosis. Thus, Chojkier et al.(1) first showed that MDA increased significantly the collagen ␣1(I) (Col1a1) mRNA in cultured human fetal fibroblasts, and Maher et al. (2) found that collagen synthesis doubled in response to MDA in rat kidney fibroblasts. Likewise, Parola et al. (3,4) showed that 4HNE and other 4-hydroxy-2,3-alkenals, aldehydic end products of lipid peroxidations, were able to stimulate col1a1 gene expression and collagen synthesis in cultured hepatic stellate cells (HSC). Similar results have been reported by Tsukamoto and co-workers (5, 6), who also observed a significant correlation between the liver MDA and 4HNE levels and the hepatic collagen accumulation in a rat model of alcoholic liver disease.Mechanisms by which these reactive aldehydes induce col1a1 gene expression and synthesis are still unclear. However, a number of studies have provided evidence supporting the role of aldehyde-protein adducts in the regulation of col1a1 gene expression. These aldehydes are known to react with sulfhydryl or amino groups to form aldehyde-protein adducts (7). These adducts have been found in alcoholic liver disease (8, 9) and other clinical conditions of chronic liver injury associated with active fibrogenesis, as well as in animal models of lipid peroxidation (6, 10 -14). Moreover, antioxidant treatment significantly decreased the production of these adducts and prevented the fibrogenesis cascade (10, 13, 15). The purpose of this study was to clarify the mechanisms ...

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Section: Discussionsupporting

confidence: 60%

Sp1 and Sp3 Transcription Factors Mediate Malondialdehyde-induced Collagen α1(I) Gene Expression in Cultured Hepatic Stellate Cells

Garcia‐Ruiz

Torre

Díaz

et al. 2002

Journal of Biological Chemistry

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“…Exposure of the retina to LPS leads to increased oxidative stress as monitored by the levels of HNE. Several studies have shown that iron overload causes oxidative stress and that HNE levels increase under these conditions [36][37][38][39]. The LPS-induced oxidative stress in vivo in the retina is accompanied with apoptosis in specific cell types.…”

Section: Discussionmentioning

confidence: 99%

Hepcidin expression in mouse retina and its regulation via lipopolysaccharide/Toll-like receptor-4 pathway independent of Hfe

Gnana-Prakasam

Martin

Mysona

et al. 2008

Biochemical Journal

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SummaryHepcidin is a hormone central to the regulation of iron homeostasis in the body. It is believed to be produced exclusively by the liver. Ferroportin, an iron exporter, is the receptor for hepcidin. This transporter/receptor is expressed in Müller cells, photoreceptor cells, and retinal pigment epithelium (RPE) within the retina. Since the retina is protected by the retinal-blood barriers, we asked whether ferroportin in the retina is regulated by hepcidin in the circulation or whether the retina produces hepcidin for regulation of its own iron homeostasis. Here we show that hepcidin is expressed robustly in Müller cells, photoreceptor cells, and RPE, closely resembling the expression pattern of ferroportin. We also show that bacterial lipopolysaccharide (LPS) is a regulator of hepcidin expression in Müller cells and RPE, both in vitro and in vivo, and that the regulation occurs at the transcriptional level. The action of LPS on hepcidin expression is mediated by the Toll-like receptor-4. The upregulation of hepcidin by LPS occurs independent of Hfe (Human leukocyte antigen-like protein involved in Fe homeostasis). The increase in hepcidin levels in retinal cells in response to LPS treatment is associated with a decrease in ferroportin levels. The LPS-induced upregulation of hepcidin and consequent downregulation of ferroportin is associated with increased oxidative stress and apoptosis within the retina in vivo. We conclude that retinal iron homeostasis may be regulated in an autonomous manner by hepcidin generated within the retina and that chronic bacterial infection/inflammation of the retina may disrupt iron homeostasis and retinal function.

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“…GHstep by which excess iron causes cellular injury. [3][4][5] heterozygote status was assigned where there was one HLA haplo-…”

Section: Methodsmentioning

confidence: 99%

Excess iron induces hepatic oxidative stress and transforming growth factor β1 in genetic hemochromatosis

et al. 1997

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the absence of inflammation. TGF-b1 mediates many cellular Genetic hemochromatosis (GH) is associated with excess functions, including growth stimulation and inhibition, iron deposition in hepatocytes, which results in progressive apoptosis, increased extracellular matrix protein synthesis, hepatic injury. The pathogenesis of hepatic injury in GH is and decreased extracellular matrix degradation. [8][9][10][11][12] The colopoorly understood. In this study, we found enhanced oxidacalization of increased hepatic collagen a1(I) mRNA with tive stress in patients with GH, as evidenced by hepatic malon-TGF-b1 immunostaining suggests that TGF-b1 may also be dialdehyde (MDA)-protein adducts and by increased oxidaimportant in hepatic fibrogenesis associated with iron overtively modified serum proteins. MDA-lysine epitopes and load. The molecular mechanisms of TGF-b1 induction in oxidatively modified serum proteins, as well as immunogloburesponse to excess iron and enhanced lipid peroxidation in lin G autoantibodies against MDA-lysine epitopes, were inthe animal model of hemochromatosis are not known. creased in untreated GH patients and to a lesser extent in Iron directly or through the induction of cytokines, such GH heterozygotes compared with normal individuals. These as TGF-b1, could also play an important role in the developmarkers of ongoing oxidative stress decreased with phlebotment of liver injury 13-15 because excess iron removal in preomy treatment in GH patients. In addition, TGF-b1 colocalcirrhotic patients with GH prevents the development of fibroized with hepatic iron and MDA protein adducts in hepatosis and hepatocellular carcinoma formation. 16 However, it is cytes and sinusoidal cells of hepatic acinar zone 1 and not known whether excess hepatic iron in patients with GH normalized after iron removal. Our data suggest that iron is also associated with increased lipid peroxidation and TGFoverload increases both lipid peroxidation and TGF-b1 exb1 expression. In this study we analyzed whether hepatic pression, which together could promote hepatic injury and iron overload induces lipid peroxidation and TGF-b1 expresfibrogenesis. (HEPATOLOGY 1997;26:605-610.) sion in patients with GH. Genetic hemochromatosis (GH) is associated with excess PATIENTS AND METHODSiron deposition in hepatocytes, which results in hepatic injury. 1,2 The mechanisms responsible for the development of hydrazine to form a hydrazone complex, which was measured specof California, San Diego, CA; and 2 The Joint Liver Program, University of Queensland trophotometrically as described. 17 The hydrazone derivative has a

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Malondialdehyde and 4-hydroxynonenal protein adducts in plasma and liver of rats with iron overload.

Cited by 240 publications

References 38 publications

Sp1 and Sp3 Transcription Factors Mediate Malondialdehyde-induced Collagen α1(I) Gene Expression in Cultured Hepatic Stellate Cells

Sp1 and Sp3 Transcription Factors Mediate Malondialdehyde-induced Collagen α1(I) Gene Expression in Cultured Hepatic Stellate Cells

Hepcidin expression in mouse retina and its regulation via lipopolysaccharide/Toll-like receptor-4 pathway independent of Hfe

Excess iron induces hepatic oxidative stress and transforming growth factor β1 in genetic hemochromatosis

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