Clofibrate pretreatment in mice confers resistance against hepatic lipid peroxidation

Nicholls-Grzemski, Felicity A.; Belling, G. Brian; Priestly, Brian G.; Calder, I. C.; Burcham, Philip

doi:10.1002/1099-0461(2000)14:6<335::aid-jbt6>3.0.co;2-o

Cited by 16 publications

(3 citation statements)

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“…The increased glutathione availability and catalase activity by clofibrate were not the primary protective pathway in the protection against acetaminophen-induced hepatotoxicity and hepatic lipid peroxidation. [48][49][50] Thus, peroxisome proliferators are likely acting through the L-FABP pathway to scavenge high levels of ROS. Collectively, our data indicate that L-FABP is a strong endogenous antioxidant.…”

Section: Discussionmentioning

confidence: 99%

Antioxidative Function of L-FABP in L-FABP Stably Transfected Chang Liver Cells *

et al. 2005

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C ellular oxidative stress is one of the factors responsible for the propagation of liver diseases, such as hepatitis, cirrhosis, and hepatoma. 1 Several primary antioxidant defense systems such as superoxide dismutase (SOD), catalase, glutathione (GSH), and glutathione peroxidase are present intracellularly. These systems scavenge reactive oxygen species (ROS) such as hydrogen peroxide, superoxide, lipid peroxides, and free radicals. Exposure to oxidative stress may, however, deplete the cellular antioxidant capacity. Therefore, other antioxidant defense systems are expected to play an important role in oxidative stress.Liver fatty acid binding protein (L-FABP) is a 14-kd protein found abundantly in the cytoplasm and the nucleus of hepatocytes. 2,3 L-FABP is very likely to be an effective endogenous antioxidant, because it has high affinity and capacity to bind long-chain fatty acid oxidation products. 4,5 Hepatocyte L-FABP concentration could be as high as 0.4 mmol/L, 6 and it contains a large number of reducing amino acid residues (1 cysteine and 7 methionine residues) in its molecular structure. With an accessible volume enclosed by the molecular surface of L-FABP of 28,600 Å 3,7 the concentration of total methionine residues in L-FABP could be as high as approximately 400 mmol/L. Methionine and cysteine amino acids are regarded as cellular scavengers of activated xenobiotics and

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Section: Discussionmentioning

confidence: 99%

Antioxidative Function of L-FABP in L-FABP Stably Transfected Chang Liver Cells *

et al. 2005

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“…This observation is important because multiple peroxisome proliferators protect from APAP hepatotoxicity (Nicholls-Grzemski et al, 1992;Nguyen et al, 1999). In addition to its antioxidant properties, cysteamine decreases covalent binding of APAP to target hepatic proteins and reduces lipid peroxidation (Tredger et al, 1980;Stroo et al, 1985), as also seen with CFB-mediated hepatoprotection (Manautou et al, 1994;Nicholls-Grzemski et al, 2000a). Furthermore, primary hepatocytes isolated from mice treated in vivo with CFB are resistant to APAP, even with depletion of GSH by diethyl maleate (Nicholls-Grzemski et al, 2000b).…”

Section: Discussionmentioning

confidence: 99%

Differential gene expression in mouse liver associated with the hepatoprotective effect of clofibrate☆

Moffit

Koza-Taylor

Holland

et al. 2007

Toxicology and Applied Pharmacology

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Pretreatment of mice with the peroxisome proliferator clofibrate (CFB) protects against acetaminophen (APAP)-induced hepatotoxicity. Previous studies have shown that activation of the nuclear peroxisome proliferator activated receptor-alpha (PPARalpha) is required for this effect. The present study utilizes gene expression profile analysis to identify potential pathways contributing to PPARalpha-mediated hepatoprotection. Gene expression profiles were compared between wild type and PPARalpha-null mice pretreated with vehicle or CFB (500 mg/kg, i.p., daily for 10 days) and then challenged with APAP (400 mg/kg, p.o.). Total hepatic RNA was isolated 4 h after APAP treatment and hybridized to Affymetrix Mouse Genome MGU74 v2.0 GeneChips. Gene expression analysis was performed utilizing GeneSpring software. Our analysis identified 53 genes of interest including vanin-1, cell cycle regulators, lipid-metabolizing enzymes, and aldehyde dehydrogenase 2, an acetaminophen binding protein. Vanin-1 could be important for CFB-mediated hepatoprotection because this protein is involved in the synthesis of cysteamine and cystamine. These are potent antioxidants capable of ameliorating APAP toxicity in rodents and humans. HPLC-ESI/MS/MS analysis of liver extracts indicates that enhanced vanin-1 gene expression results in elevated cystamine levels, which could be mechanistically associated with CFB-mediated hepatoprotection.

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“…Galvinoxyl (1 ml of a 5-M solution) was added to a 1-cm quartz cuvette, and reactions were started by adding 10-l volumes of test compounds to yield a final concentration of 2.5 M. Galvinoxyl consumption was monitored at room temperature using a Hitachi U-2000 UV/VIS spectrophotometer (429-nm wavelength) (Hitachi Software Engineering, Yokohama, Japan). Lipid peroxidation in cell monolayers was assessed using the thiobarbituric acid assay (Nicholls-Grzemski et al, 2000).…”

Section: Methodsmentioning

confidence: 99%

Chaperone Heat Shock Protein 90 Mobilization and Hydralazine Cytoprotection against Acrolein-Induced Carbonyl Stress

Burcham

Raso²,

Kaminskas

2012

Mol Pharmacol

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Toxic carbonyls such as acrolein participate in many degenerative diseases. Although the nucleophilic vasodilatory drug hydralazine readily traps such species under "test-tube" conditions, whether these reactions adequately explain its efficacy in animal models of carbonyl-mediated disease is uncertain. We have previously shown that hydralazine attacks carbonyl-adducted proteins in an "adduct-trapping" reaction that appears to take precedence over direct "carbonyl-sequestering" reactions, but how this reaction conferred cytoprotection was unclear. This study explored the possibility that by increasing the bulkiness of acrolein-adducted proteins, adduct-trapping might alter the redistribution of chaperones to damaged cytoskeletal proteins that are known targets for acrolein. Using A549 lung adenocarcinoma cells, the levels of chaperones heat shock protein (Hsp) 40, Hsp70, Hsp90, and Hsp110 were measured in intermediate filament extracts prepared after a 3-h exposure to acrolein. Exposure to acrolein alone modestly increased the levels of all four chaperones. Coexposure to hydralazine (10 -100 M) strongly suppressed cell ATP loss while producing strong adduct-trapping in intermediate filaments. Most strikingly, hydralazine selectively boosted the levels of cytoskeletal-associated Hsp90, including a high-mass species that was sensitive to the Hsp90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin. Biochemical fractionation of acrolein-and hydralazine-treated cells revealed that hydralazine likely promoted Hsp90 migration from cytosol into other subcellular compartments. A role for Hsp90 mobilization in cytoprotection was confirmed by the finding that brief heat shock treatment suppressed acute acrolein toxicity in A549 cells. Taken together, these findings suggest that by increasing the steric bulk of carbonyl-adducted proteins, adduct-trapping drugs trigger the intracellular mobilization of the key molecular chaperone Hsp90.

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Clofibrate pretreatment in mice confers resistance against hepatic lipid peroxidation

Cited by 16 publications

References 62 publications

Antioxidative Function of L-FABP in L-FABP Stably Transfected Chang Liver Cells *

Antioxidative Function of L-FABP in L-FABP Stably Transfected Chang Liver Cells *

Differential gene expression in mouse liver associated with the hepatoprotective effect of clofibrate☆

Chaperone Heat Shock Protein 90 Mobilization and Hydralazine Cytoprotection against Acrolein-Induced Carbonyl Stress

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