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The role of aldehyde oxidase in ethanol-induced hepatic lipid peroxidation in the rat.

ABSTRACT: Hepatic lipid peroxidation has been implicated in the pathogenesis of alcohol-induced liver injury, but the mechanism(s) by which ethanol metabolism or resultant free radicals initiate lipid peroxidation is not fully defined. The role of the molybdenum-containing enzymes aldehyde oxidase and xanthine oxidase in the generation of such free radicals was investigated by measuring alkane production (lipoperoxidation products) in isolated rat hepatocytes during ethanol metabolism. Inhibition of aldehyde oxidase and xanthine oxidase (by feeding tungstate at 100 mg/day per kg) decreased alkane production (80-95%), whereas allopurinol (20 mg/kg by mouth), a marked inhibitor of xanthine oxidase, inhibited alkane production by only 35-50%. Addition of acetaldehyde (0-100 microM) (in the presence of 50 microM-4-methylpyrazole) increased alkane production in a dose-dependent manner (Km of aldehyde oxidase for acetaldehyde 1 mM); menadione, an inhibitor of aldehyde oxidase, virtually inhibited alkane production. Desferrioxamine (5-10 microM) completely abolished alkane production induced by both ethanol and acetaldehyde, indicating the importance of catalytic iron. Thus free radicals generated during the metabolism of acetaldehyde by aldehyde oxidase may be a fundamental mechanism in the initiation of alcohol-induced liver injury.

SUBMITTER: Shaw S

PROVIDER: S-EPMC1131477 | biostudies-other | 1990 Jun

REPOSITORIES: biostudies-other

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A signature of enhanced lipid metabolism, lipid peroxidation and aldehyde stress in therapy-induced senescence.

Project description:At their proliferative limit, normal cells arrest and undergo replicative senescence, displaying large cell size, flat morphology, and senescence-associated beta-galactosidase (SA-β-Gal) activity. Normal or tumor cells exposed to genotoxic stress undergo therapy-induced senescence (TIS), displaying a similar phenotype. Senescence is considered a DNA damage response, but cellular heterogeneity has frustrated identification of senescence-specific markers and targets. To explore the senescent cell proteome, we treated tumor cells with etoposide and enriched SA-β-GalHI cells by fluorescence-activated cell sorting (FACS). The enriched TIS cells were compared to proliferating or quiescent cells by label-free quantitative LC-MS/MS proteomics and systems analysis, revealing activation of multiple lipid metabolism pathways. Senescent cells accumulated lipid droplets and imported lipid tracers, while treating proliferating cells with specific lipids induced senescence. Senescent cells also displayed increased lipid aldehydes and upregulation of aldehyde detoxifying enzymes. These results place deregulation of lipid metabolism alongside genotoxic stress as factors regulating cellular senescence.

| S-EPMC5661608 | biostudies-literature

The Structural Integrity of the Model Lipid Membrane during Induced Lipid Peroxidation: The Role of Flavonols in the Inhibition of Lipid Peroxidation.

Project description:The structural integrity, elasticity, and fluidity of lipid membranes are critical for cellular activities such as communication between cells, exocytosis, and endocytosis. Unsaturated lipids, the main components of biological membranes, are particularly susceptible to the oxidative attack of reactive oxygen species. The peroxidation of unsaturated lipids, in our case 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), induces the structural reorganization of the membrane. We have employed a multi-technique approach to analyze typical properties of lipid bilayers, i.e., roughness, thickness, elasticity, and fluidity. We compared the alteration of the membrane properties upon initiated lipid peroxidation and examined the ability of flavonols, namely quercetin (QUE), myricetin (MCE), and myricitrin (MCI) at different molar fractions, to inhibit this change. Using Mass Spectrometry (MS) and Fourier Transform Infrared Spectroscopy (FTIR), we identified various carbonyl products and examined the extent of the reaction. From Atomic Force Microscopy (AFM), Force Spectroscopy (FS), Small Angle X-Ray Scattering (SAXS), and Electron Paramagnetic Resonance (EPR) experiments, we concluded that the membranes with inserted flavonols exhibit resistance against the structural changes induced by the oxidative attack, which is a finding with multiple biological implications. Our approach reveals the interplay between the flavonol molecular structure and the crucial membrane properties under oxidative attack and provides insight into the pathophysiology of cellular oxidative injury.

| S-EPMC7278707 | biostudies-literature

Activation of aldehyde dehydrogenase 2 protects ethanol-induced osteonecrosis of the femoral head in rat model.

Project description:ObjectivesOsteonecrosis of the femoral head (ONFH) is a devastating disease characterized by destructive bone structures, enlarged adipocyte accumulation and impaired vascularization. The aldehyde dehydrogenase 2 (ALDH 2) is the limiting enzyme for ethanol metabolism with many physiological functions. The aim was investigated the potential protective role of activated ALDH 2 by Alda-1 for ethanol-induced ONFH.Materials and methodsThe ethanol-induced ONFH in rat was performed to explore the protective of Alda-1 by various experimental methods. Subsequently, the effect of Alda-1 and ethanol on the osteogenic and adipogenic differentiation was investigated via multiple cellular and molecular methods. Finally, the effect of Alda-1 and ethanol on the neo-vascularization was detected in Human umbilical vein endothelial cells (HUVECs) and ONFH model.ResultsFirstly, radiographical and pathological measurements indicated that alda-1 protected ethanol-induced ONFH. Moreover, ethanol significantly inhibited the proliferation and osteogenic differentiation of BMSCs, whereas Alda-1 could distinctly rescue it by PI3K/AKT signalling. Secondly, ethanol remarkably promoted the lipid vacuoles formation of BMSCs, while Alda-1 significantly retarded it on BMSCs by AMPK signalling pathway. Finally, ethanol significantly inhibited proliferation and growth factor level resulting in reduced angiogenesis, whereas Alda-1 could rescue the effect of ethanol. Additionally, Alda-1 significantly reduced the occurrence of ONFH and promoted vessel number and distribution in alcoholic ONFH.ConclusionsAlda-1 activation of ALDH 2 was highly demonstrated to protect ethanol-induced ONFH by triggering new bone formation, reducing adipogenesis and stimulating vascularization.

| S-EPMC9201375 | biostudies-literature

Ethanol augments PDGF-induced NADPH oxidase activity and proliferation in rat pancreatic stellate cells.

Project description:Background/aimsActivated stellate cells are considered the principal mediators of chronic alcoholic pancreatitis/fibrosis. However the mechanisms of alcohol action on pancreatic stellate cells (PaSCs) are poorly understood. The aims of this study were to determine the presence and role of the NADPH oxidase system in mediating alcohol effects on PaSCs with specific emphasis on proliferation.MethodsPaSC NADPH oxidase components mRNA and protein were determined by RT-PCR and Western blot. The NADPH oxidase activity was measured by detecting the production of reactive oxygen species using lucigenin-derived chemiluminescence assay. PaSC DNA synthesis, a measure of proliferation, was performed by determining the [3H] thymidine incorporation into DNA.ResultsmRNA for NADPH oxidase components Nox1, gp91(phox), Nox4, p22(phox), p47(phox) and p67(phox) and protein for NADPH oxidase subunits gp91(phox), p22(phox), p47(phox) and p67(phox) are present in PaSCs. Treatment with platelet-derived growth factor (PDGF) significantly increased the NADPH oxidase activity and DNA synthesis in cultured PaSCs. Alcohol treatment markedly augmented both the NADPH oxidase activity and the DNA synthesis caused by PDGF, which was prevented by antioxidant N-acetyl-L-cysteine, ROS scavenger tiron, and the NADPH oxidase inhibitor diphenylene iodium. The effects of PDGF on NADPH oxidase activity and DNA synthesis were prevented in PaSCs isolated from the pancreas of mice with a genetic deficiency of p47(phox).ConclusionsEthanol causes proliferation of stellate cells by augmenting the activation of the cell's NADPH oxidase system stimulated by PDGF. These results provide new insights into the mechanisms of alcohol-induced fibrosing disorders.

| S-EPMC2826430 | biostudies-literature

Lipid droplet membrane proteome remodeling parallels ethanol-induced hepatic steatosis and its resolution.

Project description:Lipid droplets (LDs) are composed of neutral lipids enclosed in a phospholipid monolayer, which harbors membrane-associated proteins that regulate LD functions. Despite the crucial role of LDs in lipid metabolism, remodeling of LD protein composition in disease contexts, such as steatosis, remains poorly understood. We hypothesized that chronic ethanol consumption, subsequent abstinence from ethanol, or fasting differentially affects the LD membrane proteome content and that these changes influence how LDs interact with other intracellular organelles. Here, male Wistar rats were pair-fed liquid control or ethanol diets for 6 weeks, and then, randomly chosen animals from both groups were either refed a control diet for 7 days or fasted for 48 h before euthanizing. From all groups, LD membrane proteins from purified liver LDs were analyzed immunochemically and by MS proteomics. Liver LD numbers and sizes were greater in ethanol-fed rats than in pair-fed control, 7-day refed, or fasted rats. Compared with control rats, ethanol feeding markedly altered the LD membrane proteome, enriching LD structural perilipins and proteins involved in lipid biosynthesis, while lowering LD lipase levels. Ethanol feeding also lowered LD-associated mitochondrial and lysosomal proteins. In 7-day refed (i.e., ethanol-abstained) or fasted-ethanol-fed rats, we detected distinct remodeling of the LD proteome, as judged by lower levels of lipid biosynthetic proteins, and enhanced LD interaction with mitochondria and lysosomes. Our study reveals evidence of significant remodeling of the LD membrane proteome that regulates ethanol-induced steatosis, its resolution after withdrawal and abstinence, and changes in LD interactions with other intracellular organelles.

| S-EPMC8010705 | biostudies-literature

Parkin deficiency prevents chronic ethanol-induced hepatic lipid accumulation through β-catenin accumulation.

Project description:BackgroundAlcohol abuse and alcoholism lead to alcohol liver disease such as alcoholic fatty liver. Parkin is a component of the multiprotein E3 ubiquitin ligase complex and is associated with hepatic lipid accumulation. However, the role of parkin in ethanol-induced liver disease has not been reported. Here, we tested the effect of parkin on ethanol-induced fatty liver in parkin knockout (KO) mice with chronic ethanol feeding.MethodsMale wild type (WT) and parkin KO mice (10-12 weeks old, n = 10) were fed on a Lieber-DeCarli diet containing 6.6% ethanol for 10 days. Liver histological, biochemical, and gene-expression studies were performed.ResultsParkin KO mice exhibited lower hepatosteatosis after ethanol consumption. Because several studies reported that β-catenin is a critical factor in ethanol metabolism and protects against alcohol-induced hepatosteatosis, we investigated whether parkin changes β-catenin accumulation in the liver of ethanol-fed mice. Our results show that β-catenin was greatly accumulated in the livers of ethanol-fed parkin KO mice compared to ethanol-fed WT mice, and that parkin binds to β-catenin and promotes its degradation it by ubiquitination. Moreover, the β-catenin inhibitor IWR-1 abrogated the attenuation of ethanol-induced hepatic lipid accumulation by parkin deficiency in the livers of parkin KO mice and parkin siRNA-transfected human hepatic cell line.ConclusionsParkin deficiency prevents ethanol-induced hepatic lipid accumulation through promotion of β-catenin signaling by failure of β-catenin degradation.

| S-EPMC6704582 | biostudies-literature

<i>Ganoderma lucidum</i> Modulates Glucose, Lipid Peroxidation and Hepatic Metabolism in Streptozotocin-Induced Diabetic Pregnant Rats.

Project description:The consumption of functional foods, such as mushrooms, apparently influences Gestational Diabetes Mellitus (GDM), and brings benefits to maternal-fetal health. Ganoderma lucidum contains a variety of bioactive compounds, such as polysaccharides, proteins and polyphenols that are able to control blood glucose and be used in anti-cancer therapy. We aimed to evaluate the effects of the consumption of Ganoderma lucidum (Gl) on maternal-fetal outcomes in streptozotocin-induced GDM (GDM-STZ). Pregnant rats were exposed to Gl (100 mg/kg/day) before and after the induction of GDM-STZ (single dose 40 mg/kg) on the eighth pregnancy day. Biochemical and oxidative stress parameters, reproductive performance and morphometry of fetuses were assessed. Gl reduced the glycemic response in the oral glucose tolerance test. Moreover, Gl decreased AST and ALT activities. GDM increased lipid peroxidation, which was reverted by Gl. Catalase and glutathione peroxidase activities were decreased in GDM and the administered Gl after the fetus implantation increased catalase activity. Measurements of the fetal head, thorax, craniocaudal and tail showed greater values in fetuses from rats exposed to Gl compared to GDM. Ganoderma lucidum has an encouraging nutritional and medicinal potential against GDM, since it modifies glucose metabolism, reduces lipid peroxidation, and has protective effects in fetuses born from GDM dams.

| S-EPMC9219838 | biostudies-literature

Inactivation of cytosolic aldehyde dehydrogenase via S-nitrosylation in ethanol-exposed rat liver.

Project description:Aldehyde dehydrogenase (ALDH) isozymes are critically important in the metabolism of acetaldehyde, thus preventing its accumulation after ethanol-exposure. We previously reported that mitochondrial ALDH2 could be inactivated via S-nitrosylation in ethanol-exposed rats. This study was aimed at investigating whether cytosolic ALDH1, with a relatively-low-Km value (11-18 microM) for acetaldehyde, could be also inhibited in ethanol-exposed rats. Chronic or binge ethanol-exposure significantly decreased ALDH1 activity, which was restored by addition of dithiothreitol. Immunoblot analysis with the anti-S-nitroso-Cys antibody showed one immunoreactive band in the immunoprecipitated ALDH1 only from ethanol-exposed rats, but not from pair-fed controls, suggesting S-nitrosylation of ALDH1. Therefore inactivation of ALDH1 via S-nitrosylation can result in accumulation of acetaldehyde upon ethanol-exposure.

| S-EPMC2693367 | biostudies-literature

Carbon tetrachloride, bromotrichloromethane and ethanol acute intoxication. New chemical evidence for lipid peroxidation in rat tissue microsomes.

Project description:Second-derivative spectroscopy was used to determine the conjugated-diene shift that measures the extent of the first step of lipid peroxidation after carbon tetrachloride (CCl4), bromotrichloromethane (BrCCl3) and ethanol intoxication. The conjugated-diene signal was recorded in the second-derivative spectra as a minimum peak at 233 nm. The use of this method enabled us to show that, under our experimental conditions, CCl4- and BrCCl3-dependent conjugated-diene formation in rat liver microsomes is not dose-dependent and increases linearly with time up to 3h. Proportionality was not obtained between the second-derivative-spectroscopy method, and the thiobarbituric acid and difference-spectra methods. In addition, whereas the thiobarbituric acid and difference-spectra methods gave positive results at zero time, second-derivative spectroscopy showed no evidence of formation of conjugated dienes under the same experimental conditions. Intoxication with ethanol was shown by the appearance of the conjugated-diene signal in liver microsomes 24 h after the administration of the toxin. Intoxication with either of the haloalkanes or ethanol did not give rise to any similar peak in lung and brain microsomes. The results obtained are discussed.

| S-EPMC1153136 | biostudies-other

Pharmacologic Ascorbate Radiosensitizes Pancreatic Cancer but Radioprotects Normal Tissue: The Role of Oxidative Stress-Induced Lipid Peroxidation.

Project description:The toxicity of ionizing radiation limits its effectiveness in the treatment of pancreatic ductal adenocarcinoma. Pharmacologic ascorbate (P-AscH-) has been shown to radiosensitize pancreatic cancer cells while simultaneously radioprotecting normal cells. We hypothesize that P-AscH- protects the small intestine while radiosensitizing pancreatic cancer cells partially through an oxidative stress mechanism. Duodenal samples from pancreaticoduodenectomy specimens of patients who underwent radio-chemotherapy ± P-AscH- and mouse tumor and jejunal samples treated with radiation ± P-AscH- were evaluated. Pancreatic cancer and non-tumorigenic cells were treated with radiation ± P-AscH- to assess lipid peroxidation. To determine the mechanism, pancreatic cancer cells were treated with selenomethionine or RSL3, an inhibitor of glutathione peroxidase 4 (GPx4). Radiation-induced decreases in villi length and increases in 4-HNE immunofluorescence were reversed with P-AscH- in human duodenum. In vivo, radiation-induced decreases in villi length and increased collagen deposition were reversed in P-AscH--treated jejunal samples. P-AscH- and radiation increased BODIPY oxidation in pancreatic cancer cells but not in non-tumorigenic cells. Selenomethionine increased GPx4 protein and activity in pancreatic cancer and reversed P-AscH--induced toxicity and lipid peroxidation. RSL3 treatment inhibited GPx4 activity and increased lipid peroxidation. Differences in oxidative stress may play a role in radioprotecting normal cells while radiosensitizing pancreatic cancer cells when treated with P-AscH-.

| S-EPMC10967795 | biostudies-literature

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