Abstract
BackgroundThe ceramide generation is an early event in the apoptotic response to numerous stimuli including the oxidative stress and ceramide analogs mimic the stress effect and induce apoptosis. Flavonoids of German chamomile are reported to exhibit the hepatoprotective effect. Flavonoids affect sphingolipid metabolism and reduce the elevated ceramide level in the aged liver. In the present paper, the ceramide content and production in the CCl4- and ethanol-treated liver and hepatocytes as well as the correction of sphingolipid metabolism in the damaged liver using the mixture of German chamomile flavonoids (chamiloflan) or apigenin-7-glucoside (AP7Glu) have been investigated.ResultsThe experiments were performed in either the rat liver or hepatocytes of normal, CCl4- and ethanol-treated or flavonoid- and toxin plus flavonoid-treated animals. [14C]palmitic acid and [methyl-14C-phosphorylcholine]sphingomyelin were used to investigate the sphingolipid turnover. Addition of the CCl4 or ethanol to isolated hepatocyte suspensions caused loss of cell viability and increased the lactate dehydrogenase release from the cells into supernatant and ceramide level in the cells. CCl4 administration to the rats enlarged ceramide mass as well as neutral sphingomyelinase (SMase) activity and reduced ceramide degradation by the neutral ceramidase. Pretreatment of isolated hepatocytes with flavonoids abrogated the CCl4 effects on the cell membrane integrity and normalized the ceramide content. Flavonoid administration to the rats normalized the elevated ceramide content in the damaged liver via neutral SMase inhibition and ceramidase activation.ConclusionThe data obtained have demonstrated that flavonoids affect sphingolipid metabolism in the CCl4- and ethanol-damaged liver and liver cells. Flavonoids normalized activities of key enzymes of sphingolipid turnover (neutral SMase and ceramidase) and ceramide contents in the damaged liver and liver cells, and stabilized the hepatocyte membranes.
Highlights
The rapid ceramide generation is an early event in the apoptotic response to numerous stimuli including the oxidative stress and the ceramide analogs mimic the stress effect and induce apoptosis [2]
The ceramide induced hepatocyte necrosis was associated with adenosine triphosphate depletion and mitochondrial depolarization suggesting that the ceramides caused mitochondrial dysfunction
It is well documented that cell death induced by ethanol is associated with stimulation of neutral and acidic SMases and ceramide generation, as well as with the activation of the stress-related kinases, c-Jun Nterminal kinase, p38 mitogen-activated protein kinase and extracellular signal-regulated kinase (ERK) pathways [6,19,20]
Summary
The ceramide generation is an early event in the apoptotic response to numerous stimuli including the oxidative stress and ceramide analogs mimic the stress effect and induce apoptosis. Sphingolipids are a structurally diverse group of compounds composed of a long-chain sphingoid base backbone and amino group, which is often substituted with a long-chain fatty acid They are found primarily in cell membranes and are known to play roles in cell-cell and cell-matrix interactions, and as second messengers [1,2,3,4]. The rapid ceramide generation is an early event in the apoptotic response to numerous stimuli including the oxidative stress and the ceramide analogs mimic the stress effect and induce apoptosis [2]. The ceramide induced hepatocyte necrosis was associated with adenosine triphosphate depletion and mitochondrial depolarization suggesting that the ceramides caused mitochondrial dysfunction
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