Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1905529 | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | 2009 | 10 Pages |
Abstract
Inflammatory response has recently been shown to induce endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), which either recovers proper ER function or activates apoptosis. Here we show that endotoxin (lipopolysaccharide = LPS) can lead to functional ER failure tentatively via a mitochondrion-dependent pathway in livers of rats. Histological examination did not reveal significant damage to liver in form of necroses. Electron microscopy displayed transparent rings appearing around morphologically unchanged mitochondria, which were identified as dilated ER. The spliced mRNA variant of X-box protein-1 (XBP1) and also the mRNA of 78Â kDa glucose-regulated protein (GRP78) were up-regulated, both typical markers of ER stress. However, GRP78 was down-regulated at the protein level. A pro-apoptotic shift in the bax/bcl-XL mRNA ratio was not accompanied by translocation of apoptosis inducing factor (AIF) to the nucleus, suggesting that the cells entered a pre-apoptotic state, but apoptosis was not executed. Monooxygenase activity of p450, representing the detoxification system in ER, was decreased after administration of endotoxin. Biochemical analysis of proteins important for ER function revealed the impairment of protein folding, transport, and detoxification suggesting functional ER failure. We suggest that functional ER failure may be a reason for organ dysfunction upon excessive inflammatory response mediated by endotoxin.
Keywords
MOFLMSASsALTiNOS2-DETBARSHO-1UPRIRE1ATF6TTRGRP78RLMBHTCREAPDIA3LPSCphprotein disulfide isomerase A3ROSargininosuccinate synthaseASTAspartate aminotransferaseAlanine aminotransferaseAIFEndoplasmic reticulum stress2D electrophoresisinterleukinGene expressionproteome analysisTTR, Transthyretintumor necrosis factor-alphaTERinducible nitric oxide synthaseendoplasmic reticulumMultiple organ failureMass spectrometryapoptosis inducing factorTNF-αactivating transcription factor 6lactate dehydrogenaseLDHlipopolysaccharideRat liver mitochondriaMitochondriaLiver microsomesElectron microscopyheme oxygenase 1Inflammatory responseUnfolded protein responsePeroxiredoxin 178 kDa glucose-regulated proteinPERKcreatinineRespiratory controlReactive oxygen species
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Authors
Andrey V. Kozlov, J. Catharina Duvigneau, Ingrid Miller, Sylvia Nürnberger, Bernd Gesslbauer, Andreas Kungl, Wolfgang Ãhlinger, Romana T. Hartl, Lars Gille, Katrin Staniek, Wolfgang Gregor, Susanne Haindl, Heinz Redl,