Upstream eventLipid Peroxidation
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|CYP2E1 activation and formation of protein adducts leading to neurodegeneration||adjacent||High||High|
Life Stage Applicability
Key Event Relationship Description
Lipid peroxidation can induce apoptosis due to two different toxic effects. First of all lipids are responsible for maintaining the integrity of cellular membranes. Due to peroxidation of the lipids in the cellular membrane they lose their composition, structure and dynamics of lipid membranes. Various functions are lost, there is an increase of membrane rigidity, decrease activity of membrane-bound enzymes and altered permeability. Secondly there is the formation of highly reactive compounds such as lipid peroxides (MDA, HNE). These lipid peroxides can generate more ROS or can crosslink with important proteins in the cell. Several apoptosis pathways are started due to increased levels of ROS and HNE. p53 is induced and phosphorylated by HNE, as well as inducement of death receptor Fas (CD95). Also due to lipid peroxidation an energetic disturbance is reached, since the protein pumps lost their function. This can lead to neuronal cell death.
Evidence Supporting this KER
It is biological plausible that lipid peroxidation can lead to apoptosis of cells.
There are two mechanisms of apoptosis induced by HNE (main product of lipid peroxidation), which are the extrinsic and the intrinsic pathway. Extrinsic pathway is triggered by the binding of tumour necrosis factor (TNF) to their death receptors (DR) on the cell surface. HNE can induce extrinsic apoptosis in two different ways, but is mainly activated by Fas aggregation by to HNE adduct formation on the cysteins of the Fas. The promotion of Fas/CD95 DR expression, which belong to the TNF-α family, is induced by HNE. Li et al. showed that a higher concentration in HLE B-3 cells leads to a higher expression of Fas. Furthermore knockout GSTA4 mouse, GSTA4 is an antioxidant for HNE, showed a higher expression of Fas since HNE concentration increased. These studies were performed in different organ tissues of mice. After activation and expression of Fas a pathway is started towards apoptosis by ASK1, JNK an Jun proteins. Jun stimulates the intrinsic apoptotic pathway and stimulate AP-1, pro apoptotic genes, expression after phosphorylation. Sharma et al. showed that an increased HNE concentration leads to a higher expression of ASK1 and JNK. When Fas was inhibited apoptosis was stopped. On the other hand HNE can stimulate a negative feedback loop against apoptosis by stimulating the expression of Daxx, which has a negative effect on ASK1-JNK.
In the intrinsic pathway HNE can affect mitochondrial injury, leading to an increased level of Ca2+. This induces apoptotic signals as well as cytochrome c which is released from the mitochondria (known as mitochondrial outer membrane permeabilization (MOMP). Also the redox status of mitochondria can be affected by HNE, leading to mitochondrial crisis and activation of caspases. Liu et al. showed that HNE treatment in Jurkat cells induced caspase 8,3 and 9 activity. Caspase 9 is part of the intrinsic apoptotic pathway. HNE can also cause DNA damage since HNE is genotoxic, which induces activation of p53 in combination with oxidative stress. p53 also interacts with the intrinsic apoptotic pathway.
In two more recent studies a more direct link is shown between lipid peroxidation and cell death. With the use of Deuterated Polyunsaturated Fatty Acid (D-PUFA) treatment, which are deuterium-reinforced polyunsaturated fatty acids and are more sensitive against ROS, a significantly decrease in cell death was shown with toxicant inducement. Also a decrease was shown in lipid peroxidation products. D-PUFA works as an inhibitor against lipid peroxidation.
Uncertainties and Inconsistencies
Apoptosis is a mechanism of cell death which occurs during lipid peroxidation. Since cell death is a general term used other mechanisms could also play a role. When enormous levels of ROS and HNE are generated even necrosis can occur. Another form is apoptosis is ferroptosis, which is also linked with lipid peroxidation. Also the defence mechanisms of cells against HNE are not described, which should be taken into account.
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Ayala, A., Muñoz, M. F. & Argüelles, S. Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxidative Medicine and Cellular Longevity 2014, (2014).
Sultana, R., Perluigi, M. & Butterfield, D. A. Lipid peroxidation triggers neurodegeneration: A redox proteomics view into the Alzheimer disease brain. Free Radical Biology and Medicine 62, 157–169 (2013).
Gaschler, M. M. & Stockwell, B. R. Lipid peroxidation in cell death. Biochemical and Biophysical Research Communications 482, 419–425 (2017).
Dalleau, S., Baradat, M., Guéraud, F. & Huc, L. Cell death and diseases related to oxidative stress: 4-hydroxynonenal (HNE) in the balance. Cell Death Differ. 20, 1615–30 (2013).
Li, J. et al. Regulation of CD95 (Fas) expression and Fas-mediated apoptotic signaling in HLE B-3 cells by 4-hydroxynonenal. Biochemistry 45, 12253–12264 (2006).
Engle, M. R. et al. Physiological role of mGSTA4-4, a glutathione S-transferase metabolizing 4-hydroxynonenal: Generation and analysis of mGsta4 null mouse. Toxicol. Appl. Pharmacol. 194, 296–308 (2004).
Sharma, R. et al. 4-Hydroxynonenal self-limits Fas-mediated DISC-independent apoptosis by promoting export of Daxx from the nucleus to the cytosol and its binding to Fas. Biochemistry 47, 143–156 (2008).
Salomoni, P. & Khelifi, A. F. Daxx: Death or survival protein? Trends in Cell Biology 16, 97–104 (2006).
Liu, W., Porter, N. A., Schneider, C., Brash, A. R. & Yin, H. Formation of 4-hydroxynonenal from cardiolipin oxidation: Intramolecular peroxyl radical addition and decomposition. Free Radic. Biol. Med. 50, 166–178 (2011).
Moreira, P. I. et al. Mitochondria: A therapeutic target in neurodegeneration. Biochimica et Biophysica Acta - Molecular Basis of Disease 1802, 212–220 (2010).
Liu, W. et al. 4-Hydroxynonenal Induces a Cellular Redox Status-Related Activation of the Caspase Cascade for Apoptotic Cell Death. J. Cell Sci. 113 ( Pt 4, 635–641 (2000).
Knoll, N. et al. Genotoxicity of 4-hydroxy-2-nonenal in human colon tumor cells is associated with cellular levels of glutathione and the modulation of glutathione S-transferase A4 expression by butyrate. Toxicol. Sci. 86, 27–35 (2005).
Angelova, P. R. et al. Lipid peroxidation is essential for ??-synuclein-induced cell death. J. Neurochem. 133, 582–589 (2015).
Elharram, A. et al. Deuterium-reinforced polyunsaturated fatty acids improve cognition in a mouse model of sporadic Alzheimer’s disease. FEBS J. (2017). doi:10.1111/febs.14291