What is Lipid Peroxidation and Its Function in the Body?
Lipid peroxidation is a free radical-mediated chain reaction that oxidizes polyunsaturated fatty acids (PUFAs) in cell membranes, serving primarily as a pathological process rather than a beneficial physiological function, though it plays a crucial role in ferroptotic cell death and generates signaling molecules that can influence cellular responses. 1
Definition and Biochemical Mechanism
Lipid peroxidation is the oxidative degradation of lipids containing carbon-carbon double bonds, particularly polyunsaturated fatty acids like linoleic acid and arachidonic acid. 2, 3 This process occurs when reactive oxygen species (ROS), especially hydroxyl radicals and hydrogen peroxide, attack the polyunsaturated fatty acids within cellular membranes. 4
The Chain Reaction Process
- The process initiates when free radicals extract hydrogen atoms from methylene groups in PUFAs, creating lipid radicals that propagate in a self-sustaining chain reaction. 4, 5
- Polyunsaturated phospholipids, particularly phosphatidylethanolamines (PE), are the major substrates for peroxidation, especially in the context of ferroptosis. 1
- The reaction generates toxic aldehydes including malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), which can form adducts with DNA and proteins, altering their functions. 1, 2, 3
Role in Ferroptosis (A Regulated Cell Death Pathway)
Lipid peroxidation is the defining characteristic of ferroptotic cell death, an iron-dependent form of regulated cell death discovered in 2012. 1
Key Mechanisms
- The enzyme ACSL4 (acyl-CoA synthetase long chain family member 4), along with ALOX and POR, promotes the peroxidation of PUFA-containing phospholipids (PUFA-PL), driving ferroptosis forward. 1, 6
- The SLC7A11-GSH-GPX4 axis normally inhibits lipid peroxidation by converting glutathione (GSH) to oxidized glutathione (GSSG), with GPX4 reducing lipid peroxides to lipid alcohols. 1
- When this protective system fails, unrestricted lipid peroxidation occurs, leading to membrane damage and cell death. 1
Pathological Functions and Disease Implications
Rather than serving beneficial physiological functions, lipid peroxidation is predominantly a destructive process implicated in numerous disease states. 4, 5
Cardiovascular and Metabolic Diseases
- In hypertensive patients, elevated lipid peroxidation in erythrocytes correlates with disease severity, with untreated patients showing higher levels than treated patients. 1
- In type 2 diabetes mellitus, chronic hyperglycemia increases ROS/RNS production, leading to lipid peroxidation that impairs pancreatic β-cell function and exacerbates insulin resistance. 1, 7
- Lipid peroxidation contributes to atherosclerosis development through oxidative damage to vascular tissues. 4, 5
Neurological Disorders
- In Alzheimer's disease, amyloid-β peptide causes oxidative damage to red blood cells, disrupting erythrocyte membrane phospholipids through lipid peroxidation. 1
- Lipid peroxidation is implicated in Parkinson's disease pathogenesis through oxidative damage mechanisms. 4
Pregnancy and Developmental Programming
- Enhanced lipid peroxidation in women with excessive gestational weight gain positively correlates with neonatal adiposity. 1
- Higher urinary concentrations of 8-iso-prostaglandin F2α (a lipid peroxidation marker) during pregnancy associate with lower birthweight and rapid infant weight gain, increasing obesity risk later in life. 1
- Oxidative stress leading to PUFA peroxidation damages cell membranes and alters cell signaling, potentially priming offspring for overweight and obesity through unknown mechanisms. 1
Limited Signaling Functions
While primarily destructive, lipid peroxidation products can serve as signaling molecules in specific contexts. 3, 8
- 4-HNE can stimulate gene expression and cell survival at low concentrations, but becomes cytotoxic at higher levels, inhibiting gene expression and promoting cell death. 3
- Lipid peroxides can interfere with the regulation of metabolic pathways, including interactions with prostaglandins and leukotrienes derived from controlled arachidonic acid oxidation. 8
Protective Mechanisms Against Lipid Peroxidation
The body maintains multilevel defense systems to prevent excessive lipid peroxidation, though these can be overwhelmed in pathological states. 4, 8
Enzymatic Defenses
- Catalase, superoxide dismutase (SOD), and glutathione peroxidase (GPx) provide enzymatic protection against lipid peroxidation. 4
- In untreated hypertensive patients, the activity of CAT, SOD, and GPx is reduced in erythrocytes and blood compared to normotensive patients. 1
Non-Enzymatic Defenses
- Vitamins A and E serve as non-enzymatic antioxidants that can be depleted in disease states. 4
- Glutathione (GSH) concentrations are diminished in untreated hypertensive patients but higher in treated patients compared to normotensive individuals. 1
Clinical Measurement and Detection
Multiple techniques exist for assessing lipid peroxidation in clinical and research settings. 1
- Liquid chromatography-mass spectrometry (LC-MS) is the preferred methodology for detecting and identifying peroxidized ferroptosis biomarkers, offering exceptional sensitivity and specificity. 1
- The TBARS assay measures malondialdehyde (MDA) levels spectrophotometrically but lacks specificity as other reactive aldehydes can interfere. 1
- Fluorescent probes like BODIPY-581/591-C11 undergo fluorescence shifts from red to green when oxidatively disrupted, allowing real-time detection. 1
Critical Clinical Considerations
The initial oxidation of only a few lipid molecules can result in significant tissue damage due to the self-propagating chain reaction nature of lipid peroxidation. 4 This amplification effect makes early intervention crucial in conditions where lipid peroxidation is elevated. The debate continues whether lipid peroxidation is a cause or effect of pathological conditions, though evidence increasingly supports it as both an initiating factor and a consequence that perpetuates disease progression. 4, 5