Lipid peroxidation

Lipid peroxidation is the oxidative breakdown of lipids, primarily targeting polyunsaturated fatty acids (PUFAs) due to their multiple unstable double bonds. 2 Peat described it as a process where free radicals extract electrons from lipids, generating a cascade of toxic byproducts including malondialdehyde (MDA), acrolein, and 4-hydroxynonenal (4-HNE). 2 While enzymatic peroxide formation occurs in controlled pathways, the term lipid peroxidation typically denotes the spontaneous, uncontrolled chain reaction that propagates through cell structures, destroying the unstable PUFAs and leaving behind a residue of saturated fats. 2 This chain reaction continues until something intervenes to break it, with the smaller oxidized fragments often being the most toxic and capable of spreading the oxidation further. 2

The toxicity of lipid peroxidation products is mechanistically precise and devastating. Acrolein, released during PUFA degradation, directly inhibits mitochondrial function by poisoning cytochrome oxidase, the crucial respiratory enzyme, resulting in a decreased ability to produce energy. 6 It also inhibits the cellular regulation of the excitatory amino acid glutamate, contributing to prolonged nerve excitation. 6 Malondialdehyde is a known human carcinogen that acts like a glue, wrecking cellular architecture, while the aldehydes produced by fat breakdown react with cell proteins, making them antigenic and triggering autoimmune responses. 2 Peat argued that lipid peroxidation products are chaotropic, meaning they lower the rigidity of cellular regions by damaging the underlying protein skeleton, and that the resulting "membrane fluidity" often corresponds to the chaos of a damaged cell protein structure rather than a healthy state. 10

Peat identified several catalysts that accelerate lipid peroxidation, with iron playing a central role. When metals like iron, aluminum, or lead accumulate in cells, they accelerate peroxidation in proportion to the unsaturation of the cell's lipids. 1 The stress-induced enzyme heme oxygenase releases free iron from heme groups, and the resulting free bilirubin is associated with lipid peroxidation and DNA damage. 1 Estrogen synergizes with this process by increasing hypoxia inducible factor (HIF), which promotes iron absorption and activates aromatase, creating a vicious cycle. 1 Nitric oxide, whose synthesis estrogen promotes in the brain, is a free radical that directly activates peroxidation. 5 Cortisol also contributes, as its destabilizing effects lead to increased lipid peroxidation, which in turn decreases protective steroid synthesis. 12

The pathological consequences of lipid peroxidation are most evident in the brain and vascular system. High levels of acrolein and other PUFA degradation products are found in the brain in Alzheimer's disease, and the "prion" diseases like CJD and mad cow disease produce their damage by activating lipases that release PUFAs and generate lipid peroxides. 6 In multiple sclerosis, lipid peroxidation is very high, with elevated isoprostanes and prostaglandins in brain tissue, and the intolerance for heat in MS patients may relate to the release of free fatty acids that fuel further peroxidation. 5 The process also depletes brain DHA, and Chris Masterjohn noted that some neurological problems may stem from this depletion caused by peroxidation. 7 In atherosclerosis, the plaques contain very little unsaturated fat precisely because it has been peroxidized so rapidly. 5 An oil researcher consuming an Eskimo-style diet saw his blood lipid peroxides, measured as MDA, reach a level 50 times higher than normal, and his sperm count dropped to zero. 2

The body possesses some defenses against this process, but they reveal the inherent toxicity of the substrates. Georgi Dinkov explained that the enzyme catalase is specifically activated to detoxify the aldehydes produced during PUFA metabolism, and it does not get activated when saturated fat is consumed. 3 However, chronically elevated catalase is itself correlated with cancer. 3 Peat observed that traditional Eskimos, despite high PUFA intake, may have been protected by consuming whole animals including the thyroid gland and brain, which provided thyroid hormone, cholesterol, and the protective steroids pregnenolone, progesterone, and DHEA that broadly protect against peroxidative damage. 2 Saturated fats like coconut oil do not produce these aldehydes and are metabolized differently, similar to glucose, entering mitochondria directly without generating the toxic byproducts. 2 Peat's personal experience with coconut oil produced an immediate increase in metabolic rate, suggesting his metabolism had been chronically inhibited by something easily alleviated by diluting the toxic unsaturated fats. 10