Bioactive oxidised products of omega-6 and omega-3, excess oxidative stress, oxidised dietary intake and antioxidant nutrient deficiencies, in the context of a modern diet

Abstract

The physiological and metabolic importance of linoleic acid (LA) and alpha linolenic acid (ALA), the LA/ALA balance, their relevance to oxidative stress signalling and metabolic function are underappreciated. LA and ALA followed by other 18-carbon fats are the preferred peroxisomal beta-oxidation substrates. Peroxisomal beta-oxidation products include short-chain fats, ACoA and peroxide. Human function, particularly existence, is conditional on essential nutrients. LA and ALA are the primary lipids in plant material and most common terrestrial lipids; supply is dependent on environmental fecundity; their oxidised products are multiple and bioactive in many pathways, required for reproduction and may ultimately synchronise reproduction to environmental LA availability, control human capacity to reproduce and related mating behavioural characteristics. Oxidised and elongated LA products–key regulators in important biological mechanisms and systems including; macrophage- and microglia-related tissue destruction; creation and repair; oxidative stress-based signalling for; inflammation; immune function and defence; hormone production; pheromones; placental and foetal development; parturition; energy regulation; and fat deposition,–and ultimately control reproductive capacity. This explains why LA oxylipins and related products play central roles in “Western” “inflammatory” non-communicable diseases, including obesity. Oxidised LA products 9 and 13HODEs and family, the most common plasma oxylipins, with parent LA, are important LDL components, and when present in excess with their downstream products including Oxo-HODE, 4HNE and MDA, predicate non-communicable “Western” diseases, with roles in inflammation, tissue repair, maintenance of epithelial cells, macrophage and microglial function. 13HODE is the primary endogenous activator of PPAR gamma; excess PPAR gamma activation, along with iNOS stimulation and NO blocking of peroxisomal catalase production, promotes peroxide-based oxidative stress, including peroxisome-assisted macrophage oxidative burst capacity. Oxidation by peroxide forms highly damaging hydroxyl radicals; down-stream products include 4HNE, which results in increased oxidative stress, thereby activating COX and LOX enzymes. LA and ALA are overall preferred LOX substrates and secondary COX substrates; products include 13HODE. 13HODE via PPAR gamma activates OLR1 and CD36; oxidised LDL receptor activity is associated with “Western diseases” including cancer, diabetes, asthma and neurological, vascular, cardiac, obesity and fertility-related conditions. Intriguingly, OLR1 is “oncogenic”. PPAR gamma-related peroxisomes direct ACoA to repair pathways, including cholesterol and fat production via HMGCoA pathways. Energy deficit activates PPAR alpha peroxisomal beta-oxidation pathways. In contrast to PPAR gamma, PPAR alpha and delta activation signals for increased catalase antioxidant production, as well as for production of short-chain fats and ACoA, which is utilised via acetate, malate and ketones production providing alternate substrate for mitochondrial energy production. ALA deficits and excess dietary LA, including from vegetable oil, in the context of “Western” nutrient-depleted pre-oxidised diets are significant health risk factors, including in high-fat low-carbohydrate “paleo” diets. Phosphatidylcholine including of dietary origin is the main component in VLDL, LDL and chylomicron shells; its preference for polyunsaturated fats at the SN2 position gives phosphatidylcholine particular relevance to the delivery of polyunsaturated fats to cells, hence membrane composition and consequent function for example, LA—a key cardiolipin component—when oxidised in situ reduces mitochondrial function, including ATP metabolism, and ultimately regulates apoptosis. Dietary pre-oxidation increases crosslinking and AGE formation, damaging antioxidant related nutrients including glutathione, related amino acid cysteine, and phyto-antioxidants including fat-soluble vitamin E and retinoids. Pre-oxidised nutrient-depleted diets containing excess LA and deficient in ALA underlie cellular and energy pathway dysfunction, fuelling non-communicable “Western diseases”.