Linoleic Acid and Alpha-Linolenic Acid Have Central Roles in Brain Energy Substrate Provision, Endogenous Lipid Production, Immune and Repair Function, via Peroxisomal Beta-Oxidation-Related Pathways?
Current metabolic considerations of “fuel” sources for brain energy, and substrate creation, generally focus on glucose and externally derived ketones. However, the healthy existence of Inuit, with a common Inuit CPT1A carnitine polymorphism that substantially inhibits mitochondrial uptake of long fats, who apparently were not in ketosis, with little access to glucose, suggests humans can fuel their brains largely from peroxisomally produced medium-chain fats (MCFs), ACoA and derivatives. The health, and ability to build and run a brain, of neonates nourished with breast milk, which is high in lipids and low in carbohydrates, whom are very rarely in significant measured ketosis, adds to evidence the brain can metabolise fats as a major energy source. Whilst brain lipid research primarily focuses on arachidonic (AA) and docosahexaenoic acids (DHA); alpha-linolenic (ALA) and linolenic acids (LA), as preferred peroxisomal beta-oxidation substrates, and to lesser extents palmitic (PA) and oleic acids (OA), likely have underappreciated but fundamental roles in the brain as the primary substrates for peroxisomal beta-oxidation, so indirect sources of MCFs, ACoA and downstream-derivatives, mitochondrial “fuels” for ATP production. Alternatively ACoA is a substrate for “endogenous” lipid manufacture within the BBB, and co-peroxisomal-product peroxide acts as a signalling agent. LA and ALA cross the blood-brain-barrier (BBB), but are not significantly present in brain structural-tissue, likely being largely metabolised through peroxisomal pathways in astrocytes to substrate or energy. LA and ALA also have wider brain roles, including the following: LA-/ALA-oxidised products in injured brain tissue moderate immune function; as preferred substrates for LOX12/15; LA oxylipins the HODEs are the primary endogenous activators of PPAR gamma related peroxisomal activity; PPAR gamma and peroxide promote iNOS activity; iNOS-based NO production inhibits catalase assisting microglial oxidative function, in excess causing oxidative damage; further PPAR gamma moderates microglial function. LA oxylipin 13HODE overactivation of the PPAR gamma-related peroxisomal pathways results in imbalances in brain lipid composition; loss of LA; increased denovo lipid and cholesterol production; increased desaturation by SCD1 so increased mono- and polyunsaturated Omega-7 and Omega-9 fats including mead acid; intracellular lipid deposition including of cholesterol, increased oxidative stress; cardiolipin lipid species changes and imbalances; and mitochondrial dysfunction; which changes link to diseases of cognitive impairment, including depression and Alzheimer’s. Further changes in the LA, OA and PA desaturase products, so the lipid-membrane content including of cardiolipin, will change mitochondrial energetics. Exposure to LA oxylipins in the absence of sufficient lipid protective antioxidant capacity, makes mitochondria more susceptible to damage, including reduced cytochrome C-related ATP production, and results in release from cardiolipin of damaging LA-based oxylipins, including HODEs and 4HNE. Conversely ALA has surprising beneficial effects on brain function. A single “subchronic” injection of ALA into the bloodstream before induction of a stroke in mice reduced post-infarct ischaemic damage. Multiple pre-stroke ALA treatments improved survival by a factor of 3 at ten days, increased neurogenesis, enhanced brain plasticity, and were significantly antidepressant. The first casualties of nutrient-depleted pre-oxidised Omega-3:6 imbalanced diets are likely loss of IQ, abstract thought and crucially empathy, and arguably accompanied by increased aggression and territoriality. What is the future for individuals, nations and more widely humanity, if increasing numbers of humans are more aggressive and territorial, have falling IQs and depleted capacity for abstract thought and empathy? ‘The greatness of humanity is not being human but humane’ Gandhi.
KeywordsALA alpha-linolenic LA linoleic Astrocyte Alzheimer’s Brain Catalase CPT1 Inuit Neuron Oxidative stress Peroxide Peroxisome Mitochondria Microglia MCAD COX LOX PPAR alpha PPAR gamma PPAR delta 13HODE 9HODE 4HNE iNOS NO
Arachidonic acid (Omega-6; 20 carbon derivative of LA.)
Acetyl coenzyme A (Raw material for the energy/cholesterol pathways.)
Alpha-linolenic acid (Omega-3–18 carbon plant-based polyunsaturated fat.)
Blood–brain barrier (Barrier between blood stream and brain.)
Cluster of differentiation 36 (Fatty acid translocase receptor.)
Cyclooxygenase (Enzyme-catalysing oxidation of fatty acids.)
Carnitine palmitoyltransferase (Acts as shuttle mainly for long-chain fats C:16–18 into mitochondria.)
Docosahexaenoic acid (Omega-3–22 carbon derivative of ALA.)
Eicosapentaenoic Acid (Omega-3 fatty acid C20:5.)
3-hydroxy-3-methyl-glutaryl-CoA (Found in two forms, reductase and synthase. Reductase regulates cholesterol production. Synthase regulates HMGCoA production. HMGCoA is substrate for ketones or cholesterol.)
Inducible nitric oxide synthase (Inducible isoform involved in stress response in macrophages, microglia and other tissues.)
Linoleic acid (Omega-6–18 carbon plant-based polyunsaturated fat.)
Lipoxygenases (Enzymes-catalysing oxidation of multiple lipid-based substrates.)
Medium-chain acyl-coenzyme A (Dehydrogenation of fats C:6–12 in mitochondria and present in inner mitochondrial membrane.)
Malonaldehyde (Non-exclusive oxidation product of Omega-6.)
Medium-chain triglyceride (Triglyceride containing fats between C:6 and C:12.)
Medium-chain fat (A fat between C:6 and C:12)
Nitric oxide (An important signalling messenger and oxidant.)
Oxidised LDL receptor 1 (Receptor for oxidised LDL sometimes called LOX1.)
Palmitic acid (Saturated fat C:16.)
Peroxisome proliferator-activated receptor (3 forms alpha, gamma and delta.)
Stearic acid (Saturated fat C:18.)
Stearoyl-CoA desaturase (Delta-9-desaturase key to the formation of OA.)
Superoxide dismutase (Reduces superoxide to oxygen or peroxide.)
PPAR alpha activator (Activates PPAR alpha-related peroxisomes.)
4-hydroxynonenal (Exclusive Omega-6 fats peroxidation aldehyde.)
4-hydroxy hexenal (Exclusive Omega-3 fats peroxidation aldehyde.)
4-hydroperoxy 2-nonenal (Oxidation product of Omega-6 LA and likely AA.)
13-hydroxy-9Z, 11E-octadecadienoic acid (Major LA oxidation product of LOX12/15, COX photo-oxidation and autoxidation.)
13-hydroxy-9Z, 11E, 15Z-octadecatrienoic acid (Major ALA oxidation equivalent of LA product 13HODE.)
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