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In a Western Dietary Context Excess Oxidised Linoleic Acid of Dietary and Endogenous Origin by Over-Activation of PPAR Gamma so Immune and Inflammatory Pathways, and through Cardiolipin Damage, Increases Cardiovascular Risk

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Abstract

The heart, an organ with high ATP requirements, derives 70 % of its energy from fats, primarily delivered by LDL in the fasted state and chylomicrons in the fed state. The primary ‘cause’ of cardiovascular disease is not pure dietary ‘saturated’ fats per se, although excessively oxidised linoleic acid (LA)-rich non-ruminant animal so-called ‘saturated’ fats may well be significant factors, but is arguably due to a mixture of: excess Omega 6 LA intake within the context of a nutrient including antioxidant depleted pre-oxidised western diet, raised plasma oxidative stress including of LDL, damage to cardiolipin species and consequent release of LA oxylipins including 9- and 13-HODE 4-HNE and MDA so increased oxidised stress, consequential and wider oxidative stress related damage to mitochondria including their DNA, hence reduction in cardiac mitochondrial energy output; excess LA oxylipins of dietary and endogenous origin leading to consequent overactivation of oxidised LDL receptors and PPAR gamma pathways, so excess inflammation and immune activation including of iNOS hence raised peroxisomal peroxide-related oxidative stress; PPAR gamma activation by LA HODEs including 9 and 13 HODE and resultant PPAR gamma-related shunting of peroxisomal beta-oxidation product ACoA to lipid and cholesterol production and deposition rather than mitochondrial energy substrate production; and lack of PPAR alpha activation through exercise, fasting, or to a lesser extent by omega 3s, of mitochondrial energy substrate production-related pathways, combined with consequent damage to cell tissue as well as mitochondria, so energy inhibition and resultant malfunction including; inflammation, tissue destruction, and macrophage foam cell related and wider intra and inter-cellular lipid deposition; all facilitated by pre-oxidised excessively refined nutrient and antioxidant depleted, AGE and cross-linked protein, oxidised lipid product-rich, LA ALA-imbalanced, ‘Western’ diets, combined with constant food accessibility, exacerbated by lack of intermeal ‘fasting’ and energy expenditure including exercise.

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Abbreviations

AA:

Arachidonic acid (Omega 6; 20 carbon derivative of LA)

ACOX1:

Acyl-CoA oxidase (First step in peroxisomal beta-oxidation)

ACoA:

Acetyl coenzyme A (Raw material for the energy/cholesterol pathways)

AGE:

Advanced glycation end product (Non-enzymatic covalently bound sugar to protein or lipid)

ALA:

Alpha-linolenic acid (Omega 3; 18 carbon plant-based polyunsaturated fat)

APOE:

Apolipoprotein E (Lipid transport signature protein)

ATP:

Adenosine triphosphate (Enzyme used as an energy carrier)

CD36:

Cluster of differentiation 36 (Fatty acid translocase receptor)

COX:

Cyclooxygenase (Enzyme-catalysing oxidation of fatty acids)

CoQ10:

Ubiquinol (Fat-soluble component of mitochondrial electron transport)

CPT1:

Carnitine palmitoyl-transferase (Acts as shuttle mainly for long-chain fats C:16–18 into mitochondria)

DHA:

Docosahexaenoic acid (Omega 3; 22 carbon derivative of ALA)

EPA:

Eicosapentaenoic acid (Omega 3 fatty acid C20:5)

iNOS:

Inducible nitric oxide synthase (Inducible isoform involved in stress response in macrophages microglia and other tissues)

LA:

Linoleic acid (Omega 6; 18 carbon plant-based polyunsaturated fat)

LOX5:

Lipoxygenase (Enzyme-catalysing oxidation including AA and EPA)

LOX12/15:

Lipoxygenases (Enzyme-catalysing oxidation of multiple lipid-based substrates)

LDLR:

Low-Density Lipoprotein (LDL) Receptor (LDL receptor for minimally oxidised LDL)

LPL:

Lipoprotein lipase (Mobilises lipids from chylomicrons, VLDL, LDL both at the vascular face and intercellularly)

MDA:

Malonaldehyde (Non-exclusive oxidation product of omega 6)

MCT :

Medium chain triglyceride (Triglyceride containing fats between C6 and C12)

MCF:

Medium chain fatty acids (Fatty acids between C6 and C12)

MUFA:

Monosaturated Fatty Acid (Monosaturated fatty acid)

NAFLD:

Non-alcoholic fatty liver (Fat deposition in the liver not due to alcohol)

NO:

Nitric oxide (An important signalling messenger and oxidant)

OA:

Oleic acid (Omega 9 monosaturated fat C18:1)

OLR1:

Oxidised LDL receptor 1 (Receptor for oxidised LDL sometimes called LOX1)

Oxo-HODE:

Oxooctadecadienoic acid (Oxidation products of HODEs also called KODEs)

PA:

Palmitic Acid (Saturated fat C:16)

PPAR:

Peroxisome proliferator-activated receptor (3 forms alpha, gamma and delta)

P450:

Cytochromes P450 (Family of often oxidative enzymes)

PUFA:

Polyunsaturated fatty acid (Polyunsaturated Fatty Acid)

SA:

Stearic Acid (Saturated fat C:18)

SFA:

Saturated Fatty Acid (Saturated Fatty Acid)

SCD1:

Stearoyl-CoA desaturase (Delta-9-desaturase so key to formation of OA)

SN2:

SN2 position (Location of fat in triglycerides or phospholipids)

VEGF:

Vascular endothelial growth factor (A protein signalling angiogenesis)

Wy14643:

PPAR alpha activator (Activates PPAR alpha-related peroxisomes)

4-HNE:

4-Hydroxynonenal (Exclusive omega 6 fats peroxidation aldehyde)

9-HODE:

9-hydroxy-10E, 12Z-octadecadienoic acid (Major LA oxidation product of LOX12/15, COX, photo-oxidation and auto-oxidation)

13-HODE:

13-hydroxy-9Z, 11E-octadecadienoic acid (Major LA oxidation product of LOX12/15, COX photo-oxidation and auto-oxidation)

13-HOTE:

13-OH-9Z, 11E, 15Z-octadecatrienoic acid (Major ALA oxidation equivalent of LA product 13-HODE)

15-HETE:

15-hydroxy-eicosatetraenoic acid (Major AA LOX15 oxidation product)

15d-PGJ2:

(15-deoxy-Δ12, 14-Prostaglandin J2 (Downstream AA COX2 oxidation product and PPAR gamma activator)

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Brown, R.A. (2016). In a Western Dietary Context Excess Oxidised Linoleic Acid of Dietary and Endogenous Origin by Over-Activation of PPAR Gamma so Immune and Inflammatory Pathways, and through Cardiolipin Damage, Increases Cardiovascular Risk. In: Hegde, M., Zanwar, A., Adekar, S. (eds) Omega-3 Fatty Acids. Springer, Cham. https://doi.org/10.1007/978-3-319-40458-5_29

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