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Omega-3 Fatty Acids pp 451–463Cite as

The Crucial Relevance of ALA and LA as Primary Peroxisomal Beta-Oxidation Substrates, of Oxidised LA as the Primary Endogenous Activator of PPAR Gamma, and Energy Deficit as the Primary Activator of PPAR Alpha

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Abstract

Peroxisomes are multifunctional organelles of great physiological importance and essential to development and health. They ‘harbour’ about 50 different enzyme activities. Peroxisomal malfunction has severe functional consequences, which manifest in a variety of health conditions, including Zellweger syndrome, with widespread and significant effects, including risk of early mortality, impaired cerebral development, functional issues, and deficient energy production. There are a wide range of peroxisomal activators with different activation capacities, some of which are common between PPAR alpha, delta, and gamma, peroxisome types, and some of which are applicable to specific PPARs. Peroxisomes and their products are underappreciated partners fundamental to healthy function of energy pathways, oxidative pathways, immune function including likely supporting macrophage phagocytosis, detoxification, and lipid including cholesterol production pathways. Peroxisomes produce medium fats (MCFs), acetyl coenzyme A (ACoA), and peroxide as lipid beta-oxidation by-products. The catalase enzyme located in peroxisomes produces catalase. Crucially, LA and ALA are the preferred beta-oxidation substrates of peroxisomes. Oxidised LA products, such as the HODEs, often the most common oxylipins in plasma, are the primary endogenous activators of PPAR gamma. MCFs and ACoA produced by PPAR gamma-related peroxisomal activation are generally directed by related gene activation to support tissue maintenance and repair, including production of lipids and cholesterol. The importance and functional relevance of PPAR gamma related peroxisomes is raised by the increased consumption of LA, within the context of a highly processed antioxidant-diminished nutrient deficient preoxidised western diet. PPAR alpha-related peroxisomally produced MCFs and ACoA are likely used to significantly assist fuel the brain and wider body during periods of glucose depletion, and are arguably more important than ketosis as a fuel source. Activation of PPAR alpha pathways, as well as assisting energy production pathways through related gene activation, results in diversion of lipid substrate away from maintenance pathways so reducing related oxidative stress and inflammation, as well as being associated with increased antioxidant protection. The main PPAR alpha activators include energy deficit stress, primarily exercise or fasting, giving them particular physiological relevance.

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Abbreviations

AA:

Arachidonic acid (omega-6; 20 carbon derivative of LA)

ACoA:

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

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)

CPT1:

Carnitine palmitoyltransferase (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)

GSH:

Glutathione(s) (a very important antioxidant family)

GLA:

Gamma-linoleic acid (omega-6 fatty acid C18:3)

HMGCoA:

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)

HSL:

Hormone-sensitive lipase (different forms mobilise lipids from triglycerides and esters including from adipose tissue)

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 (enzymes 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, and LDL; both at the vascular face and intercellularly)

MCAD:

Medium-chain acyl-coenzyme A (dehydrogenation of fats C:6-12 in mitochondria and present in inner mitochondrial membrane)

MCT:

Medium-chain triglyceride (triglyceride containing fats between C:6 and C:12)

MCF:

Medium-chain fat (a fat between C:6 and C:12)

NO:

Nitric oxide (an important signalling messenger and oxidant)

OA:

Oleic acid (omega-9 monosaturated fat C18:1)

OLR1:

Oxidized LDL receptor 1 (receptor for oxidised LDL sometimes called LOX1)

PA:

Palmitic acid (saturated fat C:16)

PPAR:

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

ROS:

Reactive oxygen species (reactive molecules containing oxygen)

SA:

Stearic acid (saturated fat C:18)

SCD1:

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

SOD:

Superoxide dismutase (reduces superoxide to oxygen or peroxide)

Wy14643:

PPAR alpha activator (activates PPAR alpha-related peroxisomes)

4HNE:

4-Hydroxynonenal (exclusive omega-6 fats peroxidation aldehyde)

9HODE:

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

13HODE:

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

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  1. Chair of the McCarrison Society, Institute of Chartered Accountants, The Cottage, Le Coin Farm, Mont Cochon, St Lawrence, Jersey, C. I. JE3 1ND, UK

    Robert Andrew Brown

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  1. Real Nutrition Laboratory, Bharati Vidyapeeth University Real Nutrition Laboratory, Dhankawadi, India

    Mahabaleshwar V. Hegde

  2. Center for Innovation in Nutrition Health Disease, Bharati Vidyapeeth University , Dhankawadi Pune, India

    Anand Arvind Zanwar

  3. Western IRB Medical Vice Chair, Puyallup, Washington, USA

    Sharad P. Adekar

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Brown, R.A. (2016). The Crucial Relevance of ALA and LA as Primary Peroxisomal Beta-Oxidation Substrates, of Oxidised LA as the Primary Endogenous Activator of PPAR Gamma, and Energy Deficit as the Primary Activator of PPAR Alpha. In: Hegde, M., Zanwar, A., Adekar, S. (eds) Omega-3 Fatty Acids. Springer, Cham. https://doi.org/10.1007/978-3-319-40458-5_32

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