Introduction
Dietary lipids (fats) serve many functions in the body. Until recently it was thought that they were limited to three functions: as structural components of cell membranes, as energy stores and as insulation. As well, it was thought they were metabolically inert and that once, laid down by the developing tissue, their turnover was very slow.
It wasn’t until the mid-20th century that this belief was turned on its head. In 1982 Bengt Samuelsson, Sune Bergstrom and John Vane shared the Noble Prize for Physiology or Medicine for their discoveries related to metabolism of polyunsaturated fatty acids (PUFA), in particular arachidonic acid an omega 6, to powerful bioactive substances known collectively as eicosanoids.
Eicosanoids are a diverse group of lipid signaling molecules derived from PUFA's. They play a crucial role in various physiological processes, including inflammation, blood clotting, immune response, and cell signaling. This article explores the structure, synthesis, and functions of eicosanoids, shedding light on their importance in human health.
Structure and Synthesis
The two primary fatty acid precursors of eicosanoids, are the essential fatty acids (EFA's) arachidonic acid (AA) from omega-6 and eicosapentaenoic acid (EPA) from omega-3. For AA or EPA to produce eicosanoids they must be modified. This modification is performed by three enzymes. Cyclooxygenases (COX), lipoxygenases (LOX), and cytochrome P450 enzymes, leading to the formation of different classes of eicosanoids (see figure 1).
There are many different eicosanoids each with unique effects on the body. Once AA or EPA are released from the cell membrane, enzymes like LOX, COX, or cytochrome P450 modify them inside the cell. Production of the type of eicosanoid is situation and tissue dependent.
For example, when you cut your finger AA within the cell membrane of local blood platelets (tiny particles that are involved in clotting) are triggered to produce an eicosanoid called thromboxane A2. This stimulates the blood platelets to aggregate (cluster) forming a blood clot and preventing us from bleeding to death (it’s unlikely you would from a cut finger!!). Vasoconstriction (blood vessels become smaller) also occurs to reduce blood flow. Once bleeding has been stemmed, local endothelial cells produce prostacyclin (also a product of AA) inhibiting blood clotting and stimulating vasodilation. Thus, circulatory homeostasis has been maintained.
A more sinister effect of this same thromboxane A2 is to trigger premature clotting in the arteries of the heart causing a heart attack. Thromboxane A2 has a ½ life of 30 seconds.
Types of Eicosanoids
Eicosanoids are important examples of local hormones and act only in the immediate vicinity. They are derivatives of PUFA of which belong the essential fatty acids (EFA) omega-6 and omega-3 and comprise prostanoids and leukotrienes. Prostanoids include prostaglandins (PGs), prostacyclin's (PGI), and thromboxanes (TXs) (see figure 2).
Prostaglandins (prostacyclin was discovered in 1976) were the first biologically active eicosanoid to be identified (1950’s). It is now known that EFA’s are converted into several different eicosanoids (see figure 1). Prostaglandins have an important role in regulating inflammation, pain, and fever.
Depending on which enzyme COX, LOX or cytochrome P450, activates the respective EFA (AA omega 6 or EPA omega 3) the resultant prostaglandin will be either pro-inflammatory or anti-inflammatory. Generally omega 3 are considered anti-inflammatory and omega 6 pro-inflammatory. The exception is when omega 6 is activated by cytochrome P450, this prostaglandin exhibits potent anti-inflammatory effects.
Arachidonic acid goes down a different pathway when it’s metabolised by another enzyme known as lipoxygenase (see figure 1). This enzyme is found in many white blood cells and other types of cells. Metabolism using lipoxygenase creates a family of potent messengers known as leukotrienes. Leukotrienes play a significant role in promoting inflammation and mediating allergic reactions, asthma, and other respiratory conditions.
Maintaining homeostasis of our cardiovascular system is critical to our long term health. The eicosanoids responsible for this are prostacyclin (PGI2) and thromboxane (TXA2). Thus for healthy blood vessels production of (PGI2) by the vascular endothelial cells counteracts the effects of TX on platelet aggregation (see table 1). Their ratio and antagonistic action is important for systemic blood pressure regulation and the development of thrombosis (excessive thrombosis causes heart attacks).
Functions and Biological Significance
The immune system serves as a crucial defence mechanism, safeguarding the body against infectious agents and various harmful threats. It consists of two main components: the innate and acquired immune systems (see figure 3). Innate immunity is the first line of defence against invasion.
This intricately designed system is indispensable for sustaining life. However, a failure to regulate these processes effectively can lead to harm of the
body's own tissues, evident in chronic inflammation and autoimmune diseases.
Recognizing the significant role diet has on influencing immunity has long been understood. Dietary lipids play a significant role in influencing immune system activity When we experience inflammation we are experiencing our innate immune system in action. Inflammatory processes, involve the production of substances called lipid mediators (eicosanoids). Some medications, like nonsteroidal anti-inflammatory drugs (NSAIDS), target these lipid mediators to treat inflammatory disorders. (see figure 5).
Eicosanoids act as mediators of inflammation and immune responses, both in acute and chronic conditions. They act to augment or suppress an immune response that may lead to inflammation. Figure 4 shows the range of eicosanoids produced by omega-6 and omega-3.
In 1899 the effectiveness of aspirin in the treatment of pain and fever was reported by Heinrich Dreser.
Second generation pain relief drugs,(ibuprofen, voltaren) some working even better than aspirin, have come onto the market all of which, like aspirin, block the production of prostacyclin and thromboxanes from arachidonic acid. However, aspirin is still used for pain relief and can also act as a prophylactic when used in low-dose therapy for patients at risk from cardiovascular disease.
A more aggressive approach to pain management, especially when non-steroidal anti-inflammatory (NSAID) drugs are not effective is the use of corticosteroids such as cortisone or hydrocortisone. Commonly athletes receive corticosteroid injections for relief of chronic pain. Figure 5 is a screenshot taken from Bengt Samuelsson Nobel prize lecture. It illustrates the point at which the conversion of AA to an eicosanoid is inhibited by corticosteroids and NSAID.
Conclusion
Eicosanoids serve as crucial lipid signaling molecules, playing a vital role in regulating diverse physiological processes within the human body. A comprehensive grasp of their structure, synthesis, and functions is essential, not just for the development of targeted therapies to address various diseases, but also to underscore the profound impact our diet has on long-term health.
Hempseed oil, being a sustainable reservoir of essential fatty acids, boasts an exceptionally elevated content of plant-based omega-6 and omega-3. Opting for hempseed oil as our primary source of daily omega fatty acids aligns with a health-conscious choice, given its nutritional profile
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