Oxylipins vs Oxidized Lipids: Linking Oxidative Stress to Human Health and Disease

Lipids are crucial for numerous biological processes, from maintaining cell membrane integrity to regulating complex signaling pathways. However, when lipids undergo oxidation, they give rise to oxylipins or oxidized lipids, which play a key role in both health and disease, particularly in the context of oxidative stress. Have you ever been confused by the terms "oxylipins" and "oxidized lipids" and wondered how they differ? Furthermore, how does oxidative stress relate to lipid oxidation? In this blog, we will provide a comprehensive exploration of oxylipins and oxidized lipids, uncovering their formation mechanisms, and examining their roles in oxidative stress, as well as their impact on human health and disease. By the end, you will gain valuable insights into how lipid oxidation and oxidative stress drive disease progression and how these processes can be targeted for therapeutic interventions.

What Are Oxylipins? Types, Functions and Synthesis Pathways

Oxylipins are a diverse group of oxygenated lipids primarily produced through the oxidation of polyunsaturated fatty acids (PUFAs). These bioactive molecules are essential for regulating a wide range of physiological processes, including inflammation, immune response, cell signaling, and the resolution of inflammation. Given their involvement in numerous cellular pathways, oxylipins play a key role in both health and disease, making them a critical focus of biomedical research.

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Types of Oxylipins

Oxylipins are classified based on their chemical structure, origin, and the enzymes involved in their synthesis. Some of the most well-known types include:

1. Prostaglandins (PGs)

Prostaglandins are oxylipins derived from arachidonic acid via the cyclooxygenase (COX) pathway. They regulate inflammation, blood flow, blood pressure, smooth muscle function (e.g., uterine contractions), and pain perception, playing a critical role in immune responses, vascular tone, and reproductive processes. Prostaglandins are classified into subtypes (PGD, PGE, PGF, PGI, and TX), each with distinct biological functions. For instance, PGE2 is involved in vasodilation and fever, while PGI2 (prostacyclin) inhibits platelet aggregation and promotes vasodilation.

2. Leukotrienes (LTs)

Leukotrienes are another group of oxylipins derived from arachidonic acid through the 5-lipoxygenase (5-LOX) enzyme. They are essential for the recruitment and activation of immune cells such as neutrophils and eosinophils, driving allergic inflammation and conditions like asthma and anaphylaxis. Leukotrienes are classified into subtypes—LTB4, LTC4, LTD4, and LTE4—each with unique functions. LTB4 acts as a potent chemoattractant for neutrophils, while LTC4, LTD4, and LTE4 contribute to bronchoconstriction and increased vascular permeability.

3. Thromboxanes (TXs)

Thromboxanes are produced from arachidonic acid via the cyclooxygenase (COX) pathway. The primary thromboxane in humans is TXA2, which is synthesized from PGH2 (the precursor for prostaglandins and thromboxanes) through the action of thromboxane synthase. Thromboxanes play a key role in platelet aggregation, vasoconstriction, and blood clot formation. TXA2 is essential for hemostasis, but its overproduction is linked to thrombosis and cardiovascular diseases.

4. Hydroxyeicosatetraenoic Acids (HETEs)

Hydroxyeicosatetraenoic acids (HETEs) are metabolites of arachidonic acid produced by lipoxygenase (LOX) enzymes. HETEs are involved in regulating blood pressure, promoting smooth muscle contraction, modulating immune responses, and contributing to inflammation. They can be classified into subtypes based on the position of the hydroxyl group on the fatty acid chain, such as 5-HETE, 12-HETE, and 15-HETE. Each subtype has distinct effects: 5-HETE is involved in leukocyte migration, while 15-HETE plays a role in vascular relaxation.

5. Specialized Pro-resolving Mediators (SPMs)

Specialized pro-resolving mediators (SPMs) are oxylipins derived from omega-3 fatty acids like eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). This subclass includes resolvins, protectins, and maresins, which play crucial roles in resolving inflammation. Resolvins (e.g., Resolvin E1 and D1) inhibit the recruitment of inflammatory cells and promote the clearance of apoptotic cells, aiding tissue homeostasis. Protectins are vital for resolving neuroinflammation and preventing tissue damage, particularly in ischemic injury. Maresins help reduce inflammation and support tissue repair, especially during wound healing and regeneration.

6. Lipoxins (LXs)

Lipoxins are a group of pro-resolving oxylipins formed from arachidonic acid through the action of lipoxygenase enzymes (specifically 12-LOX and 15-LOX). They inhibit neutrophil recruitment, promote the clearance of apoptotic cells by macrophages, and facilitate the restoration of tissue function following inflammation. Lipoxins are essential for preventing chronic inflammation and promoting wound healing. They are classified into various forms, such as lipoxin A4 (LXA4) and lipoxin B4 (LXB4), each with specific roles in resolving inflammation.

Synthesis Pathways of Oxylipins

Oxylipins are derived primarily from the oxidation of polyunsaturated fatty acids (PUFAs), with the most common substrates being arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Enzymatic oxidation is the primary mechanism for oxylipin synthesis. The enzymes involved include cyclooxygenases (COX), lipoxygenases (LOX), cytochrome P450 enzymes (CYP), and aspirin-triggered pathways. Each enzyme family catalyzes specific reactions that result in the formation of different types of oxylipins.

1. Cyclooxygenase (COX) Pathway

The COX pathway is responsible for the synthesis of prostaglandins (PGs), thromboxanes (TXs), and prostacyclins (PGI). COX enzymes (COX-1 and COX-2) catalyze the conversion of arachidonic acid into prostaglandin H2 (PGH2), which is then further converted into various prostaglandins and thromboxanes. This pathway plays a central role in inflammation, immune responses, and platelet aggregation.

2. Lipoxygenase (LOX) Pathway

Lipoxygenases are enzymes that introduce oxygen into polyunsaturated fatty acids, producing hydroxylated products known as hydroxy fatty acids (HETEs) and leukotrienes (LTs). LOX enzymes, such as 5-LOX, 12-LOX, and 15-LOX, specifically catalyze the formation of various HETEs and leukotrienes. Leukotrienes are involved in allergic reactions, inflammation, and immune responses, while HETEs contribute to the regulation of vascular tone and smooth muscle contraction.

3. Cytochrome P450 (CYP) Pathway

Cytochrome P450 enzymes oxidize fatty acids to form epoxides, which are then converted into dihydroxyeicosatrienoic acids (DHETs) and other metabolites. This pathway contributes to the production of epoxyeicosatrienoic acids (EETs) and other bioactive metabolites that regulate blood pressure, inflammation, and cell signaling. CYP enzymes also participate in the synthesis of specialized pro-resolving mediators (SPMs) from omega-3 fatty acids like eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

Figure 1. Main synthesis pathways of oxylipins (Eccles and Baldwin, 2022)

What Are Oxidized Lipids? Species, Formation Mechanisms, and Impact

Oxidized lipids are a broad class of lipid molecules that have undergone chemical modifications due to exposure to reactive oxygen species (ROS), free radicals, or enzymatic oxidation. These modifications lead to changes in the chemical structure of lipids, resulting in the formation of biologically active molecules that can influence various physiological and pathological processes. Unlike oxylipins, which are specific oxygenated lipids derived primarily from polyunsaturated fatty acids (PUFAs) through enzymatic pathways, oxidized lipids encompass a wider range of lipid species, including lipid peroxides, aldehydes, and hydroxy fatty acids, that can arise from both enzymatic and non-enzymatic pathways.

Key Species of Oxidized Lipids

Oxidized lipids can be categorized into several major classes based on their structure and the type of oxidative modification they have undergone. The key species include:

1. Lipid Peroxides

Lipid peroxides are one of the primary products of lipid oxidation, formed when a lipid molecule, typically a polyunsaturated fatty acid, reacts with reactive oxygen species (ROS). These peroxides can further decompose to produce a variety of reactive aldehydes and other oxidized species. The most well-known examples are hydroperoxides and lipid hydroperoxides, which are often used as biomarkers of oxidative stress. Lipid peroxides are unstable and can break down to form several bioactive molecules, some of which have potent effects on cellular signaling and inflammation.

2. Aldehydes

Aldehydes are highly reactive products of lipid peroxidation. Key aldehydes, such as malondialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE), are produced during the breakdown of lipid peroxides. These aldehydes can covalently modify proteins, lipids, and DNA, contributing to cellular dysfunction, inflammation, and oxidative stress. Malondialdehyde, for example, is a widely studied marker of oxidative damage and has been implicated in the pathogenesis of various diseases, including cardiovascular diseases, neurodegenerative disorders, and cancer.

3. Hydroxy Fatty Acids

Hydroxy fatty acids are produced when fatty acids undergo oxidation at specific carbon positions, typically at the 9, 12, or 15 positions in the carbon chain. These compounds, such as 12-hydroxy-5,8,10-heptadecatrienoic acid (12-HHT), are produced via enzymatic action (e.g., lipoxygenase or cyclooxygenase enzymes) or as a result of non-enzymatic oxidative processes. Hydroxy fatty acids can influence cellular functions by modulating inflammatory responses, vascular tone, and cell signaling.

4. Isoprostanes

Isoprostanes are a class of prostaglandin-like compounds formed non-enzymatically through the peroxidation of arachidonic acid and other polyunsaturated fatty acids. These compounds are considered reliable markers of oxidative stress and have been linked to various pathologies, including cardiovascular diseases, cancer, and neurodegenerative disorders. Unlike prostaglandins, isoprostanes are not produced by cyclooxygenase enzymes but by free radical-induced oxidation.

5. Epoxides and Diols

Epoxides are cyclic compounds formed when fatty acids are oxidized by cytochrome P450 enzymes or through radical-induced processes. These highly reactive species are intermediates in the synthesis of several bioactive lipids, such as epoxyeicosatrienoic acids (EETs), which have vasodilatory effects and influence blood pressure regulation. When epoxides are further metabolized, they can form dihydroxyeicosatrienoic acids (DHETs), which also have important roles in vascular function and inflammation.

Formation Mechanisms of Oxidized Lipids

Oxidized lipids can be formed through both enzymatic and non-enzymatic pathways. Enzymatic oxidation of lipids is primarily the production of oxylipins mediated by enzymes such as lipoxygenases (LOX), cyclooxygenases (COX), and cytochrome P450 (CYP).  Non-enzymatic oxidation is another critical process in the generation of oxidized lipids. Non-enzymatic oxidation typically arises from elevated levels of ROS, which are produced under conditions of oxidative stress, exposure to environmental pollutants, or metabolic disturbances. The key processes involved in non-enzymatic lipid oxidation are:

Lipid Peroxidation: ROS, such as superoxide anions and hydroxyl radicals, initiate lipid peroxidation by abstracting hydrogen atoms from the carbon chains of PUFAs. This generates lipid peroxyl radicals, which propagate the oxidation process and lead to the formation of lipid peroxides. These peroxides are highly unstable and can break down into various reactive aldehydes and other oxidized lipid species.

Aldehyde Formation: Lipid peroxides, once formed, can decompose to generate reactive aldehydes like malondialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE). These aldehydes are highly reactive and can bind to proteins, lipids, and DNA, leading to cellular damage and contributing to disease progression.

Isoprostane Production: Isoprostanes are formed when free radicals non-enzymatically oxidize arachidonic acid and other PUFAs. These compounds resemble prostaglandins but are produced without the involvement of cyclooxygenase enzymes. Isoprostanes serve as biomarkers of oxidative stress and are implicated in various diseases, including cardiovascular diseases and neurodegenerative disorders.

Thus, while enzymatic oxidation plays a significant role in the production of functional lipids like oxylipins, non-enzymatic oxidation is primarily associated with oxidative stress and the generation of lipid species that can cause cellular damage and contribute to disease.

What’s the Key Difference Between Oxylipins and Oxidized Lipids?

While both oxylipins and oxidized lipids are products of lipid oxidation, their key difference lies in their origin, formation pathways, and biological roles.

1. Origin and Formation Mechanisms

Oxylipins are a specific subset of oxygenated lipids formed primarily through enzymatic pathways. These pathways involve specialized enzymes, such as lipoxygenases (LOX), cyclooxygenases (COX), and cytochrome P450 enzymes (CYP), which catalyze the oxygenation of polyunsaturated fatty acids (PUFAs), such as arachidonic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Oxylipins are biologically active molecules that regulate important physiological processes like inflammation, immune response, blood pressure regulation, and tissue repair.

Oxidized lipids, on the other hand, encompass a broader category of lipid molecules that have undergone oxidative modification, not necessarily by enzymatic pathways. They can be formed via both enzymatic and non-enzymatic processes. Non-enzymatic oxidation often occurs due to the action of reactive oxygen species (ROS) and free radicals, leading to the formation of lipid peroxides, aldehydes (such as malondialdehyde and 4-hydroxy-2-nonenal), and other reactive lipid species. These molecules are commonly associated with oxidative stress and are involved in cellular damage and pathological conditions.

Figure 2. Process of non-enzymatic oxidation and enzymatic oxidation of lipids (Stirton et al., 2021)

2. Biological Roles

Oxylipins are functional and regulatory molecules that play critical roles in maintaining physiological balance. They act as signaling molecules that mediate processes such as inflammation, immune responses, blood clotting, tissue repair, and resolution of inflammation. Many oxylipins, like prostaglandins, leukotrienes, and resolvins, are specifically involved in modulating these processes, which are essential for normal bodily function and homeostasis.

Oxidized lipids, while they can also exert biological activity, are often associated with pathological conditions due to their ability to cause oxidative damage to cells and tissues. They contribute to diseases like cancer, cardiovascular diseases, neurodegenerative disorders, and aging. For instance, lipid peroxides and aldehydes, which are products of non-enzymatic oxidation, can induce inflammation, modify proteins, and lead to cellular dysfunction, thereby exacerbating disease processes.

Oxidative Stress: A Critical Process Related to Oxylipins and Oxidized Lipids

Oxidative stress is a critical biological process characterized by an imbalance between the production of reactive oxygen species (ROS) and the body’s ability to neutralize these reactive molecules through antioxidant defenses.

1. The Mechanisms and Causes of Oxidative Stress

ROS, including free radicals like superoxide anions, hydroxyl radicals, and non-radical species like hydrogen peroxide, are highly reactive molecules that can damage cellular components such as lipids, proteins, and DNA. Under normal conditions, ROS are produced as a byproduct of cellular metabolism, particularly during mitochondrial respiration. However, external factors like pollution, UV radiation, cigarette smoke, and toxins can exacerbate ROS production. Inflammation, whether acute or chronic, is another significant source of ROS, as immune cells generate ROS to combat pathogens. Poor lifestyle choices, such as high-fat diets, excessive alcohol consumption, and smoking, can further elevate ROS levels, while genetic factors or mitochondrial dysfunction may predispose individuals to increased ROS production. ROS production exceeds the body's antioxidant capacity, it leads to oxidative stress, which is associated with cellular damage and inflammation.

2. Oxidative Stress and the Dysregulation of Oxylipins

Oxidative stress is deeply intertwined with the formation of oxylipins an. During periods of oxidative stress, the enzymatic pathways that generate these bioactive molecules can become dysregulated. Excessive ROS production can trigger the overproduction of certain oxylipins (e.g., prostaglandins, leukotrienes), contributing to chronic inflammation and tissue damage. This dysregulation of oxylipin production has been implicated in various diseases, including cardiovascular diseases, cancer, and autoimmune disorders.

3. Oxidative Stress and Its Role in Lipid Oxidation

Additionally, oxidative stress promotes non-enzymatic lipid oxidation, leading to the formation of oxidized lipids. The interaction between ROS and lipids results in lipid peroxidation, generating reactive aldehydes like malondialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE), as well as other lipid-derived species such as isoprostanes. These oxidized lipids can further exacerbate oxidative damage by modifying cellular proteins, lipids, and DNA, initiating a vicious cycle of inflammation, cellular injury, and disease progression. For instance, lipid peroxides and aldehydes produced under oxidative stress can activate pro-inflammatory pathways, leading to chronic inflammation and promoting diseases such as atherosclerosis, neurodegenerative disorders, and cancer.

The Future Trends of Oxylipins and Oxidized Lipids Research

Oxylipins and oxidized lipids play pivotal roles in regulating a wide range of physiological processes. Their involvement in inflammation, immune responses, tissue repair, and disease mechanisms has sparked increasing interest in unraveling their functions and therapeutic potential. As research progresses, several emerging trends offer promising insights that could enhance our understanding of these bioactive lipids and pave the way for novel, targeted treatment strategies.

1. Investigating the Role of Oxylipins and Oxidized Lipids in Disease Mechanisms

The role of oxylipins and oxidized lipids in the pathogenesis of various diseases remains a major focus of ongoing research. As our understanding of their involvement in processes such as cellular signaling, immune modulation, and oxidative stress continues to evolve, future studies will aim to uncover how dysregulated lipid metabolism contributes to diseases such as cancer, neurodegeneration, metabolic disorders, and cardiovascular diseases. In particular, the relationship between lipid oxidation and gene expression regulation, protein modification, and cellular signaling pathways will be explored in greater detail. This deeper mechanistic insight may lead to the identification of new drug targets for disease intervention.

2. Exploring the Therapeutic Potential of Specialized Pro-resolving Mediators (SPMs)

Specialized pro-resolving mediators (SPMs), which help resolve inflammation and promote tissue repair, are gaining increasing attention as potential therapeutic agents. Research is moving toward the development of SPM-based therapies for a wide range of inflammatory conditions, including arthritis, cardiovascular diseases, and neurodegenerative disorders. Future studies will focus on optimizing the synthesis and delivery of these compounds, investigating their safety and efficacy in clinical settings, and exploring their potential as novel anti-inflammatory drugs. The therapeutic modulation of SPMs holds promise for not only treating chronic inflammatory diseases but also for accelerating tissue regeneration.

3. The Role of Lipid Receptors and Signaling Pathways

An emerging frontier in lipid research involves understanding how oxidized lipids and oxylipins interact with specific receptors and activate intracellular signaling pathways. Future studies will focus on mapping these receptor-lipid interactions and their effects on cell function. Identifying key receptors involved in mediating the actions of oxylipins and oxidized lipids could open new avenues for targeted therapies that regulate inflammation, cell survival, and tissue repair. For example, understanding how oxidized lipids activate toll-like receptors (TLRs) or nuclear receptors could lead to the development of precision medicine strategies for treating inflammatory diseases and cancers.

Reference

Stirton H, Meek BP, Edel AL, Solati Z, Surendran A, Aukema H, et al. (2021) Oxolipidomics profile in major depressive disorder: Comparing remitters and non-remitters to repetitive transcranial magnetic stimulation treatment. PLoS ONE 16(2): e0246592. https://doi.org/10.1371/journal.pone.0246592

Eccles, J. A., & Baldwin, W. S. (2023). Detoxification Cytochrome P450s (CYPs) in Families 1–3 Produce Functional Oxylipins from Polyunsaturated Fatty Acids. Cells, 12(1), 82. https://doi.org/10.3390/cells12010082

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