Lipid-based signaling

An introduction to lipid signaling: How fats shape cellular processes

Some signaling pathways rely on lipid-derived molecules to regulate essential biological processes. Among these are docosahexaenoic acid (DHA) signaling, eicosanoid signaling and sphingosine-1-phosphate (S1P) signaling. What sets these pathways apart is their reliance on lipid-derived molecules, which serve both as structural components of cell membranes as well as highly adaptable signaling mediators. In contrast to protein-based signaling, which often depends on pre-synthesized molecules stored in vesicles, lipid signaling pathways are unique in their ability to generate signaling molecules when they are needed, directly at the site of action. (1, 2)

Their dual role as structural components of membranes and dynamic mediators allows lipid signaling molecules to seamlessly integrate environmental cues with cellular responses to coordinate physiological and environmental signals and modulate processes like inflammation, tissue repair and cellular communication. This action helps keep the body resilient and able to maintain homeostasis, even under stress. (1, 2)

Docosahexaenoic acid: A vital lipid for brain and body health

Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid that plays an essential role in the brain, where it makes up about 10–20% of the total lipids. DHA is stored in the phospholipids of cell membranes, especially in neurons and other brain cells. When the body needs it, the Ca²⁺-independent phospholipase A (iPLA2) enzyme steps in to release DHA from these membranes. (3)

Once it’s free, other enzymes convert DHA into signaling molecules called oxylipins, such as resolvins and neuroprotectins. These molecules are vital to various physiological processes like cellular homeostasis, controlling inflammation, supporting immunity and maintaining healthy vascular function. (4, 5)

DHA is a key player in brain development and function, communication between neurons, fetal development, heart health, vision and more. When DHA signaling goes wrong, serious health issues can arise, including neuropsychiatric disorders and cardiovascular diseases. (4, 5)

How DHA protects neuronal health

DHA supports neuronal health and function through a variety of mechanisms. These include its ability to modulate inflammation, support synaptic plasticity, enhance antioxidant defenses and regulate cell survival pathways.

DHA in anti-inflammatory signaling

DHA is a precursor to molecules like resolvins and protectins that help resolve inflammation. When these mediators bind to receptors such as GPR120 (G-protein coupled receptor 120), they suppress pro-inflammatory cytokines like TNF-α and IL-6 and promote healing processes. This regulation shields neurons from the harmful effects of chronic inflammation, a key player in neurodegenerative diseases like Alzheimer’s. (6)

DHA in neurotrophic and synaptic signaling

DHA plays several crucial roles in supporting brain health and connectivity. It promotes the production of brain-derived neurotrophic factor (BDNF), a key protein in processes like synaptic plasticity – the ability of neurons to adapt and strengthen their connections – making it essential for learning, memory and overall cognitive function. DHA also activates TrkB (tropomyosin receptor kinase B) receptors, which amplify BDNF’s effects and stimulate synaptogenesis, the formation of new synaptic connections. This coordinated action helps maintain the structural integrity of neuronal networks so the brain can stay flexible and responsive to new information. Furthermore, DHA preserves membrane fluidity, a vital factor for efficient signal transmission at synapses, reinforcing its importance in maintaining robust cognitive and neural function. (6)

Role of DHA in antioxidant defense and neuronal membrane stabilization

DHA is embedded in the phospholipid bilayer of neuronal cell membranes, where it plays a key role in maintaining their structure and function. Its presence there ensures membrane fluidity, stability and resilience against external stressors. In addition to this structural role, DHA activates the NRF2 or NFE2L2 (nuclear factor erythroid 2-related factor 2) signaling pathway, driving the production of antioxidant enzymes like SOD (superoxide dismutase) and GPx (glutathione peroxidase). These enzymes neutralize free radicals, protecting neurons from oxidative damage. Without adequate amounts of DHA, neuronal membranes lose their stability and become more vulnerable to oxidative stress, increasing the risk of conditions like Parkinson’s disease and ALS (amyotrophic lateral sclerosis). (7)

DHA as an apoptosis regulator

DHA is also essential for regulating apoptosis, the programmed cell death process that helps maintain cellular balance. In neurons, DHA helps prevent excessive apoptosis by influencing mitochondrial signaling pathways. It inhibits pro-apoptotic proteins like Bax (Bcl-2-associated X protein), which disrupts mitochondrial membranes, while enhancing anti-apoptotic proteins such as Bcl-2 (B-cell lymphoma 2) to preserve mitochondrial integrity and prevent cell death. In addition, DHA serves as a precursor to protectin D1, a specialized molecule that blocks the activation of caspase-3, a key enzyme driving apoptosis. This dual action protects neurons from unnecessary death, supporting brain health and cognitive function. When DHA levels are insufficient, these protective mechanisms falter, increasing the risk of neuronal loss, cognitive decline and the progression of neurodegenerative diseases. (7)

Key protein interactions in DHA signaling

DHA signaling and its effects on neurodevelopment and neuroprotection involve membrane and metabolite-mediated signal transduction mechanisms that include interactions with proteins like membrane-bound receptors, ion channels and enzymes. For example, DHA integrates into neuronal membrane phospholipids, including phosphatidylserine (PS), leading to DHA-PS-rich membrane domains that activate proteins such as Raf-1, protein kinase C (PKC) and Akt, promoting neuronal development and survival. (8)

DHA is metabolized in neural tissues to produce bioactive mediators such as NPD1 (neuroprotectin D1), which has anti-inflammatory and antioxidant effects. Another lipid mediator synthesized from DHA, synaptamide, is anti-inflammatory and promotes neurogenesis and synaptogenesis through receptors like GPR110 (also known as ADGRF1). This interaction activates the cAMP/PKA signaling pathway that promotes neurogenesis, neurite growth and synaptogenesis. (8)

Eicosanoids: Key lipid mediators of inflammation and tissue homeostasis

Eicosanoids are lipid signaling molecules derived from 20-carbon polyunsaturated fatty acids – primarily arachidonic acid – but also eicosapentaenoic acid (EPA) and dihomo-gamma-linolenic acid (DGLA). The main classes of eicosanoids include prostaglandins (PG), thromboxanes (TX), leukotrienes (LT), lipoxins (LX) and resolvins. These molecules regulate many different biological processes, including inflammation, platelet aggregation, tissue homeostasis, host defense, bronchoconstriction, bronchodilation, vascular permeability and smooth muscle contraction. (9, 10)

Eicosanoids typically act on the cells that produce them, such as macrophages, neutrophils and monocytes, or on nearby cells like T lymphocytes, endothelial cells and smooth muscle cells, through autocrine or paracrine signaling mechanisms. For example, they influence T lymphocyte function by binding to specific G-protein coupled receptors (GPCRs) on these cells, modulating the cells’ differentiation, cytokine production and survival. (9) Eicosanoids also act on platelets to regulate aggregation (10) and on tumor cells to shape the tumor microenvironment (11).

The role of eicosanoids in inflammation

Eicosanoids play a dual role in inflammation and can act as pro-inflammatory or anti-inflammatory mediators, depending on the cellular environment, receptor expression and stage of the inflammatory response. (10, 12)

For example, prostaglandin E2 (PGE₂) is a key eicosanoid involved in both promoting and resolving inflammation. As a pro-inflammatory mediator, PGE₂ drives inflammation by promoting arterial dilation, increasing vascular permeability and recruiting immune cells like neutrophils and macrophages. PGE₂ activates TH17 cells by promoting IL-23 production in dendritic cells (via EP4 receptors) and upregulating IL-23 receptors on CD4+ T cells. This stimulates the release of IL-17, a pro-inflammatory cytokine that amplifies immune cell recruitment. (10, 13)

Conversely, PGE₂ can help resolve inflammation by suppressing T cell activation. It inhibits IL-2 production and receptor expression in T cells, limiting their proliferation. In dendritic cells and monocytes, PGE₂ reduces CCL19 (a chemokine that attracts T cells) and suppresses IL-12, shifting the immune response from a pro-inflammatory TH1 profile to a tissue-repair-focused TH2 profile. This action promotes healing and reduces immune cell-mediated tissue damage. (13)

Therapeutic applications of eicosanoid pathways

Targeting eicosanoid pathways has therapeutic applications for treating a variety of inflammatory diseases, including pain, asthma and cardiovascular conditions. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase enzymes such as COX-1 and COX-2. This reduces the production of pro-inflammatory eicosanoids such as prostaglandins, thromboxanes and prostacyclins and helps manage symptoms like pain, swelling and fever. (14)

Leukotriene receptor antagonists (LTRAs) are used in managing asthma because they inhibit cysteinyl leukotriene receptor 1 (cysLT1) activity and prevent bronchoconstriction and inflammation in the airways. (15) In addition, prostacyclin analogs are used to treat pulmonary hypertension due to their potent vasodilatory and anti-thrombotic effects. (16)

Sphingosine-1-phosphate (S1P): A multifunctional lipid mediator

Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator that signals by binding to its G protein-coupled S1P receptors. It regulates cellular processes such as cell-cell and cell-matrix adhesion, cell migration, growth, differentiation, death and survival. It also regulates other physiological processes, including inflammation, vascular development, central nervous system homeostasis, immunity and tumorigenesis. Dysregulated S1P signaling is associated with cancer, nervous system diseases, cardiovascular diseases, respiratory diseases and more, making it a valuable therapeutic target for these diseases. Therapy targeting S1P signaling is currently available in treating relapsing-remitting multiple sclerosis. (17)

The role of S1P signaling in immune cell trafficking

S1P signaling plays a critical role in immune cell trafficking by creating spatial gradients that guide the movement of immune cells between tissues and lymphoid organs. Red blood cells, endothelial cells and platelets secrete S1P into the circulatory system, resulting in higher S1P concentrations in blood and lymph than in the interstitial fluid. This gradient allows lymphocytes to exit lymphoid organs via S1PR1 (sphingosine-1-phosphate receptor 1) activation, which triggers cytoskeletal rearrangements and migratory behavior in immune cells. (17)

Specialized endothelial transporters like SPNS2 (spinster homolog 2) facilitate the export of S1P from cells, helping to establish and sustain the gradient. The expression of molecules such as CD69 downregulate S1PR1 on immune cells, preventing their premature departure and retaining them in tissues where immune responses are initiated. This tightly controlled system ensures that immune cells efficiently patrol the body for pathogens while maintaining tissue homeostasis. (17)

Disruptions to the S1P gradient due to altered transporter function or receptor dysregulation can result in immune cell mis-localization and contribute to autoimmune diseases and other immune-related disorders.

Therapeutic potential of S1P signaling

S1P signaling is pivotal to pathological processes associated with autoimmune diseases, cancer and cardiovascular conditions, which has significant implications for the treatment of these diseases.

In treatments for autoimmune diseases such as multiple sclerosis, S1P signaling is targeted to prevent lymphocytes from migrating from the lymph nodes into inflammation sites, thereby reducing inflammation and autoimmunity. S1PR modulators, like fingolimod, siponimod, ozanimod and ponesimod, are currently approved for treating multiple sclerosis and more are being studied for treating other immune-mediated diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and psoriasis. (17)

In cancer, S1P signaling promotes cancer cell growth, metastasis, survival and immune tolerance to the tumor microenvironment. S1PR1 signaling can also trigger the activation of other signaling pathways involved in carcinogenesis, including PI3K/AKT, MAPK/ERK1/2, Rac and PKC/Ca. Modulating S1P signaling can disrupt processes involved in cancer progression, making S1PR signaling a potential anti-tumor therapeutic target. (18)

S1P signaling regulates cardiovascular-related functions, including endothelial function, cardiac contractility, cardiac homeostasis and vascular tone, by binding and activating S1PR1, S1PR2 and S1PR3 expressed in endothelial and smooth muscle cells, cardiomyocytes and fibroblasts. Dysregulated S1P signaling is implicated in cardiovascular diseases, including arterial hypertension and atherosclerosis. Selective S1P receptor modulators are being investigated to promote protective cardiovascular effects while minimizing adverse outcomes. (14)

References and further reading

1. Sunshine H, Iruela-Arispe ML. Membrane lipids and cell signaling. Curr Opin Lipidol. 2017;28(5):408-413. doi:10.1097/MOL.0000000000000443
2. Eyster KM. The membrane and lipids as integral participants in signal transduction: lipid signal transduction for the non-lipid biochemist. Adv Physiol Educ. 2007;31(1):5-16. doi:10.1152/advan.00088.2006
3. Weiser MJ, Butt CM, Mohajeri MH. Docosahexaenoic acid and cognition throughout the lifespan. Nutrients. 2016;8(2). doi:10.3390/nu8020099
4. Nayeem MA. Role of oxylipins in cardiovascular diseases. Acta Pharmacol Sin. 2018;39(7):1142-1154. doi:10.1038/aps.2018.24
5. Sun P, Yamamoto H, Suetsugu S, Miki H, Takenawa T, Endo T. Small GTPase Rah/Rab34 is associated with membrane ruffles and macropinosomes and promotes macropinosome formation. Journal of Biological Chemistry. 2003;278(6). doi:10.1074/jbc.M208699200
6. Petermann AB, Reyna-Jeldes M, Ortega L, Coddou C, Yévenes GE. Roles of the Unsaturated Fatty Acid Docosahexaenoic Acid in the Central Nervous System: Molecular and Cellular Insights. Int J Mol Sci. 2022;23(10). doi:10.3390/ijms23105390
7. Clementi ME, Lazzarino G, Sampaolese B, Brancato A, Tringali G. DHA protects PC12 cells against oxidative stress and apoptotic signals through the activation of the NFE2L2/HO-1 axis. Int J Mol Med. 2019;43(6). doi:10.3892/ijmm.2019.4170
8. Kim HY, Huang BX, Spector AA. Molecular and Signaling Mechanisms for Docosahexaenoic Acid-Derived Neurodevelopment and Neuroprotection. Int J Mol Sci. 2022;23(9). doi:10.3390/ijms23094635
9. Lone AM, Taskén K. Proinflammatory and immunoregulatory roles of eicosanoids in T cells. Front Immunol. 2013;4(JUN). doi:10.3389/fimmu.2013.00130
10. Yamaguchi A, Botta E, Holinstat M. Eicosanoids in inflammation in the blood and the vessel. Front Pharmacol. 2022;13. doi:10.3389/fphar.2022.997403
11. Johnson AM, Kleczko EK, Nemenoff RA. Eicosanoids in Cancer: New Roles in Immunoregulation. Front Pharmacol. 2020;11. doi:10.3389/fphar.2020.595498
12. Bruegel M, Ceglarek U, Thiery J. Eicosanoids: Essential mediators in health and disease. LaboratoriumsMedizin. 2009;33(6). doi:10.1515/JLM.2009.056
13. Nakanishi M, Rosenberg DW. Multifaceted roles of PGE2 in inflammation and cancer. Semin Immunopathol. 2013;35(2). doi:10.1007/s00281-012-0342-8
14. Wang B, Wu L, Chen J, et al. Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets. Signal Transduct Target Ther. 2021;6(1). doi:10.1038/s41392-020-00443-w
15. Sood R, Anoopkumar-Dukie S, Rudrawar S, Hall S. Neuromodulatory effects of leukotriene receptor antagonists: A comprehensive review. Eur J Pharmacol. 2024;978:176755. doi:10.1016/j.ejphar.2024.176755
16. Gomberg-Maitland M, Olschewski H. Prostacyclin therapies for the treatment of pulmonary arterial hypertension. European Respiratory Journal. 2008;31(4). doi:10.1183/09031936.00097107
17. Cartier A, Hla T. Sphingosine 1-phosphate: Lipid signaling in pathology and therapy. Science (1979). 2019;366(6463). doi:10.1126/science.aar5551
18. Rostami N, Nikkhoo A, Ajjoolabady A, et al. S1PR1 as a Novel Promising Therapeutic Target in Cancer Therapy. Mol Diagn Ther. 2019;23(4). doi:10.1007/s40291-019-00401-5