IngredientsA lipid is generally considered to be any molecule that is insoluble in water and soluble in organic solvents. Biological lipids refer to a broad grouping of naturally occurring molecules which includes fatty acids, waxes, eicosanoids, monoglycerides, diglycerides, triglycerides, phospholipids, sphingolipids, sterols, terpenes, prenols, fat-soluble vitamins (such as vitamins A, D, E and K) and others, in contrast to the other major groupings of biological molecules β the nucleic acids, amino acids, and carbohydrates.
The main biological functions of lipids include their central role in energy storage, as structural components of cell membranes, and as important signaling molecules. Although "lipid" and "fat" are frequently used interchangeably in everyday speech, the term lipid is sometimes used as a synonym for fats; however, fats are actually a subgroup of lipids called triglycerides.
The nomenclature of lipids falls into two main categories: systematic names and common or trivial names. The generally accepted guidelines for lipid systematic names have been defined by the International Union of Pure and Applied Chemists and the International Union of Biochemistry and Molecular Biology (IUPAC-IUBMB) Commission on Biochemical Nomenclature.
Biological lipids originate entirely or in part from two distinct types of biochemical subunits: ketoacyl and isoprene groups. Using this approach, lipids may be divided into eight categories: fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, saccharolipids, and polyketides (derived from condensation of ketoacyl subunits); and sterol lipids and prenol lipids (derived from condensation of isoprene subunits).
Lipids have also been broadly subdivided into "simple" and "complex" groups, with simple lipids being those yielding at most two types of products on hydrolysis (e.g., fatty acids, sterols, and acylglycerols) and complex lipids (e.g., glycerophospholipids and glycosphingolipids) yielding three or more products on hydrolysis.
The eight formal LIPID MAPS categories, each with distinct chemical characteristics, are described below:
The main fatty acids in dietary lipids are grouped into saturated, monounsaturated, and polyunsaturated fatty acids. Fatty acids are made of a hydrocarbon chain that terminates with a carboxylic acid group; this arrangement confers the molecule with a polar, hydrophilic end, and a nonpolar, hydrophobic end that is insoluble in water. The carbon chain, typically between four and 24 carbons long, may be saturated or unsaturated, and may be attached to functional groups containing oxygen, halogens, nitrogen, and sulfur. If a fatty acid contains a double bond, there is the possibility of either a cis or trans geometric isomerism, which significantly affects the molecule's configuration. Cis-double bonds cause the fatty acid chain to bend, an effect that is compounded with more double bonds in the chain.
Eicosanoids are important chemical messengers that include prostaglandins, which have a five-member ring and a carboxylic acid chain.
Polar lipids are amphiphilic lipids with a hydrophilic head and a hydrophobic tail. Polar lipids mainly include phospholipids and sphingolipids. The amphiphilic nature of some lipids allows them to form structures such as vesicles, multilamellar/unilamellar liposomes, or membranes in an aqueous environment.
Vegetable oils, including soybean, palm, linseed, rapeseed, and coconut oils, are major dietary lipid sources. Extracted from plants, these oils are typically refined to eliminate impurities and improve their quality. The refining process, tailored to the type of oil and extraction method, enhances shelf life and consumer appeal. Widely utilized in cooking and food manufacturing, vegetable oils are a key source of mono- and polyunsaturated fats.
Fish oils are an important dietary lipid source, abundant in omega-3 fatty acids such as EPA and DHA. Extracted from fish, they are valued for their health benefits, including anti-inflammatory effects and support for cardiovascular health.
Plants, fish, and animal fats have represented the primary source of lipids and fats for centuries. Nowadays, the use of fatty acid sources has taken a turn: industries are mainly interested in polyunsaturated fatty acids (PUFAs), which have beneficial properties in human health; and also, for high-value fatty acid products for innovative and green production of biofuel and feedstocks.
Phytosterols represent a distinct and clinically important sub-class. Phytosterols were described chemically for the first time in 1922, and to date, more than 250 compounds have been isolated. They belong to the triterpene family with a tetracyclic cyclopenta-Ξ±-phenanthrene ring. Phytosterols are derivatives of C-28 (e.g., campesterol) and C-29 (e.g., Ξ²-sitosterol and stigmasterol) sterols in contrast to cholesterol, which belongs to compounds of C-27. Phytostanols, including Ξ²-sitostanol and campestanol, are characterized by the lack of the Ξ5 double bond.
In supplemental form, lipids are available as fish oil capsules (soft-gel and liquid), krill oil capsules, algal oil (plant-derived DHA/EPA), plant sterol/stanol-enriched foods (spreads, margarines, yogurt drinks), medium-chain triglyceride (MCT) oils, and structured phospholipid preparations. Unlike prescription products, fish oil supplements are classified as food by the Food and Drug Administration (FDA) and are not required to undergo manufacturing oversight or clinical testing.
Fats and lipids have always had a primary role in the history of humankind, from ancient civilisations to the modern and contemporary time, going from domestic and cosmetic uses, to the first medical applications and later to the large-scale industrial uses for food, pharmaceutical, cosmetics, and biofuel production. Sources and uses of those have changed during time following the development of chemical sciences and industrial technological advances.
Ancient peoples introduced a technique based on maceration in oils of flowers, leaves, spices, resins, and in some cases, pigments. Contemporary documents describe a surprisingly broad number of sources of oils, fats, and waxes β from very common seeds such as linseed and poppy seeds, to indigenous trees like cedar and palm, fruits such as olives and avocados, fish and even some remarkable animal oils such as hippopotamus or crocodile oils β indicating that even in more primitive ages the knowledge of lipids was more developed than we assume.
This tradition was followed by the great Mediterranean societies of the ancient Greeks and Romans, who introduced new techniques for production of oils and lotions such as distillation and seed pressing. Between 400 and 1,000 AD, despite the world being preoccupied by the Dark Ages, in some parts of Europe and in China, Japan, and North America, great advances were made in the usage of oils and fats especially applied to medicine and alchemy.
Consumption of fats and oils in the ancient world was examined as a window to human nutritional needs and compared with lipid usage in the modern world, post-1900. In earlier periods, the natural and only source of edible fats and oils came from both animals and plants. These fats and oils played a vital role in the evolution of the human body structure, supporting many biochemical functions. Artifacts from prehistoric periods and the ancient world indicate that humans were evolutionarily adapted to consume saturated lipids. They also consumed unsaturated fats and oils extracted from animals and plants, now identified as omega-3 to omega-6 in the fatty acid ratio of approximately 1:1, commonly derived from naturally consumed unprocessed products and food sources.
Dietary supplements augment the nutritional value of everyday food intake and originate from the historical practices of ancient Egyptian (Ebers papyrus), Chinese (Pen Ts'ao by Shen Nung), Indian (Ayurveda), Greek (Hippocrates), and Arabic herbalists. On the Indian sub-continent, with the historical influence of Ayurvedic medicine, there is continued consumption of coconut oil, butter, and ghee. Tibetans regularly consume large quantities of yak butter.
The historical use of fish oils in Northern European and Scandinavian populations is also documented, with cod liver oil used as a traditional remedy for rickets, joint pain, and general debility from the 18th century onwards. Theodore Gobley (1847) discovered phospholipids in mammalian brain and hen egg, which he called "lecithins." Thudichum subsequently discovered in the human brain some phospholipids (cephalin), glycolipids (cerebroside), and sphingolipids (sphingomyelin).
The two most biologically active marine-sourced omega-3 PUFAs are eicosapentaenoic acid (EPA; C20:5 n-3) and docosahexaenoic acid (DHA; C22:6 n-3). The plant-derived precursor is alpha-linolenic acid (ALA; C18:3 n-3). The omega-3 fatty acids found in fish and fish oils β eicosapentaenoic and docosahexaenoic acids, EPA and DHA β have been reported to have a variety of beneficial effects in cardiovascular diseases.
The principal omega-6 fatty acid in the diet is linoleic acid (LA; C18:2 n-6), the precursor to arachidonic acid (AA; C20:4 n-6). Cells involved in the inflammatory response are typically rich in the n-6 fatty acid arachidonic acid. Eicosanoids produced from arachidonic acid have roles in inflammation.
Phospholipids play important roles in assuring the correct environment for membrane protein function, maintaining membrane order ("fluidity") and influencing lipid raft formation. Membrane phospholipids are substrates for the generation of second messengers like diacylglycerol, and it has been demonstrated that the fatty acid composition of such second messengers, which is determined by that of the precursor phospholipid, can influence their activity. In addition, membrane phospholipids are substrates for the release of (non-esterified) PUFAs intracellularly β the released PUFAs can act as signaling molecules, ligands (or precursors of ligands) for transcription factors, or precursors for biosynthesis of lipid mediators involved in regulation of many cell and tissue responses, including aspects of inflammation and immunity.
The best known biological function of phytosterols is their role in the prevention of cardiovascular diseases by lowering the level of the low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) fractions of cholesterol. The typical western diet contains only about 300 mg/day of phytosterols, so foods enriched with phytosterols are usually used to achieve higher therapeutic intakes.
When glucose is underutilized, medium-chain triglycerides (MCTs), containing octanoic acid and capric acid, can be metabolized into ketone bodies in the body, which can replace glucose for direct energy supply to the brain and improve the energy supply to the brain, thus potentially preventing the decline of brain function.
Due to their role in pre- and postnatal development of the brain, there is a growing interest for the use of gangliosides, which are sphingolipids, as a dietary supplement for pregnant/lactating mothers or infants.
Mechanisms underlying the anti-inflammatory actions of n-3 fatty acids include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro-inflammatory transcription factor nuclear factor kappa B (NF-ΞΊB), thereby reducing expression of inflammatory genes, and activation of the anti-inflammatory transcription factor NR1C3.
These fatty acids are able to inhibit partly a number of aspects of inflammation including leucocyte chemotaxis, adhesion molecule expression and leucocyte-endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid, production of inflammatory cytokines, and T cell reactivity. In parallel, EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonic acid, and EPA and DHA give rise to anti-inflammatory and inflammation-resolving resolvins and protectins.
In the context of protein regulation, PUFAs alter the composition of membrane lipids, modulate cyclooxygenase, activate SIRT1/AMPK, control intracellular metabolism, control signal transduction along with gene expression, and regulate transcription factors like SREBF1c as well as nuclear receptors HNF-4, GPCR, PPAR, LXR, and TLR-4.
Changes in membrane phospholipid fatty acid composition can influence the function of cells involved in inflammation. Changes in these compositions can modify membrane fluidity, cell signaling leading to altered gene expression, and the pattern of lipid mediator production.
Phytosterols lower LDL-cholesterol primarily through competitive inhibition of intestinal cholesterol absorption. By structurally resembling cholesterol, phytosterols displace cholesterol from intestinal micelles, thereby reducing its uptake into enterocytes and increasing its fecal excretion. Dietary supplementation with phytosterols (PhyS) has been shown to reduce the risk of CVD and is a common nutritional strategy to reduce cholesterol levels.
The brain in Alzheimer's disease shows glucose hypometabolism but may utilize ketones for energy production. Ketone levels can potentially be boosted through oral intake of medium-chain triglycerides (MCTs). Evidence from animal studies suggests that in addition to providing an extra source of energy to the brain, ketones are associated with a variety of possible beneficial effects on neurons, including protection from excitotoxicity, improved mitochondrial function, increased autophagy, stimulation of brain-derived neurotrophic factor (BDNF) production, and activation of pathways associated with decreased inflammation and longevity.
Ecological and prospective cohort studies as well as randomized controlled trials have supported the view that the effects of omega-3 fatty acids are clinically relevant. They operate via several mechanisms, all beginning with the incorporation of EPA and DHA into cell membranes.
Triglyceride lowering (strong evidence): The strongest effect of marine oils is on triglyceride concentrations. Across studies, this effect was dose-dependent and related to studies' mean baseline triglyceride concentration.
Blood pressure (high evidence of minimal effect): There is high strength of evidence, based on numerous trials, of no significant effects of marine oils on systolic or diastolic blood pressures, but there are small, yet statistically significant increases in high-density lipoprotein and low-density lipoprotein cholesterol concentrations. The clinical significance of these small changes, particularly in combination, is unclear.
Major cardiovascular events (mixed evidence): Evidence from two landmark randomized clinical trials (RCTs) regarding the cardiovascular benefits of omega-3 fatty acids remains inconclusive. The Reduction of Cardiovascular Events with Icosapent Ethyl Intervention Trial (REDUCE-IT; n = 8,179) reported that high-dose icosapent ethyl (purified and stable EPA ethyl ester, 4 g/d) significantly reduced major cardiovascular events by 25% in patients with hypertriglyceridemia over a median follow-up of 4.90 years.
In contrast, low-dose mixed omega-3 formulations have not shown consistent benefit. The ASCEND trial reported the effect of 1 g/day of prescription omega-3 FA therapy in 15,480 patients with diabetes but without evidence of atherosclerotic cardiovascular disease, and the results failed to demonstrate a reduction of first serious vascular events. This is consistent with most prior studies of omega-3 mixtures at low doses. A similar failure was reported in the VITAL study among more than 25,000 patients with low cardiovascular risk using again a low-dose prescription omega-3 at 1 g/day. In this primary prevention trial, there was no statistically significant decrease in the primary composite cardiovascular endpoint or cancer-associated endpoints.
Earlier supportive evidence: The authors of a systematic review that included six secondary-prevention trials and one primary-prevention trial of omega-3 supplementation published between 1966 and 2005 concluded that consumption of long-chain omega-3s from fish and fish oil supplements reduces rates of all-cause mortality, cardiac death, sudden death, and stroke. They noted that the evidence of benefit is stronger for secondary than for primary prevention.
Japan EPA Lipid Intervention Study (JELIS): The JELIS trial enrolled patients with total cholesterol above 6.5 mmol/L. Patients were randomly assigned to either statin alone or statin with 1,800 mg/day EPA. The composite outcome β comprising major coronary events including sudden cardiac death, fatal and nonfatal myocardial infarction, and other nonfatal events β was reduced among patients treated with the omega-3 PUFA supplement with a relative risk reduction of 19% (P = 0.01) overall.
Overall evidence characterization: Both EPA and DHA have been widely associated with positive health benefits; however, data are inconsistent regarding the benefit of combination EPA and DHA in patients with cardiovascular disease. Clinical outcome trials have failed to show a consistent cardiovascular benefit with fish oil supplements and other low-dose mixed omega-3 fatty acids. The evidence is most robust for triglyceride reduction and for high-dose purified EPA supplementation in high-risk, statin-treated patients with established hypertriglyceridemia.
Clinical studies consistently indicate that the intake of phytosterols (2 g/day) is associated with a significant reduction (8β10%) in levels of low-density lipoprotein cholesterol (LDL-cholesterol). Several guidelines recommend the intake of 2 g/day of plant sterols and/or stanols in order to reduce LDL-cholesterol levels.
A meta-analysis including eight studies published from 1992 to 2013 with a duration of 4β6 weeks and doses of phytosterols between 1 and 3 g/day in tablets or capsules observed a significant reduction in LDL-cholesterol (on average 12 mg/dL), which was similar to that observed with food enriched with phytosterols. Most studies indicate that the use of phytosterols in tablets or capsules can be effective in reducing LDL-cholesterol levels.
There is evidence that the consumption of phytosterols in association with lipid-lowering therapy is able to promote a further reduction in serum cholesterol levels.
Limitations and caveats: No data deriving from formal randomized clinical trials are available allowing translation of this well-described effect of phytosterols on plasma LDL-cholesterol levels into measurable direct clinical effects on cardiovascular morbidity and mortality. Although phytosterols decrease LDL-cholesterol levels, there is no evidence that they reduce the risk of cardiovascular diseases; on the contrary, some studies suggest an increased risk of atherosclerosis with increasing serum levels of phytosterols. Compelling evidence from recent genetic studies has linked elevated plasma concentrations of circulating plant sterols with CVD presence, thus raising concerns about the safety of phytosterol supplementation.
A positive opinion on a scientific substantiation of health claims related to lowering blood cholesterol and reduced atherosclerotic cardiovascular disease risk after phytosterols has been provided by the European Food Safety Authority (EFSA) in 2012.
In addition to drug treatment, nutritional interventions or supplementations are becoming a health strategy for CVD prevention. Phytosterols have been shown to reduce cholesterol levels, while omega-3 fatty acids have shown to reduce triglyceride levels. Studies testing plant sterols (1.7β1.9 g/day) in combination with higher (2.0 and 5.4 g/day) doses of EPA/DHA showed significant reductions in triglyceride concentrations and small or no reductions in LDL-C. These studies delivered the treatment as a single dose at breakfast, provided as oil or formulated in a yogurt drink.
To date, limited studies exist on the brain bioavailability of dietary polar lipids via either placental transfer or the blood-brain barrier. Supplementing gangliosides and phospholipids in wild-type animals and healthy infants does suggest some positive effects on cognitive performance.
MCTs for mild cognitive impairment and Alzheimer's disease: A total of 10 clinical trials (848 subjects) studying the effect of MCT and coconut oil on cognitive function in mild cognitive impairment (MCI) and Alzheimer's disease (AD) subjects have been identified in systematic reviews. Duration of follow-up across these trials ranged from 120 minutes to 15 months. Most studies employed Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and/or the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog).
A small pilot randomized controlled trial evaluated MCT supplementation in patients with MCI: Six participants with MCI were enrolled. Participants received 56 g/day of either medium-chain triglycerides (MCTs) or placebo for 24 weeks. Intake of MCT oil increased serum ketone bodies and improved memory, while intake of placebo did not show improvement in any of the cognitive measures tested. The authors noted the very small sample size as a major limitation.
A larger, more recent RCT provided more robust data: A total of 280 MCI participants were randomly assigned to a placebo group, an MCT group (14 g/d octanoic acid + 10 g/d capric acid), a DHA group (800 mg/d), and an MCT + DHA group for 12 months. Cognitive function was assessed at baseline, 6 months, and 12 months. Supplementation of MCT, DHA, and their combination for 12 months significantly improved cognitive function, mitochondrial function, and serum total ketone body levels in MCI individuals. Combined intervention was more beneficial than MCT or DHA alone.
Specific functional components such as omega-3 fatty acids, Ξ²-glucans, phytosterols, and vitamin E have been shown to significantly reduce lipid profiles and postprandial glucose levels, helping prevent cardiovascular diseases and metabolic disorders. The anti-inflammatory evidence for omega-3 fatty acids in human studies is supported mechanistically by well-characterized pathways; some of the beneficial effects of PUFA-rich foods include a reduced susceptibility to ventricular arrhythmia, antithrombogenic and antioxidant effects, retardation of atherosclerotic plaque growth, improved blood lipid and lipoprotein profile, and anti-inflammatory and hypotensive effects.
Functional lipids, including long-chain polyunsaturated fatty acids (LC-PUFAs), phytosterols, and omega-3 and omega-6 fatty acids, have been shown to reduce the risk of cardiovascular diseases by improving lipid profiles and lowering blood pressure. Antioxidant lipid supplements, such as lycopene, astaxanthin, and beta-carotene, have shown positive effects on systolic blood pressure, LDL cholesterol, HDL cholesterol, total cholesterol, and triglycerides, contributing to a reduction in cardiovascular risk.
Due to the differences observed in both concentration and proportion of polar lipids in human milk, the estimated daily intake in infants encompasses a wide range. Health authorities define neither intake recommendations nor guidelines for polar lipid intake. However, adequate intake is defined for two nutrients that are elements of these polar lipids: choline and DHA.
The following dosages are drawn directly from clinical studies and represent ranges studied in research settings, not universal prescriptive recommendations.
Commonly reported side effects of omega-3 supplements are usually mild and include unpleasant taste, bad breath, heartburn, nausea, gastrointestinal discomfort, diarrhea, headache, and odoriferous sweat.
Two large clinical trials found that taking 4 g/day of omega-3 supplements for several years slightly increased the risk of atrial fibrillation in people with CVD or at high risk of CVD. A meta-analysis found that omega-3 fatty acid supplementation was associated with a significantly increased risk for atrial fibrillation compared to placebo, with an incidence rate ratio of 1.37 (95% confidence interval 1.22β1.54; p < 0.001). These findings were particularly noted in people with high blood lipids. Omega-3 fatty acid supplementation is associated with increased atrial fibrillation risk, particularly in trials that used high doses.
Fish oil can have antiplatelet effects at high doses, although it appears to be less potent than aspirin. Fish oil might prolong clotting times, as indicated by an elevated international normalized ratio (INR), when it is taken with warfarin; however, most research indicates that doses of 3β6 g/day fish oil do not significantly affect the anticoagulant status of patients taking warfarin. Overall, it has been found that fish and krill oils did not significantly alter warfarin time in therapeutic range (TTR) or bleeding incidence. Omega-3 supplementation with fish and krill oil does not significantly affect long-term warfarin control and bleeding and thromboembolic events when consumed concurrently in patients managed at an anticoagulation clinic. Notably, in high doses, both prescription omega-3s and fish oil supplements can increase the risk of atrial fibrillation and also lead to an increased risk of bleeding.
Analysis of widely used dietary fish oil supplements shows that they may have lower amounts of omega-3 than advertised as well as significant levels of saturated fat and oxidized oils, which may actually contribute to dyslipidemia. Risks associated with fish oil supplements include heavy metal contamination, such as from mercury, or oxidation of the oil found in fish oil capsules, which can increase the risk of clogged arteries.
Despite their undoubted cholesterol-lowering effect, past experimental and human studies have demonstrated controversial results regarding the effect of phytosterol consumption on various markers of atherosclerosis. Compelling evidence from recent genetic studies has linked elevated plasma concentrations of circulating plant sterols with CVD presence, thus raising concerns about the safety of phytosterol supplementation.
In 2020, the EFSA released a statement that the safety of plant sterol oxidation products caused by heating plant sterol esters during cooking and baking remained unestablished.
Supplements such as red yeast rice, omega-3 fatty acids, garlic, cinnamon, plant sterols, and turmeric are marketed to and believed by consumers to promote "cholesterol health." However, these supplements are not subjected to the same manufacturing scrutiny by the FDA as pharmaceutical drugs. Furthermore, supplements do not have to demonstrate efficacy or safety before being marketed. Important clinical differences exist between dietary supplement and prescription omega-3 fatty acid products.
Health conditions that Lipids may help support.
Body systems that Lipids may help support.
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