Linoleic acid: chemical properties, sources, biosynthesis and biological role

Linoleic acid is a polyunsaturated fatty acid with 18 carbon atoms and two cis double bonds.[1]

In the human diet, the main sources are various vegetable oils and the seeds of many plants.[2]

Mammals are unable to synthesize it due to the lack of a specific desaturase enzyme, which is present in other organismal groups, including plants, microorganisms, and certain invertebrates. Together with alpha-linolenic acid, it is one of the two essential fatty acids for humans.[3][4]

It is found both in adipose tissue, esterified in triglycerides, and as a component of cell membranes, esterified in phospholipids.[5]

Linoleic acid, the simplest of the omega-6 polyunsaturated fatty acids, performs energetic, structural, metabolic, and regulatory functions, both directly and through its metabolites.[6]

Summary: Key Points

  • Chemical properties: linoleic acid is an essential omega-6 polyunsaturated fatty acid for humans.
  • Biosynthesis: produced by bacteria, plants, and some invertebrates via Δ12-desaturase, an enzyme absent in mammals.
  • Dietary sources: widely present in vegetable oils and seeds, its dietary concentration is currently influenced by the development of cultivars optimized for oleic acid.
  • Energy role: stored in adipose tissue triglycerides, it can undergo mitochondrial and peroxisomal β-oxidation.
  • Functions: a structural component of cell membranes where it helps modulate fluidity, acts as an activating ligand for PPARα, and serves as a precursor for the biosynthesis of arachidonic acid and α-linolenic acid.
  • Human health: acts as a precursor to bioactive lipid metabolites involved in cell signaling and the regulation of inflammation.

Contents

Chemical properties

Linoleic acid has a molecular weight of 280.447 g/mol, a molecular formula of C18H32O2, and the abbreviated notation 18:2n-6.
According to IUPAC nomenclature, its systematic name is (9Z,12Z)-octadeca-9,12-dienoic acid.[1]

Its conjugate base is called linoleate; it has the condensed formula C18H31O2–, and this is the form in which the free fatty acid is found in biological systems at physiological pH, having a pKa of approximately 4.77.[7]

Structural formula of linoleic acid (LA), an omega-6 polyunsaturated fatty acid with 18 carbon atoms and two cis double bonds.
Structural Formula of Linoleic Acid

The presence of two cis double bonds, at positions 9 and 12 relative to the carboxyl end, classifies linoleic acid in the group of unsaturated fatty acids. Furthermore, since the first double bond, relative to the methyl end, is at position 6, the molecule belongs to the group of omega-6 polyunsaturated fatty acids, also known as omega-6 fatty acids, or simply omega-6.[3]

In its purified form, it appears as a colorless to straw-colored liquid with a density of 0.9 g/mL.[8] Its melting point is 5 °C (23 °F; 268.15 K), while its boiling point is 230 °C (446 °F; 503.15 K) at 16 mm Hg.[1]

Chemical and physical properties of linoleic acid
Category Parameter Specifications Reference/Value
Identifiers IUPAC Name Systematic name (9Z,12Z)-octadeca-9,12-dienoic acid
CAS Number CAS database reference 60-33-3
PubChem CID National Center for Biotechnology Information 5280450
ChEBI ID EMBL-EBI Ontology CHEBI:17351
Chemical characteristics Molecular formula Elemental formula C18H32O2 (Linoleate: C18H31O2−)
Molecular weight Molar mass 280.447 g/mol
Structural characteristics Chemical class Fatty acid classification Long-chain fatty acid / Omega-6 polyunsaturated fatty acid
Structural notation Abbreviated notation and pKa 18:2n-6 (pKa: ≈ 4.77)
Physical properties Water solubility Solubility Practically insoluble
Physical state Appearance, density, and transition points Colorless to straw-colored liquid (density: 0.9 g/mL; m.p.: 5 °C; b.p.: 230 °C at 16 mm Hg)

Dietary sources

Linoleic acid is the most abundant of the polyunsaturated fatty acids found in the Western diet, accounting for 85–90% of all omega-6 intake.[6]

For humans, the main dietary sources are various vegetable oils and the seeds of many plants, such as safflower, sunflower, hemp, soybean, corn, and cottonseed oils, as well as oil-rich fruits like walnuts and peanuts. In terms of percentage relative to other polyunsaturated fatty acids, the highest levels are found in safflower and sunflower oils, while soybean oil is significant in terms of consumption volume. In addition to being naturally present in plant-based foods, linoleic acid is also found in animal-derived products, such as lard and eggs, as a result of its presence in animal feed.[2]

Linoleic acid content (mg/g of total lipids) in main human food sources
Food Linoleic acid
Safflower oil ≈ 740
Sunflower oil ≈ 600
Hempseed oil ≈ 550
Soybean oil ≈ 530
Corn oil ≈ 500
Cottonseed oil ≈ 480
Walnuts ≈ 340
Brazil nuts ≈ 250
Peanut oil ≈ 240
Rapeseed oil (canola) ≈ 190
Chia seed oil ≈ 180
Peanuts ≈ 140
Flaxseed oil ≈ 135

Linoleic acid is the primary polyunsaturated fatty acid even in foods with a very low fat content, such as fruits, grains, and vegetables, with the exception of beans, in which it accounts for 40–50% of total polyunsaturated fatty acids.[9]

Evolution of consumption

Linoleic acid is the only polyunsaturated fatty acid whose intake increased significantly during the 20th century, reaching, on average, 6–7% of daily energy intake, compared to pre-1930 levels ranging from 1% to 2%. In contrast, the intake of other omega-6 and omega-3 fatty acids has remained relatively constant since the early 20th century, staying below 1% of daily energy intake. This increase has shifted the ratio of total omega-6 to omega-3 polyunsaturated fatty acid intake from approximately 4:1 to as high as 16:1.[10]

The increase in linoleic acid intake was the result of several factors, linked in particular to the widespread use of vegetable oils. For example, in the U.S., consumption of these oils increased approximately 20-fold during the 20th century.[10][11] This trend was driven by:

  • the selection of cultivars designed to produce seeds with a high linoleic acid content, particularly soybeans and corn;[10]
  • increased availability and commercial accessibility of derived oils;
  • nutritional recommendations aimed at increasing their consumption as a means of lowering blood cholesterol levels—guidelines that followed, in the mid-1950s, the studies of the American physiologist Ancel Keys.[12]

In the U.S., soybean oil is the primary dietary source of linoleic acid, accounting for up to about 45% of the total.[6]

Cultivars with low linoleic acid content

In nature, linoleic acid is produced in concentrations comparable to those of α-linolenic acid.[13]

Starting in the 1930s, cultivars were selected specifically to produce seeds with a high linoleic acid content. However, in recent years, this trend has been shifting due to the selection of cultivars that produce seeds with a significantly lower linoleic acid content, in which this fatty acid has been largely replaced by oleic acid.[14]

This process has led to the production of sunflower, safflower, and soybean oils with high oleic acid content. As these new cultivars replace traditional ones, we will likely see a gradual reduction in linoleic acid intake in favor of oleic acid. Consequently, we might observe a return to intake levels comparable to those at the beginning of the 20th century.[15]

This transition could yield significant health benefits, as oleic acid consumption is associated with an improved lipid profile, including higher HDL cholesterol levels, and is a hallmark of the Mediterranean diet, which has always been rich in this monounsaturated fatty acid thanks to the use of olive oil, the cornerstone of this dietary pattern.[15]

Biosynthesis

Linoleic acid is the first omega-6 polyunsaturated fatty acid to be synthesized, and it is produced from oleic acid, an omega-9 monounsaturated fatty acid.[3] The reaction is catalyzed by Δ12-desaturase (EC 1.14.19.6), an enzyme that depends on molecular oxygen and electron transport systems, such as cytochrome b5, and involves the insertion of a second cis double bond between carbons 6 and 7 from the methyl end of the molecule, or between carbons 12 and 13 from the carboxyl end.[16][17]

Linoleic acid metabolism: from synthesis from oleic acid to conversion into alpha-linolenic acid, omega-6 fatty acids, and OXLAMs.
Linoleic Acid Metabolism

Note that Δ12-desaturase catalyzes the conversion of an omega-9 fatty acid into an omega-6 fatty acid.

For a long time, it was believed that Δ12-desaturase was present only in bacteria, protozoa, fungi, phytoplankton, and terrestrial plants, and that only these organisms were capable of synthesizing linoleic acid.[18] However, in 1961 it was demonstrated that an insect, the American cockroach (Periplaneta americana), and thus an animal, was also capable of synthesizing it.[19] Subsequently, its synthesis has also been observed in other insects and invertebrates, including various mites, crustaceans, and nematodes.[16]

Δ12-desaturase is not present in mammals, including humans, who are therefore unable to synthesize linoleic acid de novo. For this reason, linoleic acid obtained through the diet is classified as an essential fatty acid.[4]

Cellular and tissue distribution

Like other fatty acids, it is rarely found in nature in its free form, as it is mostly bound via ester bonds to other organic molecules, such as sterols, glycerol, and glycerol-3-phosphate, to form more complex lipids.[20]

Along with palmitic acid and oleic acid, it is one of the most abundant fatty acids found in triglycerides, typically esterified at the sn-1 and sn-3 positions, in adipose tissue and plasma lipoproteins, where its concentration reflects dietary intake.[2] In this regard, in the U.S., the large increase in its dietary intake has been accompanied by an increase in its content in adipose tissue, estimated to be over 135%.[21]

Given its abundance and susceptibility to oxidation, it is the most commonly oxidized fatty acid in LDL.[22] The oxidation of LDL lipids is a risk marker for coronary heart disease.[23]

Linoleic acid is a structural component of cell membranes, typically esterified at the sn-2 position of phospholipids.[5]
Although essential for fetal neurological development, it is present in low concentrations, less than 2% of all fatty acids, in brain phospholipids, a percentage much lower than that of palmitic acid, stearic acid, oleic acid, arachidonic acid (ARA), and docosahexaenoic acid (DHA), which together account for approximately 84% of the fatty acids present.[14][24]

In the epidermis, it is the most abundant polyunsaturated fatty acid.[2]

Energy role

Linoleic acid may be present in the diet in moderate amounts. Consequently, its accumulation in the triglycerides of adipose tissue is not negligible, nor is its role in energy production through mitochondrial and peroxisomal β-oxidation.[3][6]

Taking the brain as an example, although linoleic acid enters the brain at a rate comparable to that of DHA, ARA, and other fatty acids, ARA and DHA are mostly incorporated into membrane phospholipids, while nearly 60% of linoleic acid undergoes β-oxidation. Furthermore, part of the acetate produced is used for cholesterol synthesis in the brain.[14]

The presence of cis double bonds results in a slightly lower ATP yield compared to the corresponding saturated fatty acid, stearic acid. In fact, while 122 ATP molecules can be generated from stearic acid, 116.5 are obtained from linoleic acid, representing a 4.51% lower energy yield.[20]

Functions

Linoleic acid performs structural, metabolic, and regulatory functions, both directly and indirectly, as it is a precursor to bioactive molecules.

  • It is a structural component of cell membranes.[5] Along with other polyunsaturated fatty acids, it plays an essential role in regulating membrane fluidity, indirectly contributing to the modulation of responses dependent on membrane proteins.[25][26]
  • At the epidermal level, particularly in the stratum corneum of the skin, as a component of sphingolipids, it contributes to the formation of the barrier that prevents the passage of water.[27]
  • It is capable of binding to PPARα and activating it.
    PPARα is involved in the regulation of metabolism. For example, it inhibits the transcription of genes encoding enzymes involved in lipogenesis and activates the transcription of genes encoding enzymes involved in lipolysis and both mitochondrial and peroxisomal β-oxidation.[28] These actions may contribute to the ability of linoleic acid to reduce plasma levels of total cholesterol and LDL, thereby helping to lower cardiovascular risk.[29]
  • It is the precursor, even in mammals, to the other members of the omega-6 polyunsaturated fatty acid family, including ARA.[30]
  • It can be desaturated to yield α-linolenic acid, the simplest of the omega-3 polyunsaturated fatty acids. The reaction is catalyzed by Δ15-desaturase (EC 1.14.19.25), an enzyme found only in phytoplankton and terrestrial vascular plants. In this reaction, a third cis double bond is inserted between carbons 3 and 4 from the methyl end of the molecule, that is, between carbons 15 and 16 from the carboxyl end, resulting in the conversion from an omega-6 fatty acid to an omega-3 fatty acid.[2][31]

OXLAMs

Linoleic acid is the precursor of bioactive lipid mediators with autocrine and paracrine actions.[6] Released from membrane phospholipids by the action of phospholipase A2 (EC 3.1.1.4), it can undergo enzymatic oxidation in reactions catalyzed by 12-lipoxygenase (EC 1.13.11.31), 15-lipoxygenase (EC 1.13.11.33), cyclooxygenases (EC 1.14.99.1), enzymes of the cytochrome P450 family, or soluble epoxide hydrolase (EC 3.3.2.10), the same enzymes involved in the metabolism of ARA and DHA.[32] It may also undergo free-radical-mediated oxidation.[14] The metabolites produced, such as epoxide derivatives and mono-, di-, and trihydroxylated derivatives known as OXLAMs, acronym of “oxidized linoleic acid metabolites”, play a role in cell signaling and in the regulation of pain and inflammation.[32]

Linoleic acid and human health

Linoleic acid is an essential nutrient for humans and must therefore be obtained through the diet. A deficiency in linoleic acid can lead to stunted growth and delayed wound healing, dermatitis, reproductive problems, fatty liver, and polydipsia. Such a deficiency is extremely rare due to its abundance in the Western diet, and thus also in breast milk, and its presence in infant formula.[2]

Dietary intake of linoleic acid is inversely correlated with the risk of coronary heart disease when it replaces saturated fatty acids or carbohydrates.[29]

ARA can be synthesized from linoleic acid; ARA, in turn, is a precursor to both mediators with pro-inflammatory, pro-thrombotic, and atherogenic activity, and mediators with anti-inflammatory, vasodilatory, and inflammation-resolving activity. It has therefore been hypothesized that limiting linoleic acid intake could reduce tissue levels of ARA. However, at least for individuals consuming a typical Western diet, this does not appear to occur, as the conversion to ARA is very modest, ranging from 0.3% to 1%.[30]

Furthermore, it has been suggested that the profile of lipid mediators, as well as inflammatory responses to a diet rich in linoleic acid, are influenced by the FADS1 gene, which encodes Δ5-desaturase (EC 1.14.19.44), an enzyme that catalyzes the second desaturation reaction in the ARA biosynthetic pathway, namely the desaturation of dihomo-gamma-linolenic acid to form ARA.[33]

References

  1. a b c National Center for Biotechnology Information. PubChem Compound Summary for CID 5280450, Linoleic Acid. https://pubchem.ncbi.nlm.nih.gov/compound/Linoleic-Acid. Accessed Nov. 2, 2026.
  2. a b c d e f Chow C.K. Fatty acids in foods and their health implication. 3rd Edition. CRC Press, 2008. doi:10.1201/9781420006902
  3. a b c d Akoh C.C., Min D.B. Food lipids: chemistry, nutrition, and biotechnology. 4th Edition. Boca Raton: CRC Press, 2017. doi:10.1201/9781315151854
  4. a b Das U.N. Essential fatty acids: biochemistry, physiology and pathology. Biotechnol J 2006;1;420-439. doi:10.1002/biot.200600012
  5. a b c Alberts B., Heald B., Johnson A.D., Morgan D., Raff M., Roberts K., Walter P. Molecular Biology of the Cell. 7th Edition. Garland Science, 2022.
  6. a b c d e Whelan J., Fritsche K. Linoleic acid. Adv Nutr 2013;4(3): 311-312. doi:10.3945/an.113.003772
  7. ^ Kanicky J.R., Shah D.O. Effect of degree, type, and position of unsaturation on the pKa of long-chain fatty acids. J Colloid Interface Sci 2002;256(1):201-7. doi:10.1006/jcis.2001.8009
  8. ^ O’Neil M.J. The Merck index: an encyclopedia of chemicals, drugs, and biological. 15th ed. Royal Society of Chemistry, 2013.
  9. ^ U.S. Department of Agriculture, Agricultural Research Service. FoodData Central, 2019.
  10. a b c Blasbalg T.L., Hibbeln J.R., Ramsden C.E., Majchrzak S.F., Rawlings R.R. Changes in consumption of omega-3 and omega-6 fatty acids in the United States during the 20th century. Am J Clin Nutr 2011;93(5):950-962. doi:10.3945/ajcn.110.006643
  11. ^ Micha R., Khatibzadeh S., Shi P., Fahimi S., Lim S., Andrews K.G., Engell R.E., Powles J., Ezzati M., Mozaffarian D.; Global Burden of Diseases Nutrition and Chronic Diseases Expert Group NutriCoDE. Global, regional, and national consumption levels of dietary fats and oils in 1990 and 2010: a systematic analysis including 266 country-specific nutrition surveys. BMJ 2014;348:g2272. doi:10.1136/bmj.g2272
  12. ^ Keys A., Anderson J.T., Grande F. Prediction of serum-cholesterol responses of man to changes in fats in the diet. Lancet 1957;273(7003):959-66. doi:10.1016/s0140-6736(57)91998-0
  13. ^ Simopoulos A.P. Evolutionary aspects of diet: the omega-6/omega-3 ratio and the brain. Mol Neurobiol 2011;44(2):203-15. doi:10.1007/s12035-010-8162-0
  14. a b c d Taha A.Y. Linoleic acid-good or bad for the brain? NPJ Sci Food 2020;4:1. doi:10.1038/s41538-019-0061-9
  15. a b Jandacek R.J. Linoleic acid: a nutritional quandary. Healthcare 2017;5(2):25. doi:10.3390/healthcare5020025
  16. a b Malcicka M., Visser B., Ellers J. An evolutionary perspective on linoleic acid synthesis in animals. Evol Biol 2018;45:15-26. doi:10.1007/s11692-017-9436-5
  17. ^ Liu C.J. Cytochrome b5: a versatile electron carrier and regulator for plant metabolism. Front Plant Sci 2022;13:984174. doi:10.3389/fpls.2022.984174
  18. ^ De Renobales M., Ryan R.O., Heisler C.R., McLean D.L., Blomquist G.J. Linoleic acid biosynthesis in the pea aphid, Acyrthosiphon pisum (Harris). Arch Insect Biochem Physiol 1986:3(2);193-203. doi:10.1002/arch.940030209
  19. ^ Louloudes S.J., Kaplanis J.N., Robbins W. E., Monroe R.E. Lipogenesis from C14-acetate by the American cockroach. Ann Entomol Soc Am 1961;54(1):99-103. doi:10.1093/aesa/54.1.99
  20. a b Nelson D.L., Cox M.M. Lehninger. Principles of biochemistry. 8th Edition. W.H. Freeman and Company, 2021.
  21. ^ Guyenet S.J., Carlson S.E. Increase in adipose tissue linoleic acid of US adults in the last half century. Adv Nutr 2015;6(6):660-664. doi:10.3945/an.115.009944
  22. ^ Jira W., Spiteller G., Carson W., Schramm A. Strong increase in hydroxy fatty acids derived from linoleic acid in human low density lipoproteins of atherosclerotic patients. Chem Phys Lipids 1998;91(1):1-11. doi:10.1016/s0009-3084(97)00095-9
  23. ^ Meisinger C., Baumert J., Khuseyinova N., Loewel H., Koenig W. Plasma oxidized low-density lipoprotein, a strong predictor for acute coronary heart disease events in apparently healthy, middle-aged men from the general population. Circulation 2005;112(5):651-7. doi:10.1161/CIRCULATIONAHA.104.529297
  24. ^ Taha A.Y., Cheon Y., Ma K., Rapoport S.I., Rao J.S. Altered fatty acid concentrations in prefrontal cortex of schizophrenic patients. J Psychiatr Res 2013;47(5):636-43. doi:10.1016/j.jpsychires.2013.01.016
  25. ^ Stubbs C.D., Smith A.D. The modification of mammalian membrane polyunsaturated fatty acid composition in relation to membrane fluidity and function. Biochim Biophys Acta 1984;779(1):89-137. doi:10.1016/0304-4157(84)90005-4
  26. ^ Niu S.L., Mitchell D.C., Lim S.Y., Wen Z.M., Kim H.Y., Salem N. Jr, Litman B.J. Reduced G protein-coupled signaling efficiency in retinal rod outer segments in response to n-3 fatty acid deficiency. J Biol Chem 2004;279(30):31098-104. doi:10.1074/jbc.m404376200
  27. ^ Ziboh V.A. Prostaglandins, leukotrienes, and hydroxy fatty acids in epidermis. Semin Dermatol 1992;11(2):114-20.
  28. ^ Desvergne B., Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 1999;20(5):649-88. doi:10.1210/edrv.20.5.0380
  29. a b Farvid M.S., Ding M., Pan A., Sun Q., Chiuve S.E., Steffen L.M., Willett W.C., Hu F.B. Dietary linoleic acid and risk of coronary heart disease: a systematic review and meta-analysis of prospective cohort studies. Circulation 2014;130:1568-1578. doi:10.1161/CIRCULATIONAHA.114.010236
  30. a b Rett B.S., Whelan J. Increasing dietary linoleic acid does not increase tissue arachidonic acid content in adults consuming Western-type diets: a systematic review. Nutr Metab (Lond) 2011;8:36. doi:10.1186/1743-7075-8-36
  31. ^ Yadav N.S., Wierzbicki A., Aegerter M., Caster C.S., Pérez-Grau L., Kinney A.J., Hitz W.D., Booth J.R. Jr, Schweiger B., Stecca K.L., Allen S.M., Blackwell M., Reiter R.S., Carlson T.J., Russell S.H., Feldmann K.A.,  Pierce J., Browse J. Cloning of higher plant omega-3 fatty acid desaturases. Plant Physiol 1993;103(2):467-76. doi:10.1104/pp.103.2.467
  32. a b Schuster S., Johnson C.D, Hennebelle M., Holtmann T., Taha A.Y., Kirpich I.A., Eguchi A., Ramsden C.E., Papouchado B.G., McClain C.J., Feldstein A.E. Oxidized linoleic acid metabolites induce liver mitochondrial dysfunction, apoptosis and NLRP3 activation in mice. J Lipid Res 2018;59(9):1597-1609. doi:10.1194/jlr.M083741
  33. ^ Lankinen M.A., Fauland A., Shimizu B., Agren J., Wheelock C.E., Laakso M., Schwab U., Pihlajamaki J. Inflammatory response to dietary linoleic acid depends on FADS1 genotype. Am J Clin Nutr 2019;109:165-175. doi:10.1093/ajcn/nqy287

Domande Frequenti

Why is linoleic acid classified as an essential fatty acid?

Linoleic acid is essential because humans lack Δ12-desaturase, an enzyme required to insert a double bond at carbon 12 of oleic acid. Since mammals cannot synthesize it de novo, it must be obtained through dietary sources like seeds and vegetable oils.

What role does linoleic acid play in human energy metabolism?

While poorly stored in brain cell membranes compared to DHA and ARA, nearly 60% of linoleic acid in the brain undergoes mitochondrial and peroxisomal β-oxidation for energy production. Its oxidation yields 116.5 ATP molecules per molecule oxidized.

Does consuming linoleic acid significantly increase tissue ARA levels?

No. In humans consuming a typical Western diet, the metabolic conversion of dietary linoleic acid to arachidonic acid (ARA) is extremely low, estimated between 0.3% and 1%. Consequently, dietary intake has minimal impact on tissue ARA accumulation.

What are OXLAMs and how are they formed from linoleic acid?

OXLAMs (acronym of oxidized linoleic acid metabolites) are bioactive lipid mediators derived from linoleic acid oxidation via lipoxygenases, cyclooxygenases, or free radicals. They act as autocrine and paracrine signals regulating cellular pain and inflammation.

Biochemistry and Metabolism