Long-chain polyunsaturated fatty acids are synthesized by elongation and desaturation of the carbon chain from the parent essential PUFAs: LA for the ω6 series and ALA for the ω3 series (Agostoni and Bruzzese, 1992). The metabolic pathway consists of successive carbon chain elongation and desaturation steps (by inserting double bonds into the carbon chain), that are controlled by elongase and desaturase enzymes, respectively. It begins with a ∆6-desaturation step, followed by chain elongation and desaturation thereof, to yield EPA when the initial substrate is ALA, or to yield AA when the initial substrate is LA (Zárate et al., 2017).

Linoleic acid, defined as an essential fatty acid in mammals because of their inability to synthesize it (Marangoni et al., 2020), is common in the human diet, being widely distributed in foods. In many vegetable oils, it represents more than 50% of the lipid content; high amounts of LA are also present in nuts, while lower levels are found in cereals (more in whole grains), legumes, some meats, eggs, and dairy products (Marangoni et al., 2020). In animal cells can be converted into AA; however, LA conversion to AA is very low (< 1%), and increasing the intake of dietary LA does not lead to a significant increase of its metabolites tissue levels (Rett and Whelan, 2011; Whelan and Fritsche, 2013). The effect of LA on human health is still controversial: a recent review discussed evidence about the potential benefit of increasing dietary intake of LA (Marangoni et al., 2020), reporting that epidemiological studies indicate that an adequate intake of LA reduces amounts of plasma low-density lipoprotein cholesterol (LDL-C) and dietary intervention studies showed that replacing 5% of the dietary energy derived from SFA with ω6 PUFAs reduces LDL-C by up to 10% (Siri-Tarino et al., 2015). Furthermore, in prospective cohort study circulating concentrations of LA are inversely associated with new cases of type 2 diabetes (Fretts et al., 2019). On the contrary, the reevaluation of data obtained in double-blind randomized controlled trials (RCTs), together with a systematic review and meta-analysis, while reporting a significant reduction of serum cholesterol did not confirm the original hypothesis of a significant effect on the risk of death by coronary heart disease (CHD) or all causes (Ramsden et al., 2013, 2016). The controversial role of linoleic acid is also underlined by several evidence suggesting that high intake of this PUFA is associated to an increase risk of colonic inflammation and colonic cancer. Indeed the risk of colorectal adenoma increased in correlation to plasma concentrations of linoleic acid in an endoscopy-based case–control study (Pot et al., 2008), and dietary linoleic acid was found to potentially contribute to an increased risk of ulcerative colitis in a prospective cohort study (Hart et al., 2009).

Linoleic acid has also been reported to be the substrate for CYP450 enzymes, including CYP2J2, CYP2C8, CYP2C9, and CYP1A1, leading to the formation of linoleic epoxides 9,10-epoxyoctadecenoic acid (9,10-EpOME), and 12,13-epoxyoctadecenoic acid (12,13-EpOME) known as leukotoxin and isoleukotoxin (Hildreth et al., 2020); these epoxides are then metabolized by the soluble epoxide hydrolases (sEH) into the dihydroxyderivatives 9,10-DiHOME and 12,13-DiHOME. The concentration of these compounds is dependent on both the regulation of biosynthetic pathways (CYP450s and s EH) and the dietary intake of their parent fatty acid LA. 9,10-EpOME is a major contributor to pulmonary toxicity in Acute Respiratory Distress Syndrome (ARDS), an effect that is enabled by the conversion into DiHOME (Zheng et al., 2001). DiHOMEs may also play a dual role in inflammation, stimulating neutrophil chemotaxis at low concentrations while inhibiting neutrophil respiratory burst at higher concentrations (Thompson and Hammock, 2007).

Just like LA, ALA is defined as an essential fatty acid in mammals (Das, 2006), and its principal diet sources are nuts, fish, leafy vegetables, and seed oils. After absorption, it can be catabolized into longer chain and more unsaturated FAs such as EPA and DHA, but similar to LA conversion into AA within the ω6 series, the endogenous production of ALA derivatives is low in humans. Tracer studies observed conversion of ALA to EPA, ω3 docosapentaenoic acid (DPA), and DHA, from birth to adulthood, in male and female, but in infants the conversion of ALA to DHA is about 1% whereas in adults is even lower (Brenna et al., 2009). ALA supplementation (by diet, capsules etc.) generally increases EPA and DPA, but has limited effects on DHA levels in plasma fractions and in circulating blood cells, while DHA supplementation increases the concentrations of this FA in blood and tissues (Arterburn et al., 2006). It should be also underlined that there is a competition between ω3 and ω6 FAs for the same metabolic pathway enzymes (desaturases and elongases), and that an increased LA intake decreases ω3 LC-PUFAs. Indeed, dietary ALA conversion appears to be decreased by high LA/ALA dietary ratios (Brenna et al., 2009).

Inconsistent data have recently been reported from studies examining how fatty acids, and particularly ω3 LC-PUFAs, can prevent or treat food allergy, atopic dermatitis, and asthma (Venter et al., 2019). These results can be partially justified by differences in bioavailability and interindividual variability in response to supplementation. Providing preformed ω3 derivatives or foods rich in ω3 LC-PUFAs seems more effective than supplying ALA because of the reported limited conversion capability in humans.

Non enzymatic oxidation of ALA originates analogs of isoprostanes termed phytoprostanes (Galano et al., 2017), possessing antinflammatory activities (Gilles et al., 2009). ALA-enriched diet in rats was reported to reduce oxidative stress and inflammation during myocardial infarction, while increasing the formation of phytoprostane, suggesting their contribution to the observed effects (Leung et al., 2021). Recent data have also shown that novel metabolites generated by gut lactic acid bacteria from ALA, namely 13-hydroxy-octadecadienoic acid and 13-oxo-octadecadienoic acid, are capable to induce, both in vitro and in vivo, the differentiation of macrophage toward the anti-inflammatory phenotype M2 (Ohue-Kitano et al., 2018), through the activation of G protein-coupled receptor 40.

Dietary MUFAs sources are both vegetable (e.g., olive oils, nuts, and seeds) and animal (e.g., meat from poultry and pig). The most abundant MUFA within the MD is oleic acid (about 90% of all MUFAs), followed by palmitoleic and vaccenic acids. A recent meta-analysis focusing on the effects of different dietary sources of MUFAs on CVD provided evidence that only olive oil was associated with a significant risk reduction of all-cause mortality, cardiovascular events, and stroke (Schwingshackl and Hoffmann, 2014), consistent with the fact that virgin olive oil is a supplier of other biologically active components such as polyphenols (Visioli and Bernardini, 2011), in particular oleuropein, in addition to MUFA.

The beneficial effects of oils have been widely attributed to their content in phenols, and more than 8,000 phenolic compounds have been identified. The structure of polyphenols is characterized by aromatic rings surrounded by hydroxyl groups (Quideau et al., 2011). Among these bioactive oil components there are tocopherols and tocotrienols (corn oil, soybean oil, wheat oil, and others), flavonoids (olive oil, sunflower seed oil), sterols, and phenolic acids (as esterified or free molecules, aldehyde forms, and glycosides). With exception of sterols that have beneficial effect on serum lipids (decreasing LDL-C and increasing HDL-C), the other compounds possess mainly radical scavenging, antioxidant and anti-inflammatory activities (Pandey and Rizvi, 2009), and the ability to modulate the immune response, affecting the multiplication of white blood cells and the production of cytokines (Gorzynik-Debicka et al., 2018). Different components alone have been tested in vitro, in cells or cell free assays, and some extra virgin olive oil (EVOO) phenolic compounds, but not all of them, inhibit IL-1β, PGE₂, and INFγ production (Miles et al., 2005). In vitro experimental evidence also showed significant anti-neuroinflammatory effects of lignanamides from hemp seeds (Luo et al., 2017; Wang et al., 2019). In in vivo experiments, sesamol decreased oxidative stress and inflammation (Kuhad and Chopra, 2008), and sesamine (0.2% in diet) decreased lipid peroxidation in plasma and liver in rats (Yamashita et al., 2000). Sesame lignans were also investigated in human, comparing the effects of a supplement of sesamin/episesamin 1:1 ratio (10 mg) + vitamin E (101 mg) formulated in wheat germ oil with wheat germ oil alone, showing a significant increase of antioxidant capacity evaluated as an increased lag-time in plasma LDL oxidation (Takemoto et al., 2015).

The predominant compounds found in EVOO are represented by oleuropein, hydroxytyrosol, and their derivatives (Pedan et al., 2019). The European Food Safety Authority (EFSA) approved in 2011 a claim that EVOO’s polyphenols protect blood lipids against oxidative stress at a minimal dose of 5 mg/kg/day. The 5 mg of hydroxytyrosol should be available by consuming 23 g of EVOO in the context of a balanced diet (EFSA Panel on NDA, 2011).

Lipophenols are an emerging class of molecules that have been studied in these last years; they are characterized by condensation (esterification/acylation) of polyphenols and fatty acids, mainly unsaturated ones. Phenols and PUFAs, as described above, are natural compounds both endowed with biological activities on inflammation, oxidation, cancer, and CVDs, and the combination of these molecules could be of therapeutic advantage. In particular, the conjugation of polyphenols, such as flavonoids, phloroglucinol, and catechol derivatives with ω3 LC-PUFAs generates lipophenols (or phenolipids) of interest in which ω3 LC-PUFAs confer hydrophobicity, cell membrane penetration, and bioavailability to phenols, while the latter protect PUFAs from oxidation, possibly promoting their beneficial effects (Crauste et al., 2016).

Lipophenols can be obtained by enzymatic or chemical synthesis, but also from natural sources such as algae and marine species. The biological activity of lipophenols has been assessed in in vitro assays, frequently in non-cellular system, and only few studies have been performed in vivo in experimental animals. The antioxidant activity is a radical scavenging activity, even if the conjugation with FA frequently causes a decrease in the antioxidant properties of phenol, depending on the type of FA and on the phenol site of esterification (Moine et al., 2021). N-acyl dopamine and N-acyl-vanillylamines derivatives (containing a phenolic moiety), have also been shown to inhibit NO, IL-1β, IL-6, and TNF-α production, an effect that was dependent on the nature of FA with major effect for FA with a ketone group, then PUFA, MUFA, and saturated FA (Dang et al., 2011), suggesting a minor role for the phenolic moiety.

However, it must be stressed that the contribution to human health of all phenolic compounds depends on several factors including the concentration and whole oil composition, the extent of absorption and metabolism and the bioavailability in target tissues (Santangelo et al., 2017).

Vitamin E (α-tocopherol) and carotenoids are lipophilic antioxidants contained in vegetable oils (e.g., canola, olive, and soybean oil). They are known to decrease serum LDL levels and to prevent their oxidation (Upritchard et al., 2000). A large clinical trial showed a significant increase in the risk of prostate cancer in healthy men upon Vitamin E supplementation (Klein et al., 2011) and there is no specific advice on the intake of vitamin E. Its metabolism is related to vitamin C, vitamin B3, selenium, and glutathione, that all should be included within the diet to reach an optimal effect (Kurutas, 2016).

Vitamin E and carotenoids present in oils play an important role in the protection of PUFAs from oxidation: a pilot study carried out in experimental animals showed that while different preparations of fish oil resulted in similar changes in plasma lipids, a significant increase in plasma lipid peroxidation was observed in the absence of fish oil stabilization with a natural antioxidant mixture rich in α-tocopherol (Engstrm et al., 2009). Carotenoids have been well-characterized for their antioxidant activity in vitro (Sandmann, 2019), and recent data have also shown their ability to specifically limit PUFA peroxidation in lipid membranes (Widomska et al., 2019).

Vitamin A is abundant in FO, in the liver and in dairy foods, and has a role in maintaining the immune system functions (Gilbert, 2013). Most effects of vitamin A are exerted by its metabolite, retinoic acid (RA), which through ligation of nuclear receptors controls the transcriptional expression of RA target genes. Within the immune system, RA has a central role in orchestrating immune responses and dendritic cells (DCs), and macrophages seem responsible for its production (Erkelens and Mebius, 2017).

Hemp seed oil is obtained from Cannabis sativa, and is characterized by high PUFAs content and low SFAs amounts (for composition see Table 1), with significant amounts of antioxidant such as tocopherols and phenolic compounds (Smeriglio et al., 2016). While studies in humans using supplementation with hempseed oil are scarce, there are nonetheless positive reports showing effects on clinical symptoms of dermatological diseases (atopic dermatitis; Callaway et al., 2005), as well as reduction of plasma triglycerides and improvement of the ratio total cholesterol/HDL cholesterol (Schwab et al., 2006). Nevertheless, the effects on plasma lipids could not be confirmed in subsequent studies in normal volunteers (Kaul et al., 2008) and in adolescent with hyperlipidemia (Del Bo et al., 2019).

Flaxseed oil (for composition see Table 1) is a good source of essential FA and contains lignans, cyanogenic glycosides, and cyclic peptides. In spite of the rich content of essential FA, the impact of flaxseed oil on serum lipids is controversial (Pan et al., 2009; Prasad, 2009): a reduction of plasma triglycerides and the improvement of the ratio total cholesterol/HDL cholesterol have been reported (Schwab et al., 2006), but has not been confirmed (Kaul et al., 2008). With respect to potential effects on cardiovascular inflammation, a RCT in healthy abdominally obese adults treated for 8 weeks with flaxseed oil capsules found no modifications in C-reactive protein (CRP), serum amyloid A (SAA), IL-6, and TNF-α (Nelson et al., 2007). On the contrary, 6 weeks of flaxseed oil administration resulted in a significant reduction of CRP (Zhao et al., 2004), an effect confirmed by two additional studies that observed a decrease of CRP, SAA, and IL-6 (Rallidis et al., 2003; Bemelmans et al., 2004).

Olive oils (for composition see Table 1) possess many health properties of higher nutritional quality, in particular the EVOO (Martín-Peláez et al., 2013). The majority of benefits are ascribed to minimal constituents in the unsaponifiable fraction, like phenolic compounds, phytosterols, tocopherols, and pigments (Mazzocchi et al., 2019). The effects on human health have been linked to its efficacy in preventing and treating of chronic disease resulting from anti-inflammatory, antioxidant, neuroprotective, and immunomodulatory activities (Carmen Crespo et al., 2018). The phenolic part accounts from 50 to 800 mg/kg and the predominant compound is made-up by oleuropein and its breakdown derivatives, hydroxytyrosol and tyrosol, but additional components contribute to the anti-inflammatory effects of EVOO as shown by the NUTRAOLEUM study: in this double-blind RCT, patients were supplemented with three different virgin olive oils (standard, high in phenolic compounds, and enriched with triterpenes oleanolic and maslinic acids) in a 3-week intervention. Over this period of time, plasma inflammatory biomarkers (IL-8 and TNF-alpha) and DNA oxidation significantly decreased in the group of subjects receiving the functional EVOO enriched with triterpenes (Sanchez-Rodriguez et al., 2019).

Soybean oil is extracted from the seeds of the soybean (for composition see Table 1). Phytosterols present in the oil may be responsible of its reported cholesterol-lowering activity (Zhu et al., 2019). The introduction of ∆6 desaturase from primrose (Primula juliae) and ∆15-desaturase from red bread mold (Neurospora crassa) into the soybean resulted in the production of a soybean oil rich in stearidonic acid (SDA; 18:4, n-3). Together, these two enzymes reduce the amount of linoleic acid by converting it into ALA and γ-linolenic acid, which are in turn ultimately converted into SDA, representing up to 20–30% of total fatty acids in the resulting oil. SDA, unlike ALA, may then be able to raise tissue levels of EPA and possibly DHA in humans, making widely used soybean oil a potential dietary source of this “pro-EPA” fatty acid (Harris, 2012). Indeed, two separate clinical trials showed increased EPA and ω3 index in adult overweight subjects (Harris et al., 2008; Lemke et al., 2010), confirming the ability of SDA to raise EPA plasma levels.

Canola oil is obtained from the seeds of different species of Brassica family (for composition see Table 1). Brassica napus is known as rapeseed and its oil has a high content of erucic acid, a FA suspected of having pathogenic potential, but as edible oil, canola oil originates from selected Brassica typically showing erucic acid levels below 2%. Lin et al. (2013) reviewed the studies investigating the effects of canola oil, reporting significant reduction in total and LDL cholesterol, increased tocopherol levels, and insulin sensitivity. No effects were observed with respect to lipid peroxidation or susceptibility of LDL to oxidation, but platelets showed decreased ATP secretion and aggregation. Inflammatory markers were not affected by canola oil-based diets while potential linkages between canola oil usage and modifications of cancer risk remain undefined.

Recently, industries manufactured the high-oleic canola oil (HOCO), new canola oil with a modified formulation in fatty acids. HOCO is richer in MUFAs, lower in SFAs, and has a lower ratio of ω6/ω3 fatty acids than standard canola oil. A multicenter RCT provided evidence that a DHA-enriched HOCO improves lipid profiles and lowers CVD risk in abdominal obese subjects (Jones et al., 2014).

It is widely recognized that regularly eating fish decreases the risk of CVDs and related mortality (Hu et al., 2002; He et al., 2004), and dietary guidelines for ω3 LC-PUFAs and fish intake recommend two portions of fatty fish per week to assume 250–500 mg/die of EPA + DHA and prevent coronary diseases (American Heart Association Nutrition Committee et al., 2006; Mozaffarian and Rimm, 2006). While a food-based approach is preferable (Kris-Etherton et al., 2007), nutritional supplements are suitable substitutes for people who do not eat fish, and up to 3 g/day of fish oil is “generally recognized as safe” by the United States Food and Drug Administration. Cod liver oil (for composition see Table 1) is a dietary supplement extracted from Atlantic cod containing saturated, monounsaturated, and various PUFAs, including both EPA and DHA, together with vitamin A and D (Hu et al., 2019). While fish oil supplementation is recommended by the American Heart Association for CHD patients, insufficient evidence was found to grant the use in prevention for patient at high CVD risk only (Siscovick et al., 2017). A large meta-analysis of 10 recent RCT also found no effect of marine ω3 PUFAs supplementation on fatal and non-fatal CHD (Aung et al., 2018) fueling the debate about the health benefit of fish oil supplementation, but a new meta-analysis that included also three recent, large RCTs (VITAL, ASCEND, and REDUCE-IT), finally confirmed that marine ω3 supplementation reduce the risk for myocardial infarction, CHD and CVD death, also defining a clear dose-response relationship between the ω3 dose assumed and the effects (Hu et al., 2019).

In consideration of fish being a limited resource, attention to different sources of ω3 LC-PUFAs is also emerging. Krill oil, for example, is obtained from “Euphausia superba” and, along with a wide variety of fatty acid compounds (for composition see Table 1), also provides antioxidants, such as the carotenoid astaxanthin, vitamin E, and vitamin A. A RCT in healthy individuals showed a significant increase in EPA and EPA + DHA levels in plasma after consumption of 3 g/die for 4 weeks of krill oil when compared to FO (Ramprasath et al., 2013). Since both FO and krill oils deliver the same amount of total ω3 PUFAs, the results of this study may suggest that the bioavailability of ω3 PUFAs from krill oil is better than that from FO, but a reexamination of the bioavailability studies failed to confirm a difference between FO and krill oil (Salem and Kuratko, 2014). Lipids from different marine sources show a wide variability in ω3 LC-FAs content (Schuchardt and Hahn, 2013), and their bioavailability depends on several factors, including the concomitant intake of food (mainly its fat content) and the co-presence of other components (Kutzner et al., 2017). The marine sources of ω3 LC-FA not only differ in terms of absolute amounts of specific ω3 LC-FA, but also with respect to their chemical structures. In fish and in fish-derived oils, ω3 LC-FA is present primarily as triglycerides and, to a lesser extent, as free fatty acids. In krill oil, besides the two fractions mentioned, a substantial percentage of ω3 LC-FA is bound into phospholipids, raising the possibility that this form of ω3 LC-FA may also affect the bioavailability (Kutzner et al., 2017). It must be noted that in the near future, the capture of krill may also be restricted because of ecological concerns.

Algae consist of an intricate and non-specialized cluster of organisms characterized by an elementary reproductive structure and of photosynthetic nature. Currently, many species are cited in the literature as sources of bioactive compounds that are suitable as functional food ingredients (Ibañez and Cifuentes, 2013; Rengasamy et al., 2020). Micro and macro-algae represent a more sustainable source of PUFA-rich oils than fish. The PUFA profile varies among algal species: in macroalgae, lipid content is ~2–5% of dry weight, but the PUFA proportion of these lipids can represent up to 70% (Cofrades et al., 2010). Certain species of microalgae are capable of de novo production of LC-PUFAs thanks to their specific enzymatic systems, and the LC-PUFA content varies among species, but EPA and DHA are predominant in most species (Ratledge, 2004).

Algal biomass contains significant amounts of lipid-soluble carotenoids, with fucoxhantin and astaxanthin being the most abundant (Rengasamy et al., 2020). Limited evidence about their activites are available (Šimat et al., 2020), and a meta-analysis of the RCT carried out with astaxhantin showed unclear results (Wu et al., 2020) suggesting that additional studies are necessary to establish their potential health benefits.

The use of marine algae-derived antioxidants and PUFAs is a desirable goal, and in the last 2 decades, the potential of microalgae and microbes as sources of fatty acids has been increasingly recognized, leading to the large-scale production of PUFA supplements (Martins et al., 2013). The process of lipid production from microalgae and other microorganisms, i.e., single cell oil (SCO) production, has been recently proposed, and is of current industrial interest for use of these materials as dietary supplements in adults and infant nutrition (Ratledge, 2004).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.