The type of fat found in parenteral nutrition (PN) formulations is triglycerides [1]. Triglycerides consist of a trio of fatty acid molecules bound to a glycerol backbone. A fatty acid molecule consists of a hydrocarbon ring and a methyl group (CH3) at one end of the ring and a reactive carboxyl group (COOH) at the other end. Fatty acids can be classified based on the length of the hydrocarbon ring, the number of carbon–carbon double bonds in the ring (saturation), and the position of the first double bond in the ring [2]. Saturated fatty acids such as stearic acid do not have double bonds. Monounsaturated fatty acids (MUFAs) like oleic acid have one double bond and polyunsaturated fatty acids (PUFAs), such as linoleic acid, have two or more double bonds. Fatty acids can be classified according to the position of the first double bond based on the ω (non-carboxylic acid) end of the hydrocarbon ring, known as the omega (ω or n) class. Using the omega classification, fatty acids with the first double bond on the third carbon relative to the ω terminus are ω-3 fatty acids (e.g., α-linoleic acid), fatty acids with the first double bond on the sixth carbon relative to the ω terminus are ω-6 fatty acids (e.g., linoleic acid), and fatty acids with a double bond at the ninth carbon from the ω terminus are ω-9 fatty acids (e.g., oleic acid) (Fig. 1). The clinical advantages and effectiveness of MUFAs were explored in this research.

Fig. 1. Structure and naming of selected 18-carbon fatty acids (drawing by the authors).
The black arrows indicate the first double bond.
SFA = saturated fatty acid; MUFA = mono-unsaturated fatty acid; PUFA = polyunsaturated fatty acid; EFA = essential fatty acid; COOH = carboxyl group.

Olive oil is a liquid fat obtained by pressing whole olives. Olives are one of the key foods in Mediterranean cuisine and have been cultivated around the Mediterranean since 8000 BC. Today, olive oil is commonly used for frying foods or in salad dressings and is rich in ω-9 MUFAs, showing many health-related beneficial effects. In the United States (U.S.), the Food and Drug Administration allows olive oil producers to claim eligible health benefits on product labels. Due to the MUFAs, consuming roughly 2 T (23 g) of olive oil daily may lower the risk of coronary heart disease [3]. To lower the risk of heart disease, olive oil can replace a similar amount of saturated fat without increasing the total number of calories consumed per day. Several studies have shown that eating a diet high in MUFAs increases the high-density lipoprotein cholesterol concentration and reduces triacylglycerol levels [4,5]. Foods rich in MUFAs may help to regulate blood lipid profiles. Additionally, MUFAs can have a long-term hypoglycemic impact in type 2 diabetic individuals by decreasing the glycosylated hemoglobin concentration. Dietary management in type 2 diabetes mellitus (T2DM) is critical for reducing long-term complications. In a meta-analysis comparing a diet high in cis-MUFAs and a diet high in carbohydrates or PUFAs to assess metabolic risk factors in patients with T2DM [6], substantial reductions in fasting plasma glucose, triglycerides, and systolic blood pressure as well as significant increases in high-density lipoprotein cholesterol were identified when comparing high-MUFA to high-carbohydrate diets. In addition, fasting plasma glucose was significantly lower in high-MUFA diets compared to high-PUFA diets. This meta-analysis provides evidence that diets high in MUFAs can improve metabolic risk factors among patients with T2DM. For these reasons, national and international authorities recommend consumption of MUFAs [3]. However, several American societies have suggested that <20% MUFAs be consumed to prevent heart disease. Among various vegetable oils, when sorted by the ω-9 content, olive oil contains the highest percentage of MUFAs with >70% MUFAs. Therefore, olive oil may be a significant provider of MUFAs.

Lipid emulsions (LEs) are added to standard PN regimens for several reasons. First, they provide essential fatty acids. For example, both linoleic acid and α-linolenic acid are regarded as necessary fatty acids because they must be delivered to rather than being produced by the human body. LEs also allow the body to achieve the high caloric intake required by some patients without excessive glucose calories, thereby averting the hyperglycemia associated with the original glucose-rich admixture. They also help to reduce solution osmolarity, protect veins, and enhance the bioavailability of fat-soluble vitamins like vitamins A, D, E, and K. As the representative ω-3 PUFA, α-linoleic acid is converted in the body to eicosapentaenoic acid and docosahexaenoic acid through the action of several enzymes. Meanwhile, linoleic acid, the representative ω-6 PUFA, is converted to arachidonic acid through the action of the same enzymes. Among ω-6 fatty acids, the final metabolite has a proinflammatory effect, whereas the final metabolite of ω-3 fatty acids has an anti-inflammatory effect. On the other hand, oleic acid, a representative ω-9 MUFA, leads to a neutral immune response even though it undergoes a metabolic process and its metabolites do not participate in the immune response (Fig. 2).

Fig. 2. Metabolic pathways of ω-3, ω-6, and ω-9 fatty acids (drawing by the authors).

The first attempt to infuse lipid parenterally took place in 1678. In 1955, the first intravenous lipid emulsion (ILE), a cottonseed oil–based emulsion (composed of 15% cottonseed oil, 1.2% soy phospholipids, 0.3% Pluronic 568, and 4% dextrose) was approved for use in the U.S.. However, it was later withdrawn from the market because of severe adverse reactions. In 1961, a soybean oil ILE (10% or 20% soybean oil ILE and 1.2% egg phospholipids) was introduced in Europe and it was approved for use in the U.S. in 1975. Then, in May 1979, 10% and 20% ILEs containing exclusively safflower oil were introduced into the U.S. market. In 1984, this product was reformulated to 10% and 20% ILEs at a 1:1 volume ratio in a blend of soybean oil and safflower oils for the purpose of increasing the α-linolenic acid content of the emulsion. In 2010, the manufacturer of safflower oil-containing products ceased manufacturing all ILEs, leaving a single source of ILE on the U.S. market, soybean oil. An soybean oil- and olive oil-based ILE was approved for use in 2013 but it was not marketed in the U.S. until 2019. In 2016, a 4-oil ILE was approved, while an exclusive fish oil-based ILE, which had been used previously on a compassionate-use basis, was approved in 2018 [7].

In terms of nutrition support, the lipid combination has changed over time. Consider the LEs used in PN as a good example of this. The first generation of such LEs consisted purely of soybean oil, the second-generation LEs includes medium-chain triglycerides (MCTs) extracted from coconut oil, and the third generation began to include structured lipids and olive oil. Most recently, third-generation LEs containing fish oil have been introduced [8]. The evolution of lipid sources used in PN over time started with first-generation, 100% soybean oil-based ILEs in the 1960s and currently includes third-generation products such as structured lipids, olive oil-based ILEs, and fish oil-containing ILE [8,9]. The characteristics of MUFAs are as follows. First, olive oil-based PN is the main source of oleic acid. Second, this product has relatively neutral physiologic effects. Third, a high MUFA content imparts greater resistance to peroxidation.

The innate immune system is supported by olive oil-based ILEs, which may help to retain immunological function. Similarly, olive oil-based ILEs are likely to experience lower lipid peroxidation than soybean oil-based ILEs. Most studies have explained that olive oil-based ILEs maintain hepatobiliary marker and plasma lipid levels within normal or near-normal ranges. olive oil-based LEs have a higher percentage of MUFAs and lower potency of oxidation than fish oil-based LEs with PUFAs, resulting in less cell damage [10]. ω-9 fatty acids (e.g., oleic acid in olive oil) influence the metabolic effects of lipids but do not produce eicosanoids. ω-9 fatty acids reduce lipid peroxidation, preserve the immune function, and have a neutral inflammatory effect [11-14]. IV olive oil-based LEs are associated with fewer infections. A large, prospective, randomized, open-label, multicenter, non-inferiority study in China assessed the delivery, efficacy, and safety of soybean oil-based PN and olive oil-based PN in patients who required PN therapy during admission to hospitals for surgery. The results showed that the olive oil-based LE PN group experienced a significantly lower rate of infection compared to the soybean oil-based PN group [15]. In another study of trauma patients, sepsis markers improved over time in those who received olive oil-based PN and the lengths of mechanical ventilation and intensive care unit stays were shorter in the olive oil-based PN group [16]. However, there are studies which produced conflicting or seemingly unrelated results. Another prospective, double-blind, randomized controlled trial of patients receiving PN containing an soybean oil-based or olive oil-based LE showed similar overall rates of communicable and non-infectious complications, mortality, and length of stay in the intensive care unit. In addition, there were no significant differences of the metabolic, inflammatory, or immune markers among critically ill adult patients [17]. Another study showed no effect of an soybean oil-based vs. olive oil-based LE on infections, acute-phase proteins, or major health outcomes [18]. Further, since there are not many studies on the difference between olive oil-based and fish oil-based ILEs, additional research is needed in this area.

In the 2009 European Society for Clinical Nutrition and Metabolism (ESPEN) guideline, first and second generations of LEs were recommended for patients. The guideline also advised olive oil-based parenteral feeding of critically ill patients. At that time, research results of studies on fish oil were just starting to be released, as demonstrated in the guidelines [19]. According to the 2017 ESPEN surgery recommendations, postoperative PN with ω-3 fatty acids should be examined and surgical patients who receive ω-3 fatty acids have considerable advantages in terms of the postoperative infection rate and hospital length of stay [20]. With the accumulation of many research results on fish oil, the current guideline comprises a strong recommendation. In addition, the guideline recommends avoidance of ω-6 fatty acids. Alternative LEs (olive oil, fish oil, MCT) are available. olive oil also showed an advantage over soybean oil in terms of the length of hospital stay [21]. American Society for Parenteral and Enteral Nutrition classified the various ILEs available based on study design and potential benefits (Table 1) [22]. Among them, the advantages of third-generation ILEs are presented [7]. First, MUFAs produce less peroxide during oxidation than PUFAs. Second, oleic acid in olive oil is not metabolized as a mediator of inflammation or immunity. In conclusion, considering the relatively neutral physiological effects and reduced susceptibility to peroxidation, MUFAs can be effectively used for nutritional treatment of immunosuppressed or immunocompromised patients [23].

Table 1

Evolution of intravenous lipid emulsions

Generation of ILE	Description	Potential benefits
First	Soybean oil or safflower oil	Information about compatibility with regularly used drugs is provided
Second	Two-oil formulation including soybean oil and MCT	MCTs are removed more quickly and with less peroxidation
Third	Two-oil ILE using soybean oil and olive oil, resulting in a reduced amount of EFA (ω-6 FAs)	Elevated doses of MUFAs produce fewer peroxides during oxidation than PUFAs Oleic acid in olive oil is not converted to inflammatory or immune mediators Patients who are at risk of immunosuppression or have impaired immune systems may benefit from this treatment
Fourth	Four-oil ILE of soybean oil, MCT, olive oil, and fish oil	Fish oil included for critically ill and surgical patient populations
	Fish oil	Sources of FA and energy for infants and children with IFALD and may reverse IFALD

Revised from the article of Mirtallo et al. (Nutr Clin Pract 2020;35:769-82) [7] with original copyright holder’s permission.

ILE = lipid injectable emulsion; MCT = medium-chain triglyceride; EFA = essential fatty acid; FA = fatty acid; MUFA = monounsaturated fatty acid; PUFA = polyunsaturated fatty acid; IFALD = intestinal failure-associated liver disease.

MUFAs are fatty acids most commonly found in olive oil, nuts, and some animal foods. Third-generation injectable LEs may have advantages in certain clinical areas. As revealed during in vivo studies, MUFAs such as oleic acid have only one double bond and are less susceptible to lipid peroxidation compared to acids with additional double bonds. ω-9 fatty acids may benefit immunosuppressed patients because they reduce lipid peroxidation, preserve immune function, and have a neutral effect on inflammation.

Conceptualization: KWS. Formal analysis: KHK, YK. Methodology: KHK. Project administration: KHK, KWS. Supervision: KWS. Validation: KHK, KWS. Visualization: KHK, YK. Writing – original draft: KHK. Writing – review & editing: KHK, KWS.

Kyung Won Seo is an editorial board member of the journal, but was not involved in the review process of this manuscript. Otherwise, there is no conflict of interest to declare.

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