Associations of Linoleic Acid Intake and Chronic Disease

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1		Joseph Mercola	--	3292	2023-07-24 11:50:48	\|
2	Reference format revised.	Lindsay Dong	Meta information modification	3292	2023-07-25 02:34:28	\|

This entry is adapted from the peer-reviewed paper 10.3390/nu15143129

The intake of linoleic acid (LA) has increased dramatically in the standard American diet. LA is generally promoted as supporting human health, but there exists controversy regarding whether the amount of LA currently consumed in the standard American diet supports human health. While LA is considered to be an essential fatty acid and support health when consumed in modest amounts, an excessive intake of LA leads to the formation of oxidized linoleic acid metabolites (OXLAMs), impairments in mitochondrial function through suboptimal cardiolipin composition, and likely contributes to many chronic diseases that became an epidemic in the 20th century, and whose prevalence continues to increase. As LA consumption increases, the potential for OXLAM formation also increases. OXLAMs have been associated with various illnesses, including cardiovascular disease, cancer, and Alzheimer’s disease, among others. Lowering dietary LA intake can help reduce the production and accumulation of OXLAMs implicated in chronic diseases.

linoleic acid (LA) seed oils cardiolipin oxidized linoleic acid metabolites (OXLAMs) 4-hydroxynonenal (HNE) omega-3 omega-6

1. Introduction

Polyunsaturated fatty acids (PUFAs) are basic components involved in the architecture and function of cellular membranes and play key roles in several biological processes. PUFAs are endogenous mediators for cell signaling and are involved in the regulation of gene expression. They are also metabolic precursors of eicosanoids, such as prostaglandins and leukotrienes, and docosanoids, such as protectins or resolvins ^[1].

The most common source of PUFAs in the human diet today are vegetable and seed oils that contain linoleic acid (LA), which is an omega-6 fatty acid. LA is a major constituent of human tissues ^[2], and it is considered to be an essential fatty acid. Deficiencies in essential fatty acid intake among adults have been documented for decades. ^[3]^[4] Furthermore, the important effects of LA in animal and human physiology have been studied for decades ^[5]^[6]^[7]^[8]^[9], and a modest, evolutionarily consistent intake of LA has been associated with a decreased risk of atherosclerosis ^[10], hypercholesterolemia ^[11]^[12], headaches when combined with omega-3 fatty acid supplementation ^[13], and other chronic health conditions.

However, when the levels of LA become highly elevated in the blood through dietary intake in amounts that far exceed recommended amounts, this PUFA becomes a precursor to oxidized LA metabolites (OXLAMs), such as 4-Hydroxynonenal (HNE), 9- and 13-hydroxy-octadecadienoic acid (9- and 13-HODE), and 9- and 13-oxo-octadecadienoic acid (9- and 13-oxoODE).

Furthermore, LA conversion may lead to the formation of free radicals, such as 8-hydroxyoctanoic acid and heptanoic acid ^[14]. In addition, in some instances, LA may be further metabolized into arachidonic acid (AA), which is a precursor to oxidized AA metabolites (OXAAMs), including 5-, 8-, 9-, 11-, 12-, and 15-hydroxy-eicosatetraenoic acid (HETE) ^[15]. The increased circulation of oxidized metabolites and free radicals has been linked to different types of diseases (e.g., cardiovascular, atherosclerotic, hepatic, etc.) ^[16].

2. How Much LA Is Required in the Human Diet?

The first demonstration of the essential requirement for LA in animal diets was obtained by Burr and Burr in 1929–1930 ^[13]. They showed that rats receiving 0.6% of their total dietary calories as LA were 30% higher in body weight compared to total-fat-deficient rats and did not develop skin desquamation and tail necrosis ^[17]^[18]^[19].

This led to the establishment of the requirement of 1% of the total daily calories being omega-6 fat, which was later extended to 2% of the total daily calorie intake in humans to ensure sufficiency. This was confirmed by two studies where the physiological symptoms of omega-6 deficiency in human infants, as established by scaling of the skin, were abolished ^[20].

However, a careful review of the data used to establish LA being essential to the diet found that this conclusion was established using control diets that were not only deficient in omega-6 fatty acids, but also omega-3 fatty acids. This dual deficiency in the control diets seemed to invalidate the establishment of an omega-6 fatty acid requirement from these data ^[21].

Subsequent studies in rat models similar to those used to originally classify LA as an essential fatty acid have demonstrated that the dietary omega-3 fatty acid, alpha-linolenic acid (ALA), is able to diminish the symptoms of LA deficiency ^[22]. This strongly suggests that the absence of ALA in the original studies probably heightened the significance of the physiological symptoms caused by LA deficiency. It seems that, at least for the rat model, the nutritional requirement for LA has probably been seriously overestimated. A more precise estimation of the LA requirement is likely closer to a 75% reduction, or 0.5%, of the dietary energy rather than 2% ^[23].

3. The Omega 3:6 Ratio

Among the many types of omega-3 fatty acids, the three most important are eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), which are “long-chain” omega-3 fatty acids, and alpha linoleic acid (ALA)—a “short-chain” omega-3 fatty acid. The human body is unable to produce essential fatty acids endogenously.

Therefore, omega-3 fatty acids must be consumed regularly through the diet. Animal foods such as cold-water fish are ideal sources of EPA and DHA, while ALA is mainly derived from plants. EPA and DHA have anti-inflammatory effects and ALA must be converted to EPH and DHA. This conversion is an inefficient process, particularly in men, with less than 20% being converted ^[24]. Therefore, special attention should be paid to obtaining EPA and DHA through diet or supplementation.

The benefits of maintaining the proper omega 3:6 ratio are well-established. Bodily tissues consist primarily of saturated and monounsaturated fats, which are a readily utilized source of nutrients that support the development and maintenance of cells ^[25]. The primary dietary PUFAs are omega-3 and omega-6 fats, which the body needs in relatively small quantities.

It is important to consume sufficient amounts of omega-3 fatty acids to sustain optimal health, with the recommended daily serving being between 500 and 1000 milligrams of omega-3 fatty acids ^[26]^[27]. Contrary to previous perceptions, however, consuming larger servings of omega-3 fatty acids does not support an ideal ratio. Instead, excessive quantities of omega-3s may cause additional metabolic damage—similar to that which occurs due to the conversion of elevated LA levels.

4. Pathophysiological Mechanism of Elevated LA Levels

As revealed in Figure 1, the primary reason why excess LA in the body leads to cellular tissue damage is because this highly fragile PUFA is easily altered through oxidation. Like other types of PUFAs, LA consists of fragile double bonds that are susceptible to oxidative damage ^[28].

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Figure 1. Mechanism of oxidative stress generated through oxidation of polyunsaturated fats.

The double bonds are the key to understanding why PUFAs are highly perishable and prone to oxidation. LA is metabolized in a multistep pathway to arachidonic acid (AA) through the conversion to gamma-linolenic acid (GLA) due to Δ⁶desaturase enzyme, which varies based on the activity of desaturase enzymes. GLA is converted to dihomo-γ-linolenic acid (DGLA), which is the immediate precursor to AA. Chronically elevated levels of AA can contribute to a state of chronic inflammation and have been associated with autoimmunity ^[29]. This has led to some popular debate regarding the influence of LA intake on AA levels, with some recent papers suggesting that an excessive LA intake can lead to the accumulation of AA-derived pronociceptive lipid mediators and a reduction in antinociceptive lipid mediators obtained from omega-3 fatty acids ^[30]^[31]. However, a systematic review found that LA intake was not associated with tissue concentrations of AA in human beings ^[32]. Thus, the conversion of LA to AA is unlikely to be a concern to human beings at modest levels of consumption.

4.1. How Excess LA Consumption Alters Health

As noted previously, the conversion of LA to AA is unlikely to play a major role in the pathology related to excessive LA intake. LA’s well-documented propensity to enhance lipid peroxidation and the formation of oxidized LA-derived lipid metabolites (OXLAMs) is more likely to contribute significantly to its detrimental effects.

Lipid peroxidation is a well-established process associated with various chronic diseases. Excessive iron, for example, contributes to this damage through a process called ferroptosis, characterized by the accumulation of iron-dependent lipid peroxides that cause membrane injury and cell death. This mechanism plays a significant role in the development of cancer cardiovascular diseases, neurodegeneration and aging.

Membrane lipids containing PUFAs, such as LA, are particularly susceptible to peroxidation due to the weak C-H bonds between adjacent C=C double bonds. During lipid peroxidation, primary products such as lipid hydroperoxides are formed, which can further oxidize to produce reactive aldehydes, with 4-hydroxynonenal (4-HNE) being the most extensively studied and biologically relevant product of LA peroxidation. The accumulation of peroxidized lipids, including 4-HNE, can influence cellular processes, ranging from proliferation to apoptosis and necrosis, depending on their concentration.

4-hydroxynonenal (4-HNE) is an extraordinarily reactive compound and one of the most studied and seemingly biologically relevant products of lipid peroxidation, and is a product of LA peroxidation. Peroxidized lipids are bioactive. They can have effects on cells similar to those of hydrogen peroxide: low levels can stimulate proliferation; higher levels block proliferation and yet higher ones induce apoptosis and necrosis. 4-HNE tends to concentrate in biomembranes rather than in the aqueous space of cells.

When one has elevated tissue levels of LA, consuming an excess of LA, even from unprocessed whole foods, can accelerate metabolic damage. This is due to the propensity for LA to be converted to OXLAMs or OXAAMs that can damage structures, including DNA, mitochondria, cell membranes, proteins, and stem cells ^[33]^[34]^[35].

4.2. LA Remains in Tissues for Extended Time Periods

Another major reason why seed oils are pernicious to overall health is that they remain in the body for extended periods. The half-life of LA is approximately 680 days, or approximately two years ^[36]. This means that it takes approximately six years to replace 95% of the LA in the body with healthy fats—making this a primary reason to maintain low LA intake. Omega-3 fatty acids, such as DHA and EPA, have half-lives of 2.5 years and a few months, respectively ^[37]^[38]. The body also converts certain amounts of DHA to EPA.

4.3. Cardiolipin: Stealth Fat in Mitochondria

Mitochondria are subcellular organelles that are responsible for producing most of the body’s cellular energy in the form of adenosine triphosphate (ATP) ^[39]. It is the presence of mitochondria that distinguishes mammals (e.g., humans) from bacteria and allow life to be multicellular.

These organelles produce approximately 85% of the energy for the body through the generation of ATP during oxidative phosphorylation. If mitochondrial dysfunction develops, physical symptoms (e.g., chronic fatigue) may arise, along with an increased susceptibility to disease. It is vital to take preventive measures to improve and maintain mitochondrial health as it profoundly impacts longevity. Cardiolipin optimization reinforces enhanced mitochondria activity and energy production.

To emphasize the importance of this phospholipid, 20% of the fat in the mitochondria is found in the form of cardiolipin ^[40]. The human body has over 100,000 trillion mitochondria, and mitochondrial health is largely dependent upon the type of dietary fats that are available for cardiolipin synthesis within these specialized organelles.

Cardiolipin is composed of four fatty acids ^[41], unlike triglycerides, which have three fatty acids, but the individual fats that comprise cardiolipin vary widely. Examples include LA, palmitic acid, and the fatty acids found in fish oil, such as DHA and EPA. Cardiolipin is synthesized from fatty acids that are consumed through the diet; thus, the overconsumption of LA in the form of seed oils can alter the formation of the inner mitochondrial membrane, cristae, and complex IV.

Cardiolipin molecules containing one or more LA fatty acids are highly susceptible to free-radical-induced lipid peroxidation. The oxidation of cardiolipin is involved in regulating apoptosis, mitophagy, and other cellular functions. Interestingly, LA-containing cardiolipin is preferentially oxidized over other phospholipids in the inner mitochondrial membrane, even in the presence of more-oxidizable fatty acids such as arachidonic acid.

This is important, because mitochondrial lipids are necessary for maintaining the structural integrity and proper functioning of mitochondria. Cardiolipin is prone to free-radical-induced lipid peroxidation due to the presence of up to four chains of LA. The oxidation of cardiolipin plays an important role in the regulation of apoptosis, mitophagy, and other cellular functions.

The oxidation of cardiolipin plays an important role in the regulation of apoptosis, mitophagy, and other cellular functions. LA-containing cardiolipin is preferentially oxidized over other phospholipids that are found in the inner mitochondrial membrane, including phosphatidylinositol, phosphatidylserine, phosphatidylinositol, and phosphatidylethanolamine. This occurs even in the presence of more oxidizable fatty acids, such as arachidonic acid.

Emerging evidence suggests that mitochondrial lipid peroxidation not only affects the structural integrity of mitochondria, but also mitochondrial functions, such as protein transportation, respiratory metabolism for ATP generation, mitochondrial dynamics and quality control through the fission and fusion of mitochondria, and mitophagy.

Mitochondrial proteins, which constitute a significant portion of proteins within the inner mitochondrial membrane, are highly susceptible to modification by 4-HNE. Approximately thirty percent of all proteins modified by 4-HNE are mitochondrial proteins. Consequently, endogenously produced 4-HNE resulting from oxidative stress has been shown to cause mitochondrial dysfunction in various cell types and organs during both physiological and pathological conditions. This vulnerability of mitochondrial proteins to 4-HNE modification contributes to their critical role in the development of mitochondrial dysfunction.

5. Associations between LA Intake and Chronic Disease

Oxidative stress, tissue damage, and mitochondrial dysfunction from excess LA is not only responsible for cardiovascular disease and Alzheimer’s onset, but additional chronic diseases, including cancer, dementia, obesity, and diabetes are also associated with oxidized metabolites. There is conflicting evidence on the associations between LA intake and many of these chronic diseases, which are summarized below in Table 1.

Table 1. Summary of health effects of linoleic acid.

Proposed Neutral or Health Benefits	Health Risks
Reduces cardiovascular disease risk by decreasing total cholesterol levels ^[42]	Increases risk of cardiovascular disease by increasing oxidized LDL ^[2]^[43]
Unrecognized as having an impact on cancer ^[44]	Increases risk of cancer by impairing mitochondrial function and increasing systemic oxidative stress ^[45] that adversely impacts cardiolipin in the inner mitochondrial membrane ^[46]^[47]^[48]
Reduces the risk of type 2 diabetes ^[49]	Increases risk of diabetes ^[45]
Role in obesity is contentious ^[50]	Increases risk of obesity ^[51]
Unrecognized as having an impact on dementia	Increases risk of dementia ^[52]

While the evidence is still conflicting in some instances, the mechanisms underlying excessive LA intake are reflected in a wide variety of chronic diseases. A recent study ^[53] found that high-fat diets increased the formation of vitamin A degradation products, known as bisretinoids, in ocular tissues. These degradation products are known to cause damage to the retina directly, but they also participate in the formation of lipofuscin in the retina. Lipofuscin is a byproduct of PUFA peroxidation. The study found the PUFA linoleic acid to be a causal factor of eye damage.

Soy oil is by far the most widely produced and consumed seed oil in the US. Using mice, researchers in 2020 found that a high soybean oil diet not only led to obesity and diabetes, but could also affect neurological conditions such as autism, Alzheimer’s disease, anxiety, and depression ^[54]. The same research team found in 2015 ^[55] that soy oil induced obesity, diabetes, insulin resistance, and fatty liver in mice. Then, in a 2017 study ^[56], the same group learned that if soy oil was engineered to be low in LA, it induced less obesity and insulin resistance.

Type I diabetes is an autoimmune condition. The beta-cells of the pancreas are attacked by antibodies from the immune system, over time leading to their destruction and the inability to produce insulin. One study ^[57] found that the reason for antibody production was the overexpression of the enzyme 12/15-lipoxygenase, which is an enzyme involved not only in synthesizing inflammatory leukotrienes, but also metastatic cancer.

Leukotrienes are PUFA metabolites and are responsible for the development of type I diabetes. This suggests that a 12/15-LOX inhibitor would be therapeutic. This study administered a leukotriene inhibitor and found it effective in preventing the development of beta-cell autoimmunity. A more fundamental approach would be to avoid or replace the source of leukotrienes, which would be dietary PUFAs.

6. Dietary Sources of LA and Mitigation Strategies

In general, the lowest LA-containing source of fats would be the preferred fats of choice for lowering the LA burden in the diet. Olive oil is a popular cooking oil that is prominently featured in Mediterranean diets, which generally contain far fewer seed oils considering the abundant use of olive oil.

However, olive oil demonstrated a nearly 10-fold wide variability in the percentage of LA and the vast majority of commercial olive oil, and avocado oils, are adulterated with seed oils. A recent study evaluated 89 olive cultivars and found a range of 3% to 27% levels of LA ^[58]. Tests have also revealed that anywhere from 60 to 90% of the olive oils sold in American grocery stores and restaurants are adulterated with cheap, oxidized, omega-6 vegetable oils, such as sunflower oil or peanut oil, or nonhuman-grade olive oils, which are harmful to health in a number of ways ^[59].

Although this problem is concerning, instead of avoiding all cooking oils (e.g., vegetable and seed oil), healthier choices include those that have been used for centuries, such as butter and beef tallow. In addition to containing the lowest LA content, these sources of fats also provide the fat-soluble vitamins A, D, and K₂.

Despite these sources being readily available, most Americans simply fail to obtain enough preformed vitamin A in their diet. This can contribute to many chronic diseases, including cardiovascular disease ^[60] and cancers ^[61]. An elevated seed oil intake also adversely impacts health, survival, and vision ^[62]. Coconut oil is also very low in LA but does not have the essential fat-soluble vitamins that tallow and butter contain.

6.1. Sources of Animal Protein and Varying LA Contents

Animals are typically fed corn, soy, or other seeds and grains, which is radically different from their native, traditional, or ancestral diet. This presents a problem for nonruminant animals due to the concentration of LA in the seeds and grains they are fed. Ruminants are animals with multiple parts to their stomachs. This includes cows, buffalo, sheep, lamb, goats, deer, elk, and many other game animals.

Ruminants have low LA in both their meat and milk, no matter what they eat ^[63]. This is because their stomach has a ‘biohydrogenation chamber’ that contains bacteria that can convert the high LA fat they eat from grains and seeds into saturated and monounsaturated fats. This is in contrast to animals with one stomach, such as chickens and pigs, that when fed a diet high in LA, including corn and soy, experience an increase in high levels of LA in their tissues, similar to the process that has been observed in humans ^[64].

The ability of the biohydrogenation chamber to efficiently convert high LA fat to saturated and monounsaturated fats is well known, as the difference in LA in ruminants that are 100% grass-fed and those that are fed corn and soy is only approximately 0.5%. This is why, from an LA intake perspective, there is not much difference between concentrated animal feeding operation (CAFO) beef and grass-fed-only beef. However, grass-fed beef is preferred, as it contains less glyphosate, other toxins, and hormones.

6.2. Carnosine Helps Lower Oxidative Damage from LA

Carnosine is an endogenously produced dipeptide, and it consists of only two amino acids, beta-alanine and histidine ^[65]. It is a potent antioxidant that helps limit the damage from excess LA by binding to ALEs. It serves as a sacrificial sink for reactive oxygen species (ROS) and ALEs ^[66] by letting these damaging molecules destroy it rather than mitochondria, DNA, or proteins, as depicted in Figure 2.

/media/item_content/202307/64bf1808e4940nutrients-15-03129-g005.png

Figure 2. Carnosine scavenges ROS and ALES such as 4-HNE generated through the oxidation of fatty acid cell membranes during oxidative stress.

The highest concentrations of carnosine are found in the muscles and brain ^[67]. Carnosine is also found in meats but is not contained in any plant foods. That is why individuals following a vegetarian or vegan diet typically have lower levels of carnosine in their muscles. This is also one reason why many strict vegans who do not properly compensate for low carnosine intake from meat and other nutritional deficiencies may experience difficulties building muscle.

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