Next Article in Journal
Relationship between Nutritional Status and Clinical and Biochemical Parameters in Hospitalized Patients with Heart Failure with Reduced Ejection Fraction, with 1-year Follow-Up
Next Article in Special Issue
Expert Opinion on Benefits of Long-Chain Omega-3 Fatty Acids (DHA and EPA) in Aging and Clinical Nutrition
Previous Article in Journal
Circadian Variation in Human Milk Composition, a Systematic Review
Previous Article in Special Issue
Dietary n-6/n-3 Ratio Influences Brain Fatty Acid Composition in Adult Rats
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Effects of Linoleic Acid Consumption on Lipid Risk Markers for Cardiovascular Disease in Healthy Individuals: A Review of Human Intervention Trials

Department of Nutrition and Food Science, Huntley College of Agriculture, California State Polytechnic University, Pomona, CA 91768, USA
*
Author to whom correspondence should be addressed.
Submission received: 11 July 2020 / Revised: 30 July 2020 / Accepted: 1 August 2020 / Published: 4 August 2020
(This article belongs to the Special Issue Polyunsaturated Fatty Acids Intake and Human Health)

Abstract

:
Cardiovascular disease (CVD) is the leading cause of death worldwide. Risk factors for developing this disease include high serum concentrations of total cholesterol, triglycerides, low-density lipoproteins, very-low density lipoproteins, and low concentrations of high-density lipoproteins. One proposed dietary strategy for decreasing risk factors involves replacing a portion of dietary saturated fatty acids with mono- and polyunsaturated fatty acids (PUFAs). The essential omega-6 PUFA, linoleic acid (LA), is suggested to decrease the risk for CVD by affecting these lipid risk markers. Reviewing human intervention trials will provide further evidence of the effects of LA consumption on risk factors for CVD. PubMed was used to search for peer-reviewed articles. The purpose of this review was: (1) To summarize human intervention trials that studied the effects of LA consumption on lipid risk markers for CVD in healthy individuals, (2) to provide mechanistic details, and (3) to provide recommendations regarding the consumption of LA to decrease the lipid risk markers for CVD. The results from this review provided evidence that LA consumption decreases CVD lipid risk markers in healthy individuals.

1. Introduction

Heart disease is the number one cause of death in the United States, accounting for 647,457 (23%) of the deaths, followed by cancer with 599,108 deaths (21.3%). Stroke is the fifth leading cause of death, contributing to 146,383 deaths (5.2%) in 2017 [1]. Worldwide, heart disease and stroke are the largest contributors to death, accounting for 15.2 million deaths in 2016 [2]. A suggested dietary strategy to decrease the risk factors for cardiovascular disease (CVD) (includes heart disease and stroke) is to decrease the consumption of saturated fatty acids and increase unsaturated fatty acids [3,4,5,6,7]. However, this recommendation has been questioned by various authors/publications [8,9,10,11,12,13]. One such controversy is the recommendation of linoleic acid (LA) intake, an essential omega-6 (or n-6) polyunsaturated fatty acid (PUFA) [14,15,16]. For example, it has been suggested that replacement of saturated fat with LA decreases serum cholesterol, but does not decrease the risk of death from coronary heart disease (CHD) [9]. Additionally, there has been concern that consuming high amounts of LA may increase the risk of inflammation [17].
In a recent analysis of 30 prospective observational studies, higher tissue and circulating concentrations of LA were significantly associated with a decreased risk of cardiovascular events [18]. The Cardiovascular Health Study, a prospective cohort study, found that higher circulating LA (but not other omega-6 fatty acids) decreased total and CHD mortality in older adults [19]. In a prospective cohort study, replacing 5% of energy from saturated fats with PUFAs, was associated with a 25% decreased risk of CHD [20]. In one population-based cohort study, there was an inverse association between total dietary PUFAs, including LA and omega-3 PUFAs, and CVD mortality [21]. Furthermore, according to meta-analyses of prospective cohort studies, a low consumption of n-6 PUFAs and higher intakes of saturated and trans-fatty acids increased CHD mortality [22]. Another meta-analysis of prospective cohort studies indicated that LA consumption decreased the risk of CHD events and deaths, and the authors recommended replacing saturated fat with LA to prevent CHD [23]. In a systematic review of 19 randomized controlled trials in which dietary saturated and monounsaturated fatty acids were replaced with omega-6 fatty acids, Hooper et al. [24] discovered that increasing omega-6 fats decreased the risk for myocardial infarction and that omega-6 fats decreased total serum cholesterol but not “other blood fat fractions”. It was also emphasized that “the benefits of omega-6 fats remain to be proven” [24].
The “diet-heart” hypothesis states that a high consumption of saturated fat and cholesterol and a low consumption of polyunsaturated fat, such as LA, increase the accumulation of cholesterol and plaques in artery walls. These events subsequently lead to the development of atherosclerosis, heart disease, and myocardial infarction [9,10]. However, there are various mechanisms that increase the risk of CHD, such as high blood pressure, thrombosis, arrhythmia, inflammation, endothelial dysfunction, insulin resistance, oxidative stress, cigarette smoking, family history, obesity, and overall dietary patterns, among others [10,25]. Lipid levels are another such mechanism that have been suggested to be “strong” risk factors for CVD and mortality, such as high cholesterol, triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), lipoprotein(a) (Lp(a)), very-low-density lipoprotein cholesterol (VLDL-C), and low high-density lipoprotein cholesterol (HDL-C) [10,26]. Additionally, apolipoprotein A1 (apoA1; associated with HDL) and apoB (associated with LDL) have also been utilized as risk markers for CVD and mortality [26].
Recent reviews have primarily focused on n-3 PUFAs (such as the essential omega-3 fatty acid alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)) and CVD risk, with limited attention to other fatty acids such as LA [27,28,29,30]. Thus, this review focused on the consumption of LA impacting lipid risk factors for CVD in healthy individuals. Specifically, the main objective of this paper was to review human intervention trials that investigated the consumption of LA on lipid levels that have been suggested to affect the risk for CVD, including cholesterol, TGs, LDL-C, VLDL-C, HDL-C, Lp(a), apoA1/2, and apoB. Significant oil and food sources of LA are included in Table 1 and Table 2, respectively. Results from this review will provide human clinical evidence of the effects of LA consumption on CVD risk factors in healthy individuals.

2. Materials and Methods

PubMed [32] was utilized to locate peer-reviewed journal articles that investigated the effects of LA consumption on lipid markers of CVD risk in healthy individuals. The search of journal articles occurred during April–June of 2020. The following search terms were used: Linoleic acid, omega-6, n-6, polyunsaturated fatty acids, supplement, lipoprotein, healthy, human clinical trial, randomized controlled trial, VLDL, LDL, HDL, triglycerides, cholesterol, and combinations thereof. Articles were included if they contained information on LA consumption, such as grams or percentage of energy, on lipid biomarkers for CVD risk in healthy individuals. The article was included if the authors stated that the subjects were “healthy”. There were no age restrictions and most of the participants were not obese. Human intervention trials were at least 1 week in length; therefore, postprandial and animal studies were not included. Articles were also excluded if the authors did not state the amount of LA consumed and if it was not indicated whether the subjects were healthy. Using these criteria, 16 journal articles were found.

3. Results

The literature search included results from human intervention trials investigating the effects of LA consumption on lipid biomarkers for CVD risk in healthy individuals. The findings are organized by cholesterol, TGs, LDL-C, VLDL-C, HDL-C, Lp(a), and apoA1, apoA2, and apoB. The detailed results are presented in Table 3.

3.1. Total Blood Cholesterol

LA intakes decreased total cholesterol concentrations compared with a typical U.S. diet [33], diets high in stearic acid (SA) [34], saturated fatty acids (SFAs) [35], monounsaturated fatty acids (MUFAs) [36], or medium-chain fatty acids (MCFAs) [37]. A higher percentage of energy from LA produced a more significant decrease in cholesterol concentrations [33,36,38], such as compared with palmitic acid (PA) consumption [38]. However, consuming a diet high in dietary cholesterol and LA increased cholesterol concentrations [39]. Goyens et al. [40] demonstrated that a high consumption of alpha-linolenic acid (ALA), along with LA, significantly decreased cholesterol concentrations compared to control with the same percentage of LA. No significant differences in cholesterol were observed after comparing consumption of a diet high in LA with a diet high in EPA and DHA [41], diets rich in oleic acid (OA) [42,43], SA [43], or ALA [44]. Consuming high and low amounts of LA—along with fish oil capsules (rich in EPA and DHA) or olive oil (rich in OA)—were also not different [45]. Furthermore, consumption of high and low amounts of LA with the same amount of ALA (~1% energy (E)) did not impact cholesterol concentrations [46]. In a study by Dias et al. [47], participants consumed a SFA-rich diet or an n-6 PUFA-rich diet (12.7% E LA), both supplemented with EPA and DHA, for 6 weeks, and found no significant differences in cholesterol concentrations.

3.2. Triglycerides (TGs)

LA consumption decreased TGs compared with diets rich in SA [34], OA [36], or MCFAs [37]. High and low LA consumption, with fish oil capsules (rich in EPA and DHA), decreased TGs compared with high and low LA consumption with olive oil capsules (rich in OA). Low consumption of LA with fish oil resulted in more of a decrease in TGs compared to high LA consumption and fish oil; however, it was not statistically significant [45]. Interestingly, a SFA-rich diet and an n-6 PUFA-rich diet, both supplemented with EPA and DHA, decreased total TGs; however, there were no significant differences between diets [47]. In contrast, LA increased TGs compared to diets supplemented with fish oil (rich in EPA and DHA) [35,41]. There were no significant differences between lower and higher LA consumption [33,40,46], a diet high in OA versus a diet high in LA [42], an ALA-rich diet versus an LA-rich diet [44], or a diet high in SA versus a diet high in LA [43].

3.3. Low-Density Lipoprotein Cholesterol (LDL-C)

Consumption of LA decreased LDL-C, with more significant decreases produced from a higher LA diet [33]. Diets containing LA decreased LDL-C compared with a diet rich in SA [34,48], SFAs [35], trans-fatty acids (TFAs) [48], OA [36], or MCFAs [37]. Gradually increasing dietary LA (up to 10% E) decreased LDL-C, with most significant decreases observed at the highest % E of LA (10%). Palmitic acid (PA) (10% E) remained constant during this study design [38]. In contrast, LA increased LDL-C compared with a diet rich in MUFA (14.5% E OA) [48]. There were no significant differences in LA consumption compared with diets rich in OA [42,43], ALA [44], or SA [43]. Consumption of low and high LA diets, with ALA maintained at about 1% for each diet, did not differ regarding LDL-C concentrations [46]. Furthermore, LDL-C concentrations did not differ following consumption of low and high LA diets—along with fish oil capsules (high in EPA and DHA) or olive oil capsules (rich in OA) [45]. Lastly, consumption of a SFA-rich diet or an n-6 PUFA-rich diet (12.7% E LA)—both supplemented with EPA and DHA—resulted in no differences in LDL-C [47].

3.4. Very-Low-Density Lipoprotein Cholesterol (VLDL-C)

VLDL-C concentrations decreased following consumption of a PUFA-rich corn oil (11.3% E LA) compared with a MUFA-rich mixture of olive and sunflower oils (13.6% E OA) [36]. A low consumption of LA (3% E) decreased medium VLDL compared to control diet (7% E LA) [40]. Consumption of a supplement spread containing mostly LA decreased VLDL-C compared with consumption of a supplement spread containing MCFAs [37]. In contrast, there were no significant differences in VLDL-C concentrations after consumption of a SFA-rich diet or an n-6 PUFA-rich diet (12.7% E LA)—both supplemented with EPA and DHA; however, both diets reduced VLDL-C [47].

3.5. High-Density Lipoprotein Cholesterol (HDL-C)

LA consumption increased HDL-C compared with a diet high in SA [34]. Interestingly, consumption of LA increased HDL3-C and decreased HDL2-C compared with an n-3 diet (1.5% E EPA and DHA) [35]. Diets higher in LA decreased HDL-C compared with consumption of a fish oil supplement (rich in EPA and DHA) [41] or a diet rich in PA [38]. There were no significant differences in HDL-C following consumption of higher and lower amounts of LA [33,40,46], a diet high in LA compared with diets rich in OA [36,42,43], ALA [40,44], or SA [43]. Consumption of high and low amounts of LA, with supplements of fish oil capsules (rich in EPA and DHA) or olive oil capsules (rich in OA), did not significantly differ in regards to HDL-C [45]. Furthermore, the consumption of a SFA-rich diet or an n-6 PUFA-rich diet (12.7% E LA)—both supplemented with EPA and DHA—did not significantly differ with respect to HDL-C [47].

3.6. Lipoprotein(a) (Lp(a)) Particles

A high consumption of LA decreased Lp(a) compared to a diet high in TFAs [48]. However, consumption of LA (1.5% E) increased Lp(a) compared with a SFA-rich diet [35]. No significant differences were observed when LA consumption (about 12% E) was compared to diets high in SFA, OA, and SA [48].

3.7. Apolipoprotein (apo) A1, ApoA2, and ApoB

ApoA1 increased following consumption of both a lower and higher LA diet compared to a typical U.S. diet [33]. Consumption of LA (1.5% E) increased apoA2 compared with an n-3 diet (1.5% E of EPA and DHA) [35]. ApoA1 and apoA2 decreased after an LA-rich diet compared with a diet high in OA [42]. There were no significant differences in apoA1 concentrations following consumption of lower and higher LA diets [40], and consumption of LA compared with diets high in SA or OA [43].
Lower and higher LA consumption decreased apoB compared with a typical U.S. diet, with further decreases generated by the higher LA diet (10.8% E) [33]. An LA-rich diet also decreased apoB compared to diets high in SA, elaidic acid (a TFA) [34], or SFAs [35]. Consumption of a high-ALA diet (7% E LA; 1.1% E ALA) decreased apoB compared to the control diet (7% E LA; 0.4% E ALA) [40]. No significant differences were observed in apoB concentrations after consumption of LA compared to diets rich in OA [42,43] or SA [43].

4. Discussion

The major findings from the review will be presented in this section. Relating the results to the proposed mechanisms will also be discussed. Lastly, recommended intakes of LA and future studies will be suggested.

4.1. Major Findings of the Reviewed Studies of LA Decreasing the Risk Factors for CVD

This review sought to summarize the results from human intervention trials that investigated the effects of LA consumption on lipid risk markers for CVD. In the review of the literature, it was found that various amounts of LA decreased these risk markers for CVD in healthy individuals. Additionally, consumption of LA decreased total cholesterol concentrations compared with a common U.S. diet [33] and diets rich in SA [34], PA [38], SFAs [35], MUFAs [36], and MCFAs [37], and higher percentages of LA intakes reduced cholesterol concentrations [33,36,38]. LA consumption also reduced TG concentrations compared with diets high in SA [34], OA [36], or MCFAs [37]. Further evidence included intakes of LA decreasing LDL-C compared to diets high in SA [34,48], SFAs [35], TFAs [48], OA [36], or MCFAs [37]. Interestingly, higher amounts of LA decreased LDL-C, while PA consumption remained constant [38]. After consumption of LA, VLDL-C also decreased compared with a diet rich in OA [36] or MCFAs [37]. HDL-C increased following LA consumption compared to a diet high in SA [34]. Furthermore, LA consumption decreased Lp(a) compared to a TFA-rich diet [48] and increased apoA1 compared to a usual U.S. diet [33]. Lastly, apoB decreased after intakes of LA compared to a common U.S. diet [33] and diets rich in SA, elaidic acid (a TFA) [34], or SFAs [35].

4.2. Mechanisms by Which PUFAs Decrease Total Cholesterol

According to the aforementioned studies, LA decreased total serum cholesterol compared with other dietary patterns that were not rich in PUFAs [33,34,35,36,37,38]. It was demonstrated that PUFAs increase liver X receptor alpha (LXRα) gene transcription [49,50], perhaps via peroxisome proliferator activated receptors (PPARs) [49]. LXRα increases the expression of cholesterol 7α-hydroxylase (CYP7), which converts cholesterol to bile acids; therefore, by stimulating CYP7 activity, PUFAs help to catabolize cholesterol [51]. The studies that did not observe a significant difference between groups with regards to cholesterol levels primarily involved the additions of n-3 fatty acids (ALA, EPA, and/or DHA)—along with lower and/or higher amounts of LA or n-3 fatty acids as a separate treatment [41,44,45,46,47]. Based on the reviewed studies, LA (or PUFA) consumption decreases total serum cholesterol, which is in agreement with the proposed mechanisms.

4.3. Mechanisms by Which PUFAs Decrease Triglycerides

LA consumption decreased TG concentrations compared to a diet rich in MCFAs [37]. On the other hand, there were mixed results with the consumption of LA affecting TG concentrations compared with SA [34,43] or OA [36,42]. The lower % of E (7%) of LA and SA did not differ after consuming each diet for 5 weeks, whereas the higher % of E (~12%) of LA lowered TGs compared to SA after 3 weeks on each diet. Higher consumption of OA (~18% of E) or LA (~18% of E) on TG levels did not differ after 8 weeks on each diet, whereas the intakes of PUFA-rich corn oil (11.3% E of LA and 9.6% E of OA) decreased TG levels compared to consumption of a MUFA-rich mixture (5.7% E of LA and 13.6% E OA) after 2 weeks. The results of these studies (and other reviewed studies) suggest that different treatment durations and percent of E may be factors that lead to different outcomes.
The consumption of EPA and DHA was more pronounced, which resulted in more significant decreases in TG concentrations [35,41,45]. Furthermore, supplementation with EPA and DHA as part of SFA- and n-6 PUFA-rich diets decreased total TGs (no significant differences between groups) [47]. These results provide further evidence of the TG-lowering properties of EPA and DHA, which coincide with the proposed mechanisms.
Unsaturated fatty acids interact with peroxisome proliferator activated receptor alpha (PPARα), more so than SFAs [52]. PPARα interacts with peroxisome proliferator response elements (PPREs) in the promoter regions of genes, such as apoC-III and lipoprotein lipase (LPL). Certain fatty acids lower TG concentrations by increasing catabolism of lipoproteins and decreasing VLDL secretion from the liver [53]. Fatty acids stimulate LPL, which hydrolyzes TGs from chylomicrons and VLDLs [51,54]. Human studies indicate that dietary omega-3 fatty acids decrease VLDL [55]. It has been suggested that LPL may be “more reactive” to VLDL with PUFA TGs, thereby increasing hydrolysis of TG-rich lipoproteins [51,56].
ApoC-III inhibits LPL activity [57] and, therefore, increases TG concentrations. It is suggested that fatty acids, such as n-3 fatty acids, reduce apoC-III, which increases LPL activity and subsequently VLDL catabolism [51]. It has also been reported that omega-3 PUFAs (including EPA and DHA) decrease TGs [58,59] by decreasing diacylglycerol acyltransferase, fatty acid synthase, and acetyl coenzyme A (CoA) carboxylase [27,60], with DHA possessing more TG-lowering effects [61,62].

4.4. Mechanisms by Which PUFAs Decrease LDL-C

The reviewed studies demonstrated that the consumption of LA decreases LDL-C, primarily compared with diets rich in SFAs [34,35,38,48], TFAs [48], or MCFAs [37]. On the other hand, the inclusions of omega-3 fatty acids (ALA, EPA, and/or DHA) with dietary treatments of LA did not differ with respect to LDL-C [44,45,46,47]. These results are in agreement that LA (or PUFA) consumption lowers LDL-C compared to intakes of SFAs or TFAs.
One such mechanism by which SFAs (such as palmitic acid) increase LDL-C is by decreasing LDL receptor protein levels. In contrast, a diet rich in LA has been shown to increase LDL receptor levels [63]. However, it has been suggested that a high consumption of cholesterol decreases LDL receptor messenger ribonucleic acid (mRNA) and, thus, a high consumption will likely not be affected by fatty acid intakes [51]. This is in agreement with one of the reviewed studies whereby a high consumption of cholesterol and LA produced high cholesterol concentrations [39]. SFAs, especially lauric acid (12:0), myristic acid (14:0), and palmitic acid (16:0), decrease LDL receptor activity, protein, and mRNA, whereas unsaturated fatty acids increase these components [51].
PUFAs may exert their LDL-C-lowering properties by increasing membrane fluidity [51,63,64], which increases LDL receptor activity, decreasing LDL apoB and increasing LDL catabolism [65,66,67]. It has been demonstrated that consumption of lauric and myristic acids produce higher LDL-C compared to consumption of long-chain SFAs [65]. Additionally, intakes of lauric, myristic, and palmitic acids increased LDL-C compared to consumption of stearic acid (18:0) by decreasing LDL receptor activity and increasing synthesis of LDL [68]. Interestingly, DHA increases LDL particle size; however, the significance of this outcome needs further clarification [27,30,58,59]. As mentioned previously, PUFAs increase CYP7 activity, thereby converting cholesterol to bile acids in the liver; this mechanism will likely indirectly increase LDL receptor production [51].
It should be noted that the size of LDL particles may differentially affect atherogenesis, as small LDL particles appear to have increased atherogenic effects compared to large LDL particles [13]. It has been suggested that the consumption of SFAs increases large LDL particles. In a recent randomized controlled trial by Bergeron et al. [69], it was demonstrated that higher SFA consumption (~14% E; replaced MUFAs) increased large LDL particles but not medium or small LDLs. These results are in agreement with a previous investigation in which higher SFA intake (18% E) was inversely associated with concentrations of small, dense LDL particles [70].

4.5. Mechanisms by Which PUFAs Decrease VLDL-C

PUFAs have been shown to inhibit gene transcription of sterol regulatory element-binding protein-1 (SREBP-1) [71], which is involved in lipogenesis and cholesterol synthesis in the liver [72]. Omega-3 PUFAs, more so than omega-6 PUFAs, seem to possess inhibitory effects on SREBP-1 gene transcription and/or protein [73]. Hence, diets rich in omega-3 PUFAs decrease synthesis of MUFAs, TGs, and cholesterol—in addition to reducing VLDL secretion from the liver [51,73]. It has also been suggested that consumption of n-6 PUFAs increases VLDL catabolism and uptake, which contributes to lower VLDL-C and TG concentrations [27,37]. As previously noted, increased LPL activity, and, therefore, VLDL uptake, are mediated by PPAR via PUFAs [27,52].
These mechanisms add insights as to why intakes of LA decreased VLDL-C compared to diets rich in OA [36] and MCFAs [37], as these are monounsaturated and saturated fatty acids, respectively. Moreover, consumption of SFA- or LA-rich diets (supplemented with EPA and DHA) both lowered VLDL-C [47], as these dietary treatments were rich in n-3 PUFAs (EPA and DHA).

4.6. Mechanisms by Which PUFAs Affect HDL-C

HDL particles help to decrease the risk for CVD through a variety of mechanisms, such as removal of cholesterol from macrophages, improvement of endothelial function, and increasing antioxidant and anti-inflammatory properties [74]. Consumption of a Western diet (high fat, high cholesterol) [75] increased oxidized lipids in HDL, such as oxidized arachidonic acid (AA) and LA [76,77,78]. Oxidized fatty acids in lipoproteins have been suggested to increase atherogenesis [79]. As observed in one of the reviewed studies, a high consumption of LA (~18% of E) increased oxidized HDL compared with a diet rich in OA, which is a MUFA [42]. Fish consumption is typically low in a Western diet and, therefore, low in EPA and DHA [30]. Interestingly, it has been reported that EPA lowers HDL3-C, whereas DHA increases HDL2-C, which is more “cardioprotective” [80,81].
According to a reviewed study, intake of LA increased HDL3-C and lowered HDL2-C compared to an n-3 diet (1.5% E EPA and DHA) [35]. These results agree with the proposed mechanisms for EPA and DHA. Additionally, diets higher in LA decreased total HDL-C compared with consumption of a fish oil supplement [41].
Replacement of SFAs with MUFAs or PUFAs results in lower total cholesterol and LDL-C—along with “slightly” lower HDL-C. However, there is a lower total-C:HDL-C ratio [4,82]. Consumption of LA raised HDL-C compared with a diet high in SA [34]. This suggests that SA is not as potent an inducer of HDL-C as is lauric acid, for example [82]. As expected, higher dietary intakes of LA decreased HDL-C compared with consumption of a diet rich in PA [38]. As previously discussed, there were studies that did not show a significant difference in HDL-C. These investigations used higher and lower amounts of LA [33,40,46], or added n-3 fatty acids to the LA interventions or were compared as separate groups [40,44,45,47]. Furthermore, there were no significant differences comparing LA consumption and diets rich in OA [36,42,43], suggesting that LA and OA have similar effects on HDL-C.

4.7. Lipoprotein A as a Risk Factor for CVD

Lp(a), which is made in the liver [83], is a risk factor for CVD (discussed in [84]). Lp(a) contains apolipoprotein (a) (apo(a)), which is bound to apolipoprotein B-100 of “modified” LDL particles [85,86]. Lp(a) differs from LDL, as it also contains apo(a) (discussed in [87]). The biological activity of Lp(a) is not known [87]. Both Lp(a) concentrations and apo(a) size are independent risk factors for CVD [84]. It is unclear if apo(a) size affects atherosclerosis [86]; however, high concentrations of Lp(a) have been suggested to increase the risk for CVD [84,86,88]. Genetics account for more than 90% of Lp(a) concentrations [89]; therefore, concentrations are not typically impacted by diet or exercise [88]. However, it has been reported that elaidic acid (a TFA) increased Lp(a) compared to OA and PA [90]. These results are in agreement with one study whereby consumption of LA reduced Lp(a) compared with a TFA-rich diet [48]. In a previous study, consumption of SA increased Lp(a) compared to PA and lauric + myristic acids [91]. In a reviewed study, consumption of LA increased Lp(a) compared to a SFA diet; however, a low percentage of LA was consumed (1.5% E) [35].

4.8. ApoA Is Associated with HDL Particles

ApoA1 and apoA2 are two forms of apoA. HDL particles consist of apoA1, which binds to the Adenosine triphosphate (ATP)-binding cassette transporter (ABCA-1) on cell surfaces. Additionally, apoA1 is a cofactor for lecithin cholesterol acyl transferase, which forms mature HDL (discussed in [26,92]). Plasma apoA1 concentrations are typically related to HDL-C concentrations [26]. The biological activity of apoA2 is less understood [93]. PPARα also interacts with PPREs in the promoter regions of the genes in the liver for apoA1 and apoA2 [53]. Therefore, this provides a mechanism by which PUFAs may influence apoA1 expression [51].
According to the reviewed studies, consumption of LA increased apoA1 compared to a common U.S. diet [33]. However, LA consumption resulted in no significant differences in apoA1 concentrations compared to diets rich in SA or OA [43], which suggests that these fatty acids have a similar impact on apoA1. On the other hand, apoA1 decreased after an LA-rich diet compared with a diet high in OA [42]. As discussed, there are mixed results comparing LA and OA intakes on CVD risk factors.

4.9. ApoB and the ApoB/ApoA1 Ratio as Risk Markers for CVD

ApoB also exists in two forms, apoB-48 and apoB-100. The intestine produces apoB-48, which is a component of chylomicrons. The liver generates apoB-100, which is a component of VLDL and LDL particles. Under fasting conditions, >95% of circulating apoB exists as apoB-100. ApoB is needed for the binding of the lipoproteins to the LDL receptor. Plasma concentrations of apoB is “strongly correlated” with LDL-C concentrations (discussed in [26,94]). It has been reported that apoA1, apoB, and the apoB/apoA1 ratio are more associated with reduced risk of CVD and/or mortality than with total cholesterol, HDL-C, and LDL-C as CVD risk markers [26,95,96,97]. An additional study demonstrated that high concentrations of apoB increase the risk for CVD, while apoA1 has a “protective” effect [26,98].
It has been shown that PUFAs increase LDL fractional catabolic rate and thus decrease apoB compared to SFAs [65]. Based on the reviewed studies, LA consumption reduced apoB concentrations compared to a common U.S. diet [33] and diets rich in SA, elaidic acid (a TFA) [34], or SFA [35]. Consumption of higher amounts of ALA, decreased apoB, compared to a control diet with the same percentage of LA [40]. However, there were no significant differences in regards to apoB after comparing LA and OA intakes [42,43]. These results suggest LA and OA similarly impact apoB concentrations.

4.10. Linoleic Acid Consumption and Recommended Intakes

In the United States, the usual consumption of LA is about 6% of E [17], with men consuming 16 g/d and women consuming 12.6 g/d, on average [99]. The dietary reference intakes (DRIs), generated by the Institute of Medicine of the National Academies, are provided as adequate intakes (AIs), as not enough scientific information is available to provide recommended dietary allowances (RDAs) for LA. As such, the AIs for men and women (19–50 years) are 17 g/d and 12 g/d of LA, respectively. For men and women ages 51 to 70 years of age, the AIs are 14 g/d and 11 g/d of LA, respectively. The American Heart Association recommends consuming 5 to 10% of E of LA for adults in order to decrease the risk for CHD [15,17]. The World Health Organization recommends 2.5 to 9% of E from LA. It is indicated that the lower percentage prevents deficiency, whereas the higher percentage—along with a “healthy diet”-decreases LDL and total cholesterol levels, and thus decreases the risk for CHD [100]. The amount of LA needed to prevent essential fatty acid deficiency is thought to be 1 to 2% of E [101].
It is suggested that “current data are insufficient” to recommend LA intakes above those that meet the requirements for the essential fatty acid [14]. It is recommended to replace SFAs with MUFAs and/or PUFAs to decrease the risk for CVD. Studies have demonstrated the consumption of both n-6 PUFAs and n-3 PUFAs, such as plant-based ALA and n-3 PUFAs from fish, reduce the risk for CVD. However, the n-6:n-3 ratio is suggested to be a “less relevant indicator” in regards to CVD prevention (discussed in [3,4,10]). Rather, the “Omega-3 Index”, which indicates the EPA + DHA content in red blood cells, is a more useful biomarker, as many individuals consume low amounts of EPA and DHA [102]. The optimum amounts of n-6 and n-3 PUFAs should, therefore, be clarified [10]. Furthermore, it has been stated that there is an “overestimation of benefits, and underestimation of potential risks, of replacing saturated fat with vegetable oils rich in linoleic acid” [9].
There is no upper limit (UL) for LA; however, it is not advised to consume above recommendations due to lack of research studies investigating the consumption of high amounts of LA. It has been suggested that high intakes of LA increase the risk of CVD by LA converting to AA—thereby generating pro-inflammatory eicosanoids (discussed in [17,102]). However, it is thought that consumption of LA “has little effect on tissue” AA and inflammation [3,17,102,103,104]. There is more of a concern of low n-3 PUFAs increasing inflammation [102], as the omega-6 and omega-3 pathways use the same elongation and desaturation enzymes.

4.11. Future Research Directions and Insights

It has been stated that the “diet-heart” hypothesis indicates that “intermediate biomarkers” should not be overemphasized, nonrandomized studies should be interpreted with caution, and publications of randomized controlled trials (RCTs) should be timely and complete [9,12]. Concerns for RCTs include monitoring compliance with periodic dietary analyses, measurement errors in dietary assessments (such as food frequency questionnaires, 24-h recalls, and diet records), adding treatments (such as oils) and restricting other dietary components, multiple lifestyle factors influencing risk markers for CVD, smaller number of participants, shorter duration, high-dropout rates, higher cost, and low generalizability, among others [4,8]. Furthermore, it was stated that it will be difficult to determine the effects of LA on the development of atherosclerosis, as it is “confounded” by LA being a replacement for SFAs, TFAs, or n-3 PUFAs [14]. In other words, are there benefits due to increasing LA and/or decreasing another fatty acid? However, it has been proposed that “only RCTs provide sufficient data to evaluate the specific effects of the n-6 PUFA LA” [12]. On the other hand, others feel that “in most situations, large, prospective cohort studies of hard clinical endpoints, when well designed, can provide the best available evidence to inform dietary recommendations” [4]. Nevertheless, both RCTs and prospective observational cohorts are considered the “top two tiers of evidence-based medicine” [12]. However, certain researchers feel that results from RCTs and prospective observational cohorts do not support the recommendation to maintain or increase LA consumption [12].
A recent article by Krauss and Kris-Etherton [105] provided additional insights on future studies that are needed regarding fatty acid intakes on CVD risk including: (1) Interactions of fatty acids with dietary components, (2) racial and ethnic differences, (3) the need for long-term studies, (4) identifying new CVD risk markers, (5) evaluating “dose-response” of fatty acids on CVD risk markers, (6) determining genomic, “epigenomic”, and microbiome influences, and (7) evaluating the effects of individual fatty acids and fatty acid-rich foods.

4.12. Translating Fatty Acid Recommendations into Dietary Recommendations

It is generally agreed that the types of fatty acids in the diet, as opposed to total amount, “is the most important feature for reducing cardiovascular risk”, such as the partial replacement of SFAs with unsaturated fatty acids, especially PUFAs, the elimination of TFAs, and consumption of dietary EPA and DHA (rather than fish oil supplements) [4,6,10]. It is also important to emphasize “whole, natural foods and dietary patterns”, as opposed to substitutions of individual nutrients, as there will be interactions of nutrients and bioactive components that will influence CVD risk [27,106]. Translating these fatty acid recommendations into practice includes the consumption of lean meats and poultry, low-fat dairy, vegetable oils, nuts, seeds, and fish. Additional dietary recommendations to decrease the risk for chronic diseases consist of increased intakes of fruits, vegetables, whole grains, and legumes, while lowering the consumption of salt and added sugars [4,6,10].

5. Conclusions

The following list describes the main findings from this review:
  • LA consumption primarily decreased total cholesterol compared with diets that were not rich in PUFAs [33,34,35,36,37,38].
  • LA consumption produced mixed results on TG concentrations [33,34,36,37,40,42,43,44,46], whereas consumption of EPA and DHA more consistently decreased TGs [35,41,45,47].
  • LA (or PUFA) consumption decreased LDL-C compared to diets rich in SFAs [34,35,37,38,48] or TFAs [48]; there were mixed results compared with OA consumption [36,42,43,48].
  • LA consumption decreased VLDL-C compared to diets high in OA [36], or MCFAs [37]. Additionally, intake of a SFA- or LA-rich diet, both supplemented with EPA and DHA, also reduced VLDL-C [47].
  • LA consumption decreased HDL-C compared to PA [38], or EPA and DHA [41]; there were no differences compared to OA intakes [36,42,43].
  • LA consumption decreased Lp (a) compared to a TFA-rich diet [48].
  • LA consumption increased apoA1 compared with a typical U.S. diet [33].
  • LA consumption decreased apoB compared with a typical U.S. diet [33], SFAs [34,35], or TFAs [34]; there were no significant differences between LA and OA intakes [42,43].
  • As mentioned in previous studies, there were no significant differences or mixed results for certain CVD risk markers, notably when comparing LA and OA intakes. These outcomes indicate that additional studies are needed.
  • The recommended intake of LA for optimum health is not known; as such, it is not recommended to consume LA above 10% of E [14,15,17,100].

Author Contributions

E.F. conceptualized the review and wrote the first draft of the manuscript. E.F. created Table 1, Table 2, and Table 3. B.B.-W. reviewed and edited the draft, and provided edits and additions to the food and oil tables. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Deaths: Leading Causes for 2017. Available online: https://www.cdc.gov/nchs/nvss/leading-causes-of-death.htm (accessed on 14 June 2020).
  2. World Health Organization. The Top 10 Causes of Death. Available online: https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death (accessed on 16 June 2020).
  3. Anton, S.D.; Heekin, K.; Simkins, C.; Acosta, A. Differential effects of adulterated versus unadulterated forms of linoleic acid on cardiovascular health. J. Integr. Med. 2013, 11, 2–10. [Google Scholar] [CrossRef] [Green Version]
  4. Wang, D.D.; Hu, F.B. Dietary fat and risk of cardiovascular disease: Recent controversies and advances. Annu. Rev. Nutr. 2017, 37, 423–446. [Google Scholar] [CrossRef]
  5. Hu, F.B.; Willett, W.C. Optimal diets for prevention of coronary heart disease. JAMA 2002, 288, 2569–2578. [Google Scholar] [CrossRef]
  6. Zock, P.L.; Blom, W.A.; Nettleton, J.A.; Hornstra, G. Progressing insights into the role of dietary fats in the prevention of cardiovascular disease. Curr. Cardiol. Rep. 2016, 18, 111. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Millen, B.E.; Wolongevicz, D.M.; de Jesus, J.M.; Nonas, C.A.; Lichtenstein, A.H. 2013 American heart association/American college of cardiology guideline on lifestyle management to reduce cardiovascular risk: Practice opportunities for registered dietitian nutritionists. J. Acad. Nutr. Diet. 2014, 114, 1723–1729. [Google Scholar] [CrossRef] [PubMed]
  8. Harcombe, Z.; Baker, J.S.; Cooper, S.M.; Davies, B.; Sculthorpe, N.; DiNicolantonio, J.J.; Grace, F. Evidence from randomised controlled trials did not support the introduction of dietary fat guidelines in 1977 and 1983: A systematic review and meta-analysis. Open Heart 2015, 2. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  9. Ramsden, C.E.; Zamora, D.; Majchrzak-Hong, S.; Faurot, K.R.; Broste, S.K.; Frantz, R.P.; Davis, J.M.; Ringel, A.; Suchindran, C.M.; Hibbeln, J.R. Re-evaluation of the traditional diet-heart hypothesis: Analysis of recovered data from Minnesota Coronary Experiment (1968–1973). BMJ 2016, 353, 1246. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  10. Willett, W.C. Dietary fats and coronary heart disease. J. Intern. Med. 2012, 272, 13–24. [Google Scholar] [CrossRef]
  11. Whelan, J. The health implications of changing linoleic acid intakes. Prostaglandins Leukot Essent Fat. Acids 2008, 79, 165–167. [Google Scholar] [CrossRef]
  12. Ramsden, C.E.; Hibbeln, J.R.; Majchrzak-Hong, S.F. All PUFAs are not created equal: Absence of CHD benefit specific to linoleic acid in randomized controlled trials and prospective observational cohorts. World Rev. Nutr. Diet. 2011, 102, 30–43. [Google Scholar]
  13. Kris-Etherton, P.M.; Krauss, R.M. Public health guidelines should recommend reducing saturated fat consumption as much as possible: YES. Am. J. Clin. Nutr. 2020, 112, 13–18. [Google Scholar] [CrossRef] [PubMed]
  14. Jandacek, R.J. Linoleic acid: A nutritional quandary. Healthcare 2017, 5, 25. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Harris, W.S.; Mozaffarian, D.; Rimm, E.; Kris-Etherton, P.; Rudel, L.L.; Appel, L.J.; Engler, M.M.; Engler, M.B.; Sacks, F. Omega-6 fatty acids and risk for cardiovascular disease: A science advisory from the American heart association nutrition subcommittee of the council on nutrition, physical activity, and metabolism; council on cardiovascular nursing; and council on epidemiology and prevention. Circulation 2009, 119, 902–907. [Google Scholar] [PubMed] [Green Version]
  16. Vannice, G.; Rasmussen, H. Position of the academy of nutrition and dietetics: Dietary fatty acids for healthy adults. J. Acad. Nutr. Diet. 2014, 114, 136–153. [Google Scholar] [CrossRef] [Green Version]
  17. Whelan, J.; Fritsche, K. Linoleic acid. Adv. Nutr. 2013, 4, 311–312. [Google Scholar] [CrossRef]
  18. Marklund, M.; Wu, J.H.Y.; Imamura, F.; del Gobbo, L.C.; Fretts, A.; de Goede, J.; Shi, P.; Tintle, N.; Wennberg, M.; Aslibekyan, S.; et al. Biomarkers of dietary omega-6 fatty acids and incident cardiovascular disease and mortality. Circulation 2019, 139, 2422–2436. [Google Scholar] [CrossRef] [Green Version]
  19. Wu, J.H.; Lemaitre, R.N.; King, I.B.; Song, X.; Psaty, B.M.; Siscovick, D.S.; Mozaffarian, D. Circulating omega-6 polyunsaturated fatty acids and total and cause-specific mortality: The cardiovascular health study. Circulation 2014, 130, 1245–1253. [Google Scholar] [CrossRef] [Green Version]
  20. Li, Y.; Hruby, A.; Bernstein, A.M.; Ley, S.H.; Wang, D.D.; Chiuve, S.E.; Sampson, L.; Rexrode, K.M.; Rimm, E.B.; Willett, W.C.; et al. Saturated fats compared with unsaturated fats and sources of carbohydrates in relation to risk of coronary heart disease: A prospective cohort study. J. Am. Coll. Cardiol. 2015, 66, 1538–1548. [Google Scholar] [CrossRef] [Green Version]
  21. Jiao, J.; Liu, G.; Shin, H.J.; Hu, F.B.; Rimm, E.B.; Rexrode, K.M.; Manson, J.E.; Zong, G.; Sun, Q. Dietary fats and mortality among patients with type 2 diabetes: Analysis in two population based cohort studies. BMJ 2019, 366, 14009. [Google Scholar] [CrossRef] [Green Version]
  22. Wang, Q.; Afshin, A.; Yakoob, M.Y.; Singh, G.M.; Rehm, C.D.; Khatibzadeh, S.; Micha, R.; Shi, P.; Mozaffarian, D. Impact of nonoptimal intakes of saturated, polyunsaturated, and trans fat on global burdens of coronary heart disease. J. Am. Heart Assoc. 2016, 5. [Google Scholar] [CrossRef] [Green Version]
  23. 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. [Google Scholar] [CrossRef] [PubMed]
  24. Hooper, L.; Al-Khudairy, L.; Abdelhamid, A.S.; Rees, K.; Brainard, J.S.; Brown, T.J.; Ajabnoor, S.M.; O’Brien, A.T.; Winstanley, L.E.; Donaldson, D.H.; et al. Omega-6 fats for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst. Rev. 2018, 11, 11094. [Google Scholar]
  25. Xu, L.B.; Zhou, Y.F.; Yao, J.L.; Sun, S.J.; Rui, Q.; Yang, X.J.; Li, X.B. Apolipoprotein A1 polymorphisms and risk of coronary artery disease: A meta-analysis. Arch. Med. Sci. 2017, 13, 813–819. [Google Scholar] [CrossRef] [PubMed]
  26. Florvall, G.; Basu, S.; Larsson, A. Apolipoprotein A1 is a stronger prognostic marker than are HDL and LDL cholesterol for cardiovascular disease and mortality in elderly men. J. Gerontol. Biol. Sci. Med. Sci. 2006, 61, 1262–1266. [Google Scholar] [CrossRef] [Green Version]
  27. Ooi, E.M.; Watts, G.F.; Ng, T.W.; Barrett, P.H. Effect of dietary Fatty acids on human lipoprotein metabolism: A comprehensive update. Nutrients 2015, 7, 4416–4425. [Google Scholar] [CrossRef] [Green Version]
  28. Manuelli, M.; Della Guardia, L.; Cena, H. Enriching Diet with n-3 PUFAs to help prevent cardiovascular diseases in healthy adults: Results from clinical trials. Int. J. Mol. Sci. 2017, 18, 1552. [Google Scholar] [CrossRef] [Green Version]
  29. Kris-Etherton, P.M.; Richter, C.K.; Bowen, K.J.; Skulas-Ray, A.C.; Jackson, K.H.; Petersen, K.S.; Harris, W.S. Recent clinical trials shed new light on the cardiovascular benefits of Omega-3 fatty acids. Methodist DeBakey Cardiovasc. J. 2019, 15, 171–178. [Google Scholar]
  30. Innes, J.K.; Calder, P.C. Marine Omega-3 (N-3) fatty acids for cardiovascular health: An update for 2020. Int. J. Mol. Sci. 2020, 21, 1362. [Google Scholar] [CrossRef] [Green Version]
  31. U.S. Department of Agriculture (USDA). Food Data Central. Available online: https://fdc.nal.usda.gov/ (accessed on 15 June 2020).
  32. National Center for Biotechnology Information; PubMed.gov. National Library of Medicine. National Institutes of Health. Available online: https://pubmed.ncbi.nlm.nih.gov/ (accessed on 16 June 2020).
  33. Iacono, J.M.; Dougherty, R.M. Lack of effect of linoleic acid on the high-density-lipoprotein-cholesterol fraction of plasma lipoproteins. Am. J. Clin. Nutr. 1991, 53, 660–664. [Google Scholar] [CrossRef]
  34. Zock, P.L.; Katan, M.B. Hydrogenation alternatives: Effects of trans fatty acids and stearic acid versus linoleic acid on serum lipids and lipoproteins in humans. J. Lipid Res. 1992, 33, 399–410. [Google Scholar]
  35. Sanders, T.A.; Oakley, F.R.; Miller, G.J.; Mitropoulos, K.A.; Crook, D.; Oliver, M.F. Influence of n-6 versus n-3 polyunsaturated fatty acids in diets low in saturated fatty acids on plasma lipoproteins and hemostatic factors. Arterioscler. Thromb. Vasc. Biol. 1997, 17, 3449–3460. [Google Scholar] [CrossRef] [PubMed]
  36. Wagner, K.H.; Tomasch, R.; Elmadfa, I. Impact of diets containing corn oil or olive/sunflower oil mixture on the human plasma and lipoprotein lipid metabolism. Eur. J. Nutr. 2001, 40, 161–167. [Google Scholar] [CrossRef] [PubMed]
  37. van Schalkwijk, D.B.; Pasman, W.J.; Hendriks, H.F.; Verheij, E.R.; Rubingh, C.M.; van Bochove, K.; Vaes, W.H.; Adiels, M.; Freidig, A.P.; de Graaf, A.A. Dietary medium chain fatty acid supplementation leads to reduced VLDL lipolysis and uptake rates in comparison to linoleic acid supplementation. PLoS ONE 2014, 9, e100376. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. French, M.A.; Sundram, K.; Clandinin, M.T. Cholesterolaemic effect of palmitic acid in relation to other dietary fatty acids. Asia Pac. J. Clin. Nutr. 2002, 11, 401–407. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  39. Bronsgeest-Schoute, D.C.; Hautvast, J.G.; Hermus, R.J. Dependence of the effects of dietary cholesterol and experimental conditions on serum lipids in man. I. Effects of dietary cholesterol in a linoleic acid-rich diet. Am. J. Clin. Nutr. 1979, 32, 2183–2187. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  40. Goyens, P.L.; Mensink, R.P. The dietary alpha-linolenic acid to linoleic acid ratio does not affect the serum lipoprotein profile in humans. J. Nutr. 2005, 135, 2799–2804. [Google Scholar] [CrossRef] [Green Version]
  41. Sanders, T.A.; Hochland, M.C. A comparison of the influence on plasma lipids and platelet function of supplements of omega 3 and omega 6 polyunsaturated fatty acids. Br. J. Nutr. 1983, 50, 521–529. [Google Scholar] [CrossRef] [Green Version]
  42. Sola, R.; La Ville, A.E.; Richard, J.L.; Motta, C.; Bargallo, M.T.; Girona, J.; Masana, L.; Jacotot, B. Oleic acid rich diet protects against the oxidative modification of high density lipoprotein. Free Radic. Biol. Med. 1997, 22, 1037–1045. [Google Scholar] [CrossRef]
  43. Thijssen, M.A.; Mensink, R.P. Small differences in the effects of stearic acid, oleic acid, and linoleic acid on the serum lipoprotein profile of humans. Am. J. Clin. Nutr. 2005, 82, 510–516. [Google Scholar] [CrossRef]
  44. Pang, D.; Allman-Farinelli, M.A.; Wong, T.; Barnes, R.; Kingham, K.M. Replacement of linoleic acid with alpha-linolenic acid does not alter blood lipids in normolipidaemic men. Br. J. Nutr. 1998, 80, 163–167. [Google Scholar] [CrossRef] [Green Version]
  45. Damsgaard, C.T.; Frokiaer, H.; Andersen, A.D.; Lauritzen, L. Fish oil in combination with high or low intakes of linoleic acid lowers plasma triacylglycerols but does not affect other cardiovascular risk markers in healthy men. J. Nutr. 2008, 138, 1061–1066. [Google Scholar] [CrossRef] [PubMed]
  46. Liou, Y.A.; King, D.J.; Zibrik, D.; Innis, S.M. Decreasing linoleic acid with constant alpha-linolenic acid in dietary fats increases (n-3) eicosapentaenoic acid in plasma phospholipids in healthy men. J. Nutr. 2007, 137, 945–952. [Google Scholar] [CrossRef] [PubMed]
  47. Dias, C.B.; Amigo, N.; Wood, L.G.; Correig, X.; Garg, M.L. Effect of diets rich in either saturated fat or n-6 polyunsaturated fatty acids and supplemented with long-chain n-3 polyunsaturated fatty acids on plasma lipoprotein profiles. Eur. J. Clin. Nutr. 2017, 71, 1297–1302. [Google Scholar] [CrossRef] [PubMed]
  48. Mensink, R.P.; Zock, P.L.; Katan, M.B.; Hornstra, G. Effect of dietary cis and trans fatty acids on serum lipoprotein[a] levels in humans. J. Lipid Res. 1992, 33, 1493–1501. [Google Scholar]
  49. Tobin, K.A.; Steineger, H.H.; Alberti, S.; Spydevold, O.; Auwerx, J.; Gustafsson, J.A.; Nebb, H.I. Cross-talk between fatty acid and cholesterol metabolism mediated by liver X receptor-alpha. Mol. Endocrinol. 2000, 14, 741–752. [Google Scholar]
  50. Ide, T.; Shimano, H.; Yoshikawa, T.; Yahagi, N.; Amemiya-Kudo, M.; Matsuzaka, T.; Nakakuki, M.; Yatoh, S.; Iizuka, Y.; Tomita, S.; et al. Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. II. LXRs suppress lipid degradation gene promoters through inhibition of PPAR signaling. Mol. Endocrinol. 2003, 17, 1255–1267. [Google Scholar] [CrossRef] [Green Version]
  51. Fernandez, M.L.; West, K.L. Mechanisms by which dietary fatty acids modulate plasma lipids. J. Nutr. 2005, 135, 2075–2078. [Google Scholar] [CrossRef]
  52. Ferre, P. The biology of peroxisome proliferator-activated receptors: Relationship with lipid metabolism and insulin sensitivity. Diabetes 2004, 53, 43–50. [Google Scholar] [CrossRef] [Green Version]
  53. Schoonjans, K.; Staels, B.; Auwerx, J. Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. J. Lipid Res. 1996, 37, 907–925. [Google Scholar]
  54. Schoonjans, K.; Peinado-Onsurbe, J.; Lefebvre, A.M.; Heyman, R.A.; Briggs, M.; Deeb, S.; Staels, B.; Auwerx, J. PPARalpha and PPARgamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO J. 1996, 15, 5336–5348. [Google Scholar] [CrossRef]
  55. Illingworth, D.R.; Schmidt, E.B. The influence of dietary n-3 fatty acids on plasma lipids and lipoproteins. Ann. N. Y. Acad. Sci. 1993, 676, 60–69. [Google Scholar] [CrossRef] [PubMed]
  56. Vasandani, C.; Kafrouni, A.I.; Caronna, A.; Bashmakov, Y.; Gotthardt, M.; Horton, J.D.; Spady, D.K. Upregulation of hepatic LDL transport by n-3 fatty acids in LDL receptor knockout mice. J. Lipid Res. 2002, 43, 772–784. [Google Scholar] [PubMed]
  57. Shachter, N.S. Apolipoproteins C-I and C-III as important modulators of lipoprotein metabolism. Curr. Opin. Lipidol. 2001, 12, 297–304. [Google Scholar] [CrossRef] [PubMed]
  58. Cottin, S.C.; Sanders, T.A.; Hall, W.L. The differential effects of EPA and DHA on cardiovascular risk factors. Proc. Nutr. Soc. 2011, 70, 215–231. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  59. Mozaffarian, D.; Wu, J.H. (n-3) fatty acids and cardiovascular health: Are effects of EPA and DHA shared or complementary? J. Nutr. 2012, 142, 614–625. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  60. Mozaffarian, D.; Wu, J.H. Omega-3 fatty acids and cardiovascular disease: Effects on risk factors, molecular pathways, and clinical events. J. Am. Coll. Cardiol. 2011, 58, 2047–2067. [Google Scholar] [CrossRef] [Green Version]
  61. Grimsgaard, S.; Bonaa, K.H.; Hansen, J.B.; Nordoy, A. Highly purified eicosapentaenoic acid and docosahexaenoic acid in humans have similar triacylglycerol-lowering effects but divergent effects on serum fatty acids. Am. J. Clin. Nutr. 1997, 66, 649–659. [Google Scholar] [CrossRef]
  62. Allaire, J.; Couture, P.; Leclerc, M.; Charest, A.; Marin, J.; Lepine, M.C.; Talbot, D.; Tchernof, A.; Lamarche, B. A randomized, crossover, head-to-head comparison of eicosapentaenoic acid and docosahexaenoic acid supplementation to reduce inflammation markers in men and women: The comparing EPA to DHA (ComparED) study. Am. J. Clin. Nutr. 2016, 104, 280–287. [Google Scholar] [CrossRef]
  63. Mustad, V.A.; Ellsworth, J.L.; Cooper, A.D.; Kris-Etherton, P.M.; Etherton, T.D. Dietary linoleic acid increases and palmitic acid decreases hepatic LDL receptor protein and mRNA abundance in young pigs. J. Lipid Res. 1996, 37, 2310–2323. [Google Scholar]
  64. Tripodi, A.; Loria, P.; Dilengite, M.A.; Carulli, N. Effect of fish oil and coconut oil diet on the LDL receptor activity of rat liver plasma membranes. Biochim. Biophys. Acta 1991, 1083, 298–304. [Google Scholar] [CrossRef]
  65. Fernandez, M.L.; Lin, E.C.; McNamara, D.J. Differential effects of saturated fatty acids on low density lipoprotein metabolism in the guinea pig. J. Lipid Res. 1992, 33, 1833–1842. [Google Scholar] [PubMed]
  66. Caviglia, J.M.; Gayet, C.; Ota, T.; Hernandez-Ono, A.; Conlon, D.M.; Jiang, H.; Fisher, E.A.; Ginsberg, H.N. Different fatty acids inhibit apoB100 secretion by different pathways: Unique roles for ER stress, ceramide, and autophagy. J. Lipid Res. 2011, 52, 1636–1651. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Shepherd, J.; Packard, C.J.; Grundy, S.M.; Yeshurun, D.; Gotto, A.M.; Taunton, O.D. Effects of saturated and polyunsaturated fat diets on the chemical composition and metabolism of low density lipoproteins in man. J. Lipid Res. 1980, 21, 91–99. [Google Scholar] [PubMed]
  68. Woollett, L.A.; Spady, D.K.; Dietschy, J.M. Regulatory effects of the saturated fatty acids 6:0 through 18:0 on hepatic low density lipoprotein receptor activity in the hamster. J. Clin. Investig. 1992, 89, 1133–1141. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  69. Bergeron, N.; Chiu, S.; Williams, P.T.; Sarah, M.K.; Krauss, R.M. Effects of red meat, white meat, and nonmeat protein sources on atherogenic lipoprotein measures in the context of low compared with high saturated fat intake: A randomized controlled trial. Am. J. Clin. Nutr. 2019, 110, 24–33. [Google Scholar] [CrossRef]
  70. Dreon, D.M.; Fernstrom, H.A.; Campos, H.; Blanche, P.; Williams, P.T.; Krauss, R.M. Change in dietary saturated fat intake is correlated with change in mass of large low-density-lipoprotein particles in men. Am. J. Clin. Nutr. 1998, 67, 828–836. [Google Scholar] [CrossRef] [Green Version]
  71. Xu, J.; Nakamura, M.T.; Cho, H.P.; Clarke, S.D. Sterol regulatory element binding protein-1 expression is suppressed by dietary polyunsaturated fatty acids. A mechanism for the coordinate suppression of lipogenic genes by polyunsaturated fats. J. Biol. Chem. 1999, 274, 23577–23583. [Google Scholar] [CrossRef] [Green Version]
  72. Shimomura, I.; Bashmakov, Y.; Ikemoto, S.; Horton, J.D.; Brown, M.S.; Goldstein, J.L. Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. Proc. Natl. Acad. Sci. USA 1999, 96, 13656–13661. [Google Scholar] [CrossRef] [Green Version]
  73. Field, F.J.; Born, E.; Mathur, S.N. Fatty acid flux suppresses fatty acid synthesis in hamster intestine independently of SREBP-1 expression. J. Lipid Res. 2003, 44, 1199–1208. [Google Scholar] [CrossRef] [Green Version]
  74. Rosenson, R.S.; Brewer, H.B.; Ansell, B.J.; Barter, P.; Chapman, M.J.; Heinecke, J.W.; Kontush, A.; Tall, A.R.; Webb, N.R. Dysfunctional HDL and atherosclerotic cardiovascular disease. Nat. Rev. Cardiol. 2016, 13, 48–60. [Google Scholar] [CrossRef]
  75. Morgantini, C.; Trifiro, S.; Trico, D.; Meriwether, D.; Baldi, S.; Mengozzi, A.; Reddy, S.T.; Natali, A. A short-term increase in dietary cholesterol and fat intake affects high-density lipoprotein composition in healthy subjects. Nutr. Metab. Cardiovasc. Dis. 2018, 28, 575–581. [Google Scholar] [CrossRef] [PubMed]
  76. Morgantini, C.; Natali, A.; Boldrini, B.; Imaizumi, S.; Navab, M.; Fogelman, A.M.; Ferrannini, E.; Reddy, S.T. Anti-inflammatory and antioxidant properties of HDLs are impaired in type 2 diabetes. Diabetes 2011, 60, 2617–2623. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Morgantini, C.; Meriwether, D.; Baldi, S.; Venturi, E.; Pinnola, S.; Wagner, A.C.; Fogelman, A.M.; Ferrannini, E.; Natali, A.; Reddy, S.T. HDL lipid composition is profoundly altered in patients with type 2 diabetes and atherosclerotic vascular disease. Nutr. Metab. Cardiovasc. Dis. 2014, 24, 594–599. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  78. Charles-Schoeman, C.; Meriwether, D.; Lee, Y.Y.; Shahbazian, A.; Reddy, S.T. High levels of oxidized fatty acids in HDL are associated with impaired HDL function in patients with active rheumatoid arthritis. Clin. Rheumatol. 2018, 37, 615–622. [Google Scholar] [CrossRef] [PubMed]
  79. Trico, D.; Di Sessa, A.; Caprio, S.; Chalasani, N.; Liu, W.; Liang, T.; Graf, J.; Herzog, R.I.; Johnson, C.D.; Umano, G.R.; et al. Oxidized derivatives of linoleic acid in pediatric metabolic syndrome: Is their pathogenic role modulated by the genetic background and the gut microbiota? Antioxid. Redox Signal. 2019, 30, 241–250. [Google Scholar] [CrossRef]
  80. Woodman, R.J.; Mori, T.A.; Burke, V.; Puddey, I.B.; Watts, G.F.; Beilin, L.J. Effects of purified eicosapentaenoic and docosahexaenoic acids on glycemic control, blood pressure, and serum lipids in type 2 diabetic patients with treated hypertension. Am. J. Clin. Nutr. 2002, 76, 1007–1015. [Google Scholar] [CrossRef] [Green Version]
  81. Mori, T.A.; Burke, V.; Puddey, I.B.; Watts, G.F.; O’Neal, D.N.; Best, J.D.; Beilin, L.J. Purified eicosapentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipoproteins, LDL particle size, glucose, and insulin in mildly hyperlipidemic men. Am. J. Clin. Nutr. 2000, 71, 1085–1094. [Google Scholar] [CrossRef] [Green Version]
  82. Mensink, R.P.; Zock, P.L.; Kester, A.D.; Katan, M.B. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: A meta-analysis of 60 controlled trials. Am. J. Clin. Nutr. 2003, 77, 1146–1155. [Google Scholar] [CrossRef]
  83. Tsimikas, S. A test in context: Lipoprotein(a): Diagnosis, prognosis, controversies, and emerging therapies. J. Am. Coll. Cardiol. 2017, 69, 692–711. [Google Scholar] [CrossRef]
  84. Gudbjartsson, D.F.; Thorgeirsson, G.; Sulem, P.; Helgadottir, A.; Gylfason, A.; Saemundsdottir, J.; Bjornsson, E.; Norddahl, G.L.; Jonasdottir, A.; Jonasdottir, A.; et al. Lipoprotein(a) concentration and risks of cardiovascular disease and diabetes. J. Am. Coll. Cardiol. 2019, 74, 2982–2994. [Google Scholar] [CrossRef]
  85. Schmidt, K.; Noureen, A.; Kronenberg, F.; Utermann, G. Structure, function, and genetics of lipoprotein (a). J. Lipid Res. 2016, 57, 1339–1359. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Malaguarnera, M.; Vacante, M.; Russo, C.; Malaguarnera, G.; Antic, T.; Malaguarnera, L.; Bella, R.; Pennisi, G.; Galvano, F.; Frigiola, A. Lipoprotein(a) in cardiovascular diseases. BioMed Res. Int. 2013, 2013. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Tholstrup, T.; Samman, S. Postprandial lipoprotein(a) is affected differently by specific individual dietary fatty acids in healthy young men. J. Nutr. 2004, 134, 2550–2555. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Ljungberg, J.; Holmgren, A.; Bergdahl, I.A.; Hultdin, J.; Norberg, M.; Naslund, U.; Johansson, B.; Soderberg, S. Lipoprotein(a) and the apolipoprotein b/a1 ratio independently associate with surgery for aortic stenosis only in patients with concomitant coronary artery disease. J. Am. Heart Assoc. 2017, 6. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  89. Boerwinkle, E.; Leffert, C.C.; Lin, J.; Lackner, C.; Chiesa, G.; Hobbs, H.H. Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations. J. Clin. Investig. 1992, 90, 52–60. [Google Scholar] [CrossRef] [PubMed]
  90. Nestel, P.; Noakes, M.; Belling, B.; McArthur, R.; Clifton, P.; Janus, E.; Abbey, M. Plasma lipoprotein lipid and Lp[a] changes with substitution of elaidic acid for oleic acid in the diet. J. Lipid Res. 1992, 33, 1029–1036. [Google Scholar]
  91. Tholstrup, T.; Marckmann, P.; Vessby, B.; Sandstrom, B. Effect of fats high in individual saturated fatty acids on plasma lipoprotein[a] levels in young healthy men. J. Lipid Res. 1995, 36, 1447–1452. [Google Scholar]
  92. Fielding, C.J.; Shore, V.G.; Fielding, P.E. A protein cofactor of lecithin:cholesterol acyltransferase. Biochem. Biophys. Res. Commun. 1972, 46, 1493–1498. [Google Scholar] [CrossRef]
  93. Gao, X.; Yuan, S.; Jayaraman, S.; Gursky, O. Role of apolipoprotein A-II in the structure and remodeling of human high-density lipoprotein (HDL): Protein conformational ensemble on HDL. Biochemistry 2012, 51, 4633–4641. [Google Scholar]
  94. Kuyl, J.M.; Mendelsohn, D. Observed relationship between ratios HDL-cholesterol/total cholesterol and apolipoprotein A1/apolipoprotein B. Clin. Biochem. 1992, 25, 313–316. [Google Scholar] [CrossRef]
  95. Walldius, G.; Jungner, I. Apolipoprotein B and apolipoprotein A-I: Risk indicators of coronary heart disease and targets for lipid-modifying therapy. J. Intern. Med. 2004, 255, 188–205. [Google Scholar] [CrossRef]
  96. Walldius, G.; Jungner, I. Rationale for using apolipoprotein B and apolipoprotein A-I as indicators of cardiac risk and as targets for lipid-lowering therapy. Eur. Heart J. 2005, 26, 210–212. [Google Scholar] [CrossRef] [Green Version]
  97. Boekholdt, S.M.; Arsenault, B.J.; Hovingh, G.K.; Mora, S.; Pedersen, T.R.; Larosa, J.C.; Welch, K.M.; Amarenco, P.; Demicco, D.A.; Tonkin, A.M.; et al. Levels and changes of HDL cholesterol and apolipoprotein A-I in relation to risk of cardiovascular events among statin-treated patients: A meta-analysis. Circulation 2013, 128, 1504–1512. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  98. Walldius, G.; Jungner, I.; Holme, I.; Aastveit, A.H.; Kolar, W.; Steiner, E. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): A prospective study. Lancet 2001, 358, 2026–2033. [Google Scholar] [CrossRef]
  99. Barnard, N.D. Trends in food availability, 1909–2007. Am. J. Clin. Nutr. 2010, 91, 1530–1536. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  100. World Health Organization. Interim Summary of Conclusions and Dietary Recommendations on Total Fat & Fatty Acids. Available online: https://www.who.int/nutrition/topics/FFA_summary_rec_conclusion.pdf?ua=1 (accessed on 24 June 2020).
  101. Barr, L.H.; Dunn, G.D.; Brennan, M.F. Essential fatty acid deficiency during total parenteral nutrition. Ann. Surg. 1981, 193, 304–311. [Google Scholar] [CrossRef] [PubMed]
  102. Harris, W.S. The Omega-6: Omega-3 ratio: A critical appraisal and possible successor. Prostaglandins Leukot Essent Fat. Acids 2018, 132, 34–40. [Google Scholar] [CrossRef]
  103. 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. 2011, 8. [Google Scholar] [CrossRef] [Green Version]
  104. Johnson, G.H.; Fritsche, K. Effect of dietary linoleic acid on markers of inflammation in healthy persons: A systematic review of randomized controlled trials. J. Acad. Nutr. Diet. 2012, 112, 1029–1041. [Google Scholar] [CrossRef]
  105. Krauss, R.M.; Kris-Etherton, P.M. Public health guidelines should recommend reducing saturated fat consumption as much as possible: Debate consensus. Am. J. Clin. Nutr. 2020, 112, 25–26. [Google Scholar] [CrossRef]
  106. Krauss, R.M.; Kris-Etherton, P.M. Public health guidelines should recommend reducing saturated fat consumption as much as possible: NO. Am. J. Clin. Nutr. 2020, 112, 19–24. [Google Scholar] [CrossRef] [PubMed]
Table 1. Oil sources of linoleic acid (per 100 g) 1.
Table 1. Oil sources of linoleic acid (per 100 g) 1.
OilsEnergy (Kcal)Total Lipid (g)Linoleic Acid (g)Alpha-Linolenic Acid (g)Total Saturated
Fat (g)
Canola oil88410018.69.147.37
Corn oil90010053.51.1613.0
Cottonseed oil88410051.90.2025.9
Grapeseed oil88410069.60.109.60
Olive oil8841009.760.7613.8
Peanut oil88410032.00.0016.9
Safflower oil88410012.70.107.54
Sesame oil88410041.30.3014.2
Soybean oil88410051.06.7915.7
Sunflower oil88410065.70.0010.3
Walnut oil88410052.910.49.10
1 Source: U.S. Department of Agriculture, Food Data Central [31].
Table 2. Food sources of linoleic acid (per 1 ounce [28.3495 g]) 1.
Table 2. Food sources of linoleic acid (per 1 ounce [28.3495 g]) 1.
Food SourcesEnergy (Kcal)Total Lipid (g)Linoleic Acid (g)Alpha-Linolenic Acid (g)Total Saturated Fat (g)
Almonds16414.23.490.0011.08
Brazil nuts18518.86.820.014.52
Cashews15712.42.210.0182.21
Pecans19620.45.850.281.75
Pine nuts19119.49.40.0461.39
Pistachios15912.84.00.0821.68
Pumpkin seeds16313.95.550.0312.42
Sesame seeds15913.45.780.1021.88
Sunflower seeds16514.19.290.021.48
Walnuts18518.510.82.571.74
1 Source: U.S. Department of Agriculture, Food Data Central [31].
Table 3. A summary of the effects of linoleic acid consumption on lipid risk markers for cardiovascular disease in healthy individuals (ordered by date of publication).
Table 3. A summary of the effects of linoleic acid consumption on lipid risk markers for cardiovascular disease in healthy individuals (ordered by date of publication).
Author (Year)StudySubjectsAgeDurationTreatmentLinoleic Acid Results
Bronsgeest-Schoute et al. (1979) [39]Randomized crossover41 total
24 males
17 females
19–35 years
mean, 22.1 years
4 weeks14 to 15% E LA (25 to 50 g/d), with at least 600 mg C for 2 wk, and 2 wk of less than 200 mg C.↑serum C
(high C diet compared with low C diet)
↔TG
Sanders et al. (1983) [41]Randomized double-blinded crossover10 total
6 males
4 females
22–35 years4 weeks10 g/d fish oil supplement (1.7 g EPA and 1.2 g DHA) or vegetable oil (3.4 g/d LA) for 2 wk.↔total C, ↑TG, ↓HDL-C
(compared with fish oil)
Iacono et al. (1991) [33]Randomized crossover11 males44–62 years
mean, 53.6 years
100 daysBaseline period of 20 d (typical US diet, but meeting RDAs), followed by a lower LA diet (3.8% E; 16 g/100 g dietary fat) and a higher LA diet (10.8% E; 37.8 g/100 g dietary fat) for 40 d.↓total C, ↓LDL-C, ↓apoB
(both diets compared to baseline; 10.8% E LA diet had further decreases)
↔HDL-C, ↔TG, ↑apoA1
(both diets compared to baseline)
Zock et al. (1992) [34]Randomized
multiple crossover
56 total
26 males
30 females
Males: 19–48 years mean, 25 years
Females: 18–49 years mean, 24 years
9 weeksThree diets were followed for 3 wk: high in LA (12% E LA), high in SA (11.8% E SA; 3.9% E LA), and high elaidic acid (7.7% E elaidic acid; 3.8% E LA).↓total C, ↓LDL-C
↑HDL-C, ↑HDL:LDL ratio ↓TG
(compared to SA diet)
↓apoB, ↑apoA1:apoB ratio
Mensink et al. (1992) [48]Intervention trial58 total
27 males
31 females
Young (specific ages not stated)53 days17 d on a diet high in SFA (19.3% E; primarily PA and SA), followed by 36 d on a diet replacing 6.5% total E from SFA with MUFA (15.1% E; 14.5% E OA) or PUFA (12.7% E; 12.6% E LA) diets.↔Lp(a), ↑LDL-C (compared to MUFA diet)
Mensink et al. (1992) [48]Intervention trial56 total
26 males
30 females
Young (specific ages not stated)3 weeksSA diet (11.8% E), LA diet (12% E), or TFA diet (7.7% E).↔Lp(a) (compared to SA diet)
↓Lp(a) (compared to TFA diet)
↓LDL-C
Sola et al. (1997) [42]Randomized
crossover
22 malesMean, 49.7 (SE, ± 0.6 years)32 weeksStabilization period for 8 wk, followed by two 8 wk dietary treatments separated by an 8 wk washout period. The dietary treatments included a diet rich in OA (18.2% E MUFA) and one rich in LA (18.1% E PUFA).↑oxidized HDL3,
↔total C, ↔LDL-C
↔HDL2-C, ↔HDL3-C
↔TG, ↔apoB
↓apoA1, ↓apoA2
Sanders et al. (1997) [35]Randomized
crossover
26 males18–34 years17 weeks3 wk of a SFA diet (16% E SFA; mostly PA and SA), followed by 3 wk of an n-3 diet (1.5% E EPA and DHA or 5 g/d) or an n-6 diet (1.5% E LA or 5 g/d), separated by an 8 wk washout period.↑TG, ↑HDL3-C, ↑apoA2
↓HDL2-C
(compared with n-3 diet)
↓total C, ↓LDL-C, ↓apoB ↑Lp(a)
(compared with SFA diet)
Pang et al. (1998) [44]Randomized
single-blinded
29 males18–35 years8 weeksAfter a 2 wk stabilization period, the subjects followed either an ALA-rich diet (10.1 g/d, 3.5% E ALA and 12.1 g/d, 3.1% E LA; ALA:LA ratio of 1:0.9) or an LA-rich diet (1 g/d, 0.1% E ALA and 21 g/d, 6.7% E LA; ALA:LA ratio of 1:66) for 6 wk.↔total C, ↔LDL-C ↔HDL-C, ↔HDL2-C
↔HDL3-C, ↔TG
Wagner et al. (2001) [36]Randomized
double-blinded crossover
28 males19–31 years mean, 23.7 years11 weeksAfter 2 wk of adjustment, the subjects consumed 80 g/d PUFA-rich corn oil (11.3% E LA and 9.6% E OA) or 80 g of a MUFA-rich mixture of olive and sunflower oils (5.7% E LA and 13.6% E OA) for 2 wk.↓total C
(after crossover; compared with MUFA-rich mixture)
↓LDL-C, ↓TG, ↓VLDL-TG
↓VLDL-C
(after initial 2 wk)
↔HDL-C
French et al. (2002) [38]Intervention trial3 males
3 females
Mean, 25 years8 monthsThe subjects consumed 8 different diets for 21 d each, with a break of 7 d between diets. The diets provided 10% E PA, with levels of LA starting at 10% E and gradually decreasing to 2.5% E.↓total C, ↓LDL-C
(from 4.5% E to 10% E LA; 10% E LA produced the lowest LDL-C)
↓HDL-C
(from 2.5% E to 10% E LA; 2.5% E LA produced the highest HDL-C)
Goyens et al. (2005) [40]Randomized double-blinded21 males
33 females
Males: mean, 52.6 years (SD, ± 13.7)
Females: mean, 47.7 years (SD, ± 11.1)
10 weeksFollowing a 4 wk run-in period, 18 subjects per group consumed a control diet (7% E LA and 0.4% E ALA, ALA:LA ratio of 1:19), low-LA diet (3% E LA, 0.4% ALA) or high-ALA (7% E LA, 1.1% E ALA). Both treatment diets had an ALA:LA ratio of 1:7.↓total C,↓LDL-C, ↓apoB
↓total:HDL cholesterol ratio
(High-ALA group compared with control)
↔HDL-C, ↔apoA1
↔TG
(all groups)
↓medium VLDL
(Low-LA group compared with control)
↓small VLDL
(High-ALA group compared with control)
Thijssen et al. (2005) [43]Randomized crossover18 males
27 females
28-66 years mean, 51 years
(SD, ± 10)
17 weeksEach participant consumed each diet for 5 wk, with a washout period of ≥ 1 wk. The diets did not differ, except for the replacement of 7% E with SA, OA, or LA.↔total C, ↔LDL-C ↔HDL-C, ↔TG
↔apoA1, ↔apoB
↔total:HDL cholesterol ratio
↔lipoprotein particle sizes
(all diets compared)
Liou et al. (2007) [46]Randomized crossover22 males20–45 years
mean, 27.9 years
(SEM, ± 1.1)
10 weeksFollowing a 2 wk phase without consumption of fish and seafood, each subject consumed the high LA diet (10.5% E LA; LA:ALA ratio of ~10:1) and the low LA diet (3.8% E LA; LA:ALA ratio of ~4:1) for 4 wk each. ALA was maintained at ~1% E for each diet.↔total C, ↔LDL-C ↔HDL-C
↔LDL:HDL cholesterol ratio, ↔TG
Damsgaard et al. (2008) [45]Randomized
double-blinded
64 males19–40 years10 weeksFollowing a 2 wk run-in period, the participants consumed fish oil capsules (3.1 g/d n-3 LC PUFA; 1.8 g/d EPA, 0.2 g/d DPA, and 1.1 g/d DHA) or olive oil capsules (3.7 g/d OA) for 8 wk. Within each group, the subjects consumed either a low-LA diet (12.7 g LA/100 g fats or 4% E LA) or a high-LA diet (40.3 g LA/100 g fats or 7% E LA; 7.3 g/d higher LA).↓TG
(fish oil groups compared with olive oil groups; TG decreased by 51% in the low-LA group compared to a decrease of 19% in the high-LA group; not significant)
↔total C, ↔LDL-C ↔HDL-C
van Schalkwijk et al. (2014) [37]Randomized
double-blinded crossover
12 males30–60 years
mean, 51 years
(SD, ± 7)
12 weeksA supplement spread of 60 g/d MCFA (65% C8:0 and C10:0) or LCFA (71% LA) for 3 wk, with a washout period of 6 wk between treatments.↓total C, ↓LDL-C
↓VLDL-C, ↓TG
↓LDL-TG, ↓VLDL-TG
Dias et al. (2017) [47]Randomized
Intervention trial
6 males
20 females
18–65 years6 weeksA SFA-rich diet (18.9% E SFA and 2.9% E LA) or an n-6 PUFA-rich diet (12.6% E SFA and 12.7% E LA) for 6 wk. Each diet was supplemented daily with 400 mg EPA + 2000 mg DHA.↔total C, ↔VLDL-C
↔LDL-C, ↔ HDL-C
↔VLDL-TG, ↔total TG
(no difference between diets; however, both diets reduced VLDL-C, VLDL-TG and total TG)
Abbreviations: ALA, alpha-linolenic acid; apo, apolipoprotein; C, cholesterol; d, days; DHA, docosahexaenoic acid; DPA, docosapentaenoic acid; E, energy; EPA, eicosapentaenoic acid; HDL, high-density lipoprotein; LA, linoleic acid; LCFA, long-chain fatty acid; LDL, low-density lipoprotein; Lp, lipoprotein; MCFA, medium-chain fatty acid; MUFA, monounsaturated fatty acid; OA, oleic acid; PA, palmitic acid; PUFA, polyunsaturated fatty acid; SA, stearic acid; SFA, saturated fatty acid; TFA, trans-fatty acid; TG, triglyceride; VLDL, very-low-density lipoprotein; wk, weeks; ↑, increase; ↓, decrease; ↔, no significant difference between groups.

Share and Cite

MDPI and ACS Style

Froyen, E.; Burns-Whitmore, B. The Effects of Linoleic Acid Consumption on Lipid Risk Markers for Cardiovascular Disease in Healthy Individuals: A Review of Human Intervention Trials. Nutrients 2020, 12, 2329. https://0-doi-org.brum.beds.ac.uk/10.3390/nu12082329

AMA Style

Froyen E, Burns-Whitmore B. The Effects of Linoleic Acid Consumption on Lipid Risk Markers for Cardiovascular Disease in Healthy Individuals: A Review of Human Intervention Trials. Nutrients. 2020; 12(8):2329. https://0-doi-org.brum.beds.ac.uk/10.3390/nu12082329

Chicago/Turabian Style

Froyen, Erik, and Bonny Burns-Whitmore. 2020. "The Effects of Linoleic Acid Consumption on Lipid Risk Markers for Cardiovascular Disease in Healthy Individuals: A Review of Human Intervention Trials" Nutrients 12, no. 8: 2329. https://0-doi-org.brum.beds.ac.uk/10.3390/nu12082329

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop