Critical Reviews in Food Science and Nutrition

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Dietary oleic acid supplementation and blood

inflammatory markers: a systematic review and
meta-analysis of randomized controlled trials

Qiong Wang , Ruijie Liu , Ming Chang , Hui Zhang , Qingzhe Jin & Xingguo
Wang

To cite this article: Qiong Wang , Ruijie Liu , Ming Chang , Hui Zhang , Qingzhe Jin & Xingguo
Wang (2020): Dietary oleic acid supplementation and blood inflammatory markers: a systematic
review and meta-analysis of randomized controlled trials, Critical Reviews in Food Science and
Nutrition, DOI: 10.1080/10408398.2020.1854673

To link to this article: https://doi.org/10.1080/10408398.2020.1854673

Published online: 11 Dec 2020.

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CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION
https://doi.org/10.1080/10408398.2020.1854673

REVIEW

Dietary oleic acid supplementation and blood inflammatory markers: a

systematic review and meta-analysis of randomized controlled trials
Qiong Wang, Ruijie Liu, Ming Chang, Hui Zhang, Qingzhe Jin, and Xingguo Wang
Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, School of Food Science and Technology, Jiangnan
University, Wuxi, China

ABSTRACT KEYWORDS
The aim of this systematic review and meta-analysis was to analyze data from randomized con- Inflammatory markers;
trolled trials (RCTs) assessing the effects of oleic acid (OA) supplementation on blood inflammatory meta-analysis; oleic acid;
markers in adults. PubMed, EMBASE and Cochrane Library databases were systematically searched randomized controlled trials
from 1950 to 2019, with adults and a minimum intervention duration of 4 weeks. The effect size
was estimated, adopting standardized mean difference (SMD) and 95% confidence interval (CI). Of
the 719 identified studies, thirty-one RCTs involving 1634 subjects were eligible. The results of this
study revealed that increasing OA supplementation significantly reduced C-reactive protein (CRP)
(SMD:
0.11, 95% CI:
0.21,
0.01, P ¼ 0.038). However, dietary OA consumption did not signifi-
cantly affect tumor necrosis factor (TNF) (SMD:
0.05, 95% CI:
0.19, 0.10, P ¼ 0.534), interleukin 6
(IL-6) (SMD: 0.01, 95% CI:
0.10, 0.13, P ¼ 0.849), fibrinogen (SMD: 0.08, 95% CI:
0.16, 0.31,
P ¼ 0.520), plasminogen activator inhibitor type 1 (PAI-1) activity (SMD:
0.11, 95% CI:
0.34, 0.12,
P ¼ 0.355), soluble intercellular adhesion molecule-1 (sICAM-1) (SMD:
0.06, 95% CI:
0.26, 0.13,
P ¼ 0.595) or soluble vascular cell adhesion molecule-1 (sVCAM-1) (SMD:
0.04, 95% CI:
0.27,
0.18, P ¼ 0.701). Overall, the meta-analysis demonstrated that dietary OA supplementation signifi-
cantly reduced CRP, yet did not affect other inflammatory markers including TNF, IL-6, fibrinogen,
PAI-1 activity, sICAM-1or sVCAM-1.

Introduction reduction of risks for CVD and other related diseases

The World Health Organization has reported that cardiovas-
cular disease (CVD) will remain the primary cause of death
worldwide (World Health Organisation 2018). According to
previous studies, chronic low-grade inflammation is an
important risk factor for cardiovascular disease (Libby 2006)
and a critical feature in various chronic diseases, including
atherosclerosis, metabolic syndrome, abdominal obesity, type
2 diabetes (T2D), and cancer (Baker, Hayden, and Ghosh
2011; Moss and Blaser 2005; Nathalie, Nicolas, and Scheen
2015). Predominant markers of inflammation such as cyto-
kines (tumor necrosis factor (TNF), interleukin-6 (IL-6)),
acute-phase reactants (C-reactive protein (CRP), fibrinogen,
plasminogen activator inhibitor type 1 (PAI-1) activity), and
adhesion molecules (soluble intercellular adhesion molecule-
1 (sICAM-1), soluble vascular cell adhesion molecule-1
(sVCAM-1)) are not only correlated with the risk for CVD,
but also contribute to the pathogenesis of CVD
(Collaboration 2010; Kaptoge et al. 2014; Mulvihill et al.
2002; Rosner, Ronco, and Okusa 2012). Therefore, consecu-
tive attenuation of inflammatory markers has been con-
firmed as one of the mechanisms to reduce the risk of CVD.
Previous studies confirmed that the Mediterranean diet
pattern and olive oil supplements are associated with a
(Grosso et al. 2017; Martinez-Gonzalez, Dominguez, and
Delgado-Rodriguez 2014; Schwingshackl et al. 2019).
Likewise, some meta-analyses also showed that a
Mediterranean diet pattern and olive oil have a significant
lowering effect on inflammation levels (Panagiotakos et al.
2009; Schwingshackl, Christoph, and Hoffmann 2015). Oleic
acid (OA, 18:1 n-9) is a representative in monounsaturated
fatty acids (MUFAs) and is a major fatty acid in dietary fat
and in plasma triglycerides. People consume a lot of oleic
acid, especially people on the Mediterranean diet. Olive oil
is one of the most commonly fats in the Mediterranean diet
being mainly composed by the OA, which makes up 70-80%
of olive oil (Ghobadi et al. 2019). OA is the predominant
fatty acid of a variety of vegetable oils such as olive oil, can-
ola oil, high oleic sunflower oil, high oleic soybean oil, cam-
ellia seed oil, and peanut oil, among others. Over the past
few decades, there has been increasing evidence that OA has
a variety of positive effects on human health and disease,
including anti-inflammatory and antioxidant effects, improv-
ing lipoproteins, lowering blood pressure and blood glucose,
inhibiting cancer cell proliferation, and promoting wound
healing (Mateos, Sarria, and Bravo 2020; Sales-Campos et al.
2013). Some previous clinical trials determined that mono-
unsaturated fatty acids might represent a useful tool for

CONTACT Xingguo Wang wangxg1002@gmail.com Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, School of
Food Science and Technology, Jiangnan University, 1800 Lihu Avenue, Wuxi, Jiangsu 214122, P. R. China.
ß 2020 Taylor & Francis Group, LLC
2 Q. WANG ET AL.
designing diets to reduce cardiovascular disease
(Schwingshackl, Strasser, and Hoffmann 2011). Evidence from
meta-analyses of long-term prospective cohort study confirmed
the relationship between MUFAs and mortality related to
CVD (Cheng, Wang, and Shao 2016; Schwingshackl and
Hoffmann 2012). Some studies have revealed the effectiveness
of OA in decreasing CVD risk by inhibiting inflammatory fac-
tors (Borniquel et al. 2010; Harvey et al. 2010; Vassiliou et al.
2009). The effects of oleic acid on inflammatory factors have
been studied in many clinical trials, but the results of these
studies have been conflicting. For instance, researchers who
have studied consumption of oleic acid for 16 weeks signifi-
cantly attenuated TNF in obese individuals (Silver et al. 2014).
A pilot study with 772 participants recruited demonstrated that
plasma concentrations of CRP were significantly lower on the
Mediterranean diet containing oleic acid (Basu, Devaraj, and
Jialal 2006;). A previous study showed that the administration
of a high-fat meal rich in oleic acid, to healthy and hypertrigly-
ceridemia subjects resulted in a slight reduction in post-meal
levels of the inflammatory adhesion molecules sICAM-1 and
sVCAM-1 (Pacheco et al. 2008). However, some studies
showed the effects of OA intake are neutral on plasma TNF,
IL-6, CRP, sICAM-1, and sVCAM-1 (Candido et al. 2018;
Damsgaard et al. 2008; Teng et al. 2017; Thijssen, Hornstra,
and Mensink 2005). It has also been reported that OA con-
sumption increased inflammatory factors (Rozati et al. 2015).
Consequently, the effect of oleic acid supplementation on
plasma inflammatory factors has remained unclear. The
objective of this systematic review and meta-analysis was to
reveal the effects of increasing OA doses on the levels of
inflammatory factors such as cytokines (TNF, IL-6), acute
phase reactants (CRP, fibrinogen, PAI-1 activity) and adhe-
sion molecules (sICAM-1, sVCAM-1) based on randomized
controlled trials in adults.
Methods
Literature search
This systematic review and meta-analysis were performed in
accordance with the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA) checklist
(Moher et al., 2009). We conducted a systematic search of
randomized clinical trials in PubMed (1950 through March
15, 2019), EMBASE (1950 through March 15, 2019), and the
Cochrane Library (CENTRAL; through issue 3 of 12, 2019).
The text terms used to identify studies included:
(“monounsaturated fatty acids” OR “monounsaturated” OR
“MUFA” OR “oleic acid” OR "oleate" OR “olive oil” OR “tea
seed oil” OR “canola oil” OR “high oleic sunflower oil” OR
“high oleic safflower oil” OR “almond oil” OR “’hazelnut
oil” OR “avocado oil” OR “mustard oil” OR “mediterranean
diet”) AND (“cytokine” OR “tumor necrosis factor” OR
“interleukin” OR “C-reactive protein” OR “fibrinogen” OR
“adiponectin” OR “selectins” OR “adhesion molecule” OR
“TNF” OR “IL” OR “CRP” OR “ICAM-1” OR “VCAM-1”
OR “PAI-1”) AND (“randomized controlled trial” OR
“randomized” OR “randomly” OR “intervention” OR “trials”
OR “trial” OR "clinical trials as topic” OR “placebo” OR
“feeding” OR “supplements” OR “supplement” OR
“supplementation”) NOT (“animals”). Moreover, we hand-
searched the citation lists of the included studies to identify
relevant studies.
Study selection
Studies were selected if they had the following criteria: (1)
the study was confined to randomized controlled trials
(RCTs) in human, including parallel and crossover designs;
(2) a duration of intervention of at least 4 weeks in adults
participants (over 18 years old) excluding pregnant women;
(3) the intervention group was provided oleic acid either
through supplements or their diet, with only fatty acid dif-
ferences from the control group. The difference in OA
intake between high-dose and low-dose should be no less
than 1 g/day; (4) the study contained one or more outcome
measures which targeted blood concentrations of inflamma-
tory markers; (5) no language or country restrictions.
Moreover, we chose not to include: (1) ingested fatty acids
through parenteral nutrition or intravenous administration;
(2) supplementations containing n-3 long-chain PUFA or
conjugated linoleic acid (CLA) because these fatty acids have
been shown to influence inflammatory concentration.
Data extraction and quality assessment
Titles, keywords, abstracts, and full texts of all identified
articles were screened independently by two researchers.
Duplicates and irrelevant studies were excluded. The two
independent reviewers then extracted the data into specific-
ally designed spreadsheets from the relevant qualified litera-
ture. Relevant data were extracted including first author,
country, year, ages of participants, body mass index (BMI),
health status, smoking habits, study design (crossover/paral-
lel), duration, sample size, gender, OA supplement of both
experimental and control groups, method of intake, blood
inflammatory cytokines. Where disagreements regarding
extracted data arose, a third investigator was consulted.
Quality assessment was adjudicated in the present study
using the Cochrane Handbook of Systematic Reviews.
Included trials were considered as having a high, low, or
unclear level of bias in each of the seven categories.
Statistical analysis
The extracted data were the mean and standard deviation
(SD) for inflammatory factors in each of the included trials.
When the mean and SD of change were not reported, they
were calculated using the following formulas: mean change
¼mean endpoint – mean baseline, SD change ¼ square root [(SD
baseline)
2
þ (SD endpoint) 2
(2 R  SD baseline  SD endpoint)]
(R ¼ 0.5). Experimental outcomes reported as the standard
error (SE), 95% confidence interval (CI), median, and range
(or interquartile range) were calculated in the meta-analysis
after conversion into the mean and SD (Higgins and Green
2011; Hozo, Djulbegovic, and Hozo 2005). When the inflam-
matory factors in a study were detected with more than one

Figure 1. Flow chart of study selection.
measurement, only the longest one was calculated. The stat-
istical significance of changes between the intervention and
placebo groups was expressed as standardized mean differ-
ence (SMD) and the extent of heterogeneity was estimated
with I2 index. The low, moderate and high level of hetero-
geneity are expressed by I2 index higher than 25%, 50%, and
75%, respectively. We used a random-effects model
(DerSimonian-Laird, D-L) when heterogeneity test was stat-
istically significant or I2 >50%, or, with a fixed-effects
model (Inverse Variance, IV). A pre-planned subgroup anal-
yses were performed to explore the effects of various factors
on the inflammatory biomarkers by age (>50 versus
50 years), BMI (<30 versus 30 years), healthy status,
smoking habits, supplementation duration (>12 weeks ver-
sus 12weeks), sample size, gender, OA source, difference
of OA dose in intervention and control, the primary type of
fatty acid in placebo, and the baseline concentration. Meta-
regression analyses were investigated using a maximum like-
lihood method to analyze the association between effect size
of inflammatory markers and continuous variables (age,
BMI, duration, OA dose difference and the baseline
concentration).
We performed potential internal sensitivity by repeated
analyses with the omission of one trial. The potential exist-
ence of publication bias was assessed using visual inspection
of funnel plots and quantitatively investigated by the Begg’s
and Egge’s tests. All statistical analyses were generated using
STATA 14.0 software (Stata Corp, College Station, TX).
P < 0.05 were considered statistically significant.
Results
From the initial relevant citations, 719 trials were searched
after removing duplicates. By screening the titles and
abstracts, 652 studies were omitted because there were no
apparent correlations with the research topic. The remaining
67 full studies were analyzed entirely, and of those, 31
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 3
studies met inclusion criteria for the meta-analysis (as pre-
sented in Figure 1).
Characteristics of included studies
The detailed characteristics of the trials between 1998 and
2018 included in the meta-analysis are summarized in Table
1. The studies included 1634 participants with sample sizes
that varied between 14 and 195 participants. Eight trials
included only male subjects (Damsgaard et al. 2008;
Ghafoorunissa, Laxmi, and Sesikeran 2002; Karatzi et al.
2012; Kruse et al., 2015; Lichtenstein et al. 2006; Minihane
et al. 2005; Pfeuffer et al. 2011; Thijssen, Hornstra, and
Mensink 2005), while ten studies were conducted with all-
female participants (Atefi, Pishdad, and Faghih 2018;
Bumrungpert, Pavadhgul, and Kalpravidh 2016; Candido
et al. 2018; Foster, Petocz, and Samman 2013;
Ghafoorunissa, Laxmi, and Sesikeran 2002; Haghighatdoost
et al. 2012; Lichtenstein et al. 2006; Silver et al. 2014;
Thijssen, Hornstra, and Mensink 2005). The mean BMI of
subjects ranged from 21.9 (Voon et al. 2011) to 35.7 (Miller
et al. 2016) and the average age ranged from 25 (Freese et
al. 2004) to 72 (Rozati et al. 2015) years old. Trials were
conducted in various populations, including healthy (11 tri-
als), overweight or obese (nine trials), type 2 diabetes (two
trials), hypercholesterolemia (three trials), hyperlipidemia
(one trial), hyperfibrinogenaemia (one trials), hypertensive
(one trial), metabolic syndrome (one trial), CVD risk (one
trial), and chronic peripheral artery occlusive disease (one
trial). Two-thirds of the studies were performed in Europe
(12 studies, seven countries) (Damsgaard et al. 2008; Freese
et al. 2004; Junker et al. 2001; Karatzi et al. 2012;
Kontogianni et al. 2013; Kruse et al. 2015; Minihane et al.
2005; Pfeuffer et al. 2011; Stricker et al. 2008; Thijssen,
Hornstra, and Mensink 2005; Turpeinen, Basu, and Mutanen
1998; Vafeiadou et al., 2015), and Asia (eight trials, five coun-
tries) (Atefi, Pishdad, and Faghih 2018; Bumrungpert,
Pavadhgul, and Kalpravidh 2016; Ghafoorunissa, Laxmi, and
Table 1. Characteristics of 32 randomized controlled trials selected for meta-analysis. 4

Study and year Country Subjects information Age BMI Smoking No. M/F Duration Design OA dose (source) Markers
(Atefi, Pishdad, and Iran Type 2 diabetes 58 28.6 Mixed 77 0/77 4 weeks P I: 21.8 g (olive oil) CRP
Faghih 2018) I: 17.8 g (canola oil)
C: 8.3 g
(sunflower oil)
(Baril-Gravel et al. 2015) Canada Abdominal obesity 48 29.9 NR 114 54/60 4 weeks CO I: 42.9 g (canola oil) CRP, IL-6,
I: 37.7 g (canola oil) Adiponectin
Q. WANG ET AL.

C: 10.7 (flaxseed
and safflower oil)
(Bumrungpert, Pavadhgul, Thailand Hypercholesterolemia 47 25.4 Nonsmoker 50 0/50 8 weeks P I: 33 ml (camellia CRP, IL-6, TNF
and Kalpravidh 2016) oil)
C: 12 ml
(soybean oil)
(Candido et al. 2018) Brazil Overweight or obese 27 30.1 Nonsmoker 41 0/41 9 weeks P I: (25 ml olive oil) IL-6, TNF
C: (25 ml
soybean oil)
(Damsgaard et al. 2008) Denmark Healthy 25 23.2 Mixed 33 33/0 8 weeks P I: 21.1 g(rapeseed CRP, IL-6, sVCAM-1,
oil and butter) Adiponectin
C:11.3g (sunflower
oil and margarine)
(de Oliveira et al. 2017) Brazil Overweight or obese 67 33.5 Nonsmoker 76 23/53 90 days P I: 22.6 ml (olive oil) CRP
C: 6.2 ml (flaxseed
oil)
C: 9.7 ml
(sunflower oil)
(Foster, Petocz, and Australia Type 2 diabetes 65 28.6 Nonsmoker 24 0/24 12 weeks P I: 1.5 g (olive oil) CRP, IL-6, TNF
Samman 2013) C: 0 g (flaxseed oil)
(Freese et al. 2004) Finland Healthy 25 22.5 Mixed 38 10/28 6 weeks P I: 32 g (NR) CRP, sICAM-1,
C: 11.7 g (NR) sP-selectin
(Freese et al. 2004) Finland Healthy 25 22.6 Mixed 39 10/29 6 weeks P I: 32.6 g (NR) CRP, sICAM-1,
C: 11.9 g (NR) sP-selectin
(Ghafoorunissa, Laxmi, and India Healthy 43 24 Nonsmoker 40 40/0 4 months P I: 29.1 g (groundnut Fibrinogen
Sesikeran 2002) and canola oil)
C: 24.3 g (sunflower
and canola oil)
(Ghafoorunissa, Laxmi, and India Healthy 37 25 Nonsmoker 40 0/40 4 months P I: 24.7 g (groundnut Fibrinogen
Sesikeran 2002) and canola oil)
C: 19 g (sunflower
and canola oil)
(Gillingham et al. 2011) Canada Hypercholesterolemia 47 28.6 Nonsmoker 39 14/25 4 weeks CO I: 63.5 g (high-OA CRP, IL-6, sICAM-1,
rapeseed oil) sVCAM-1,
C: 44.2 g (flaxseed sE-Selectin
and high-OA
rapeseed oil)
C: 44.8 g
(western diet)
(Haghighatdoost et al. 2012) Iran Overweight 35 27.6 NR 17 0/17 6 weeks CO I: 25.5 g (olive oil) IL-6
premenopausal women C: 14.1 g (butter)
(Han et al. 2012) Korea Moderately 63 26.7 Nonsmoker 18 7/11 35 days CO I: 49.6 g (high-OA CRP
hypercholesterolemia soybean oil)
C: 17.7 g
(soybean oil)
(Junker et al. 2001) Germany Healthy 26 23.1 Nonsmoker 58 31/27 4 weeks P I: 60.2 g (olive oil) CRP, Fibrinogen, P-
C: 24.2 g selectin, PAI-
(sunflower oil) 1 activity
(Karatzi et al. 2012) Greece Hypertensive 53 28.1 Mixed 30 30/0 60 days P I: (35 g olive oil) CRP, TNF, sICAM-1
C: (35 g sesame oil)
Study and year Country Subjects information Age BMI Smoking No. M/F Duration Design OA dose (source) Markers
(Kontogianni et al. 2013) Greece Healthy 26 21.9 NR 37 8/29 6 weeks CO I: 11.3 g (olive oil) CRP, TNF,
C: 3 g (flaxseed oil) Adiponectin
(Kruse et al. 2015) Germany Moderately obese 55 29.5 NR 18 18/0 4 weeks P I: (50 g olive oil) CRP
C: (50 g
rapeseed oil)
(Lefort, Leblanc, and Canada Healthy 31 25.5 NR 48 26/26 28 days P I: 7.6 ml (high-OA IL-6, TNF
Surette 2017) sunflower oil)
C: 0.9 ml
(Arvensis oil)
(Lichtenstein et al. 2006) US Moderately hyperlipidemia 64 25.7 NR 14 14/0 35 days CO I: 57.5 g (high-OA CRP
soybean oil)
C: 20.4 g
(soybean oil)
(Lichtenstein et al. 2006) US Moderately hyperlipidemia 61 26.7 NR 16 0/16 35 days CO I: 46.7 g (high-OA CRP
soybean oil)
C: 16.6 g
(soybean oil)
(Miller et al. 2016) US Metabolic syndrome 61 35.7 NR 38 15/23 6 months P I: 10.3 g (high-OA CRP, TNF
sunflower oil)
C: 2 g (safflower oil)
(Minihane et al. 2005) UK Healthy 48 26 Nonsmoker 29 29/0 6 weeks P I: 43 g (olive oil) CRP
C: 25 g (corn oil)
(Pfeuffer et al. 2011) Germany Overweight or obese 59 28.3 Mixed 61 61/0 4 weeks P I: (4.5 g olive oil) CRP, sICAM-1,
C: (4.5 g sVCAM-1,
safflower oil) sE-Selectin
(Rozati et al. 2015) US Overweight or obese 72 29 Nonsmoker 41 14/27 3 months P I: 29 g (olive oil) IL-6, TNF
C: 9 g (corn and
soybean oil)
(Scholtz et al. 2004) South Africa Hyperfibrinogenaemic 48 28.7 Mixed 56 36/20 4 weeks P I: 11.7 g (red palm Fibrinogen, PAI-
olein) 1 activity
C: 4.6 g
(sunflower oil)
(Silver et al. 2014) US Obesity 37 35.1 Nonsmoker 91 0/91 16 weeks P I: 9 g (oleate) IL-6, TNF, PAI-
C: 0 g (linoleate) 1 Antigen
C: 0 g (stearate)
C: 0 g (placebo)
(Stricker et al. 2008) Switzerland Chronic peripheral artery 65 NR Mixed 40 27/13 8 weeks P I: 13.2 g (canola oil) CRP, PAI-1 antigen
occlusive disease C: 3.3 g
(sunflower oil)
(Teng et al. 2017) Malaysia Abdominal obesity 33 28.7 Nonsmoker 47 12/35 6 weeks CO I: 36.9 g (high-OA CRP, IL-6, sE-
sunflower oil) selectin, PAI-
C: 20.6 g (palm 1 activity
olein blended
sunflower oil)
(Teng et al. 2010) Malaysia Healthy 29 21.9 NR 41 8/33 5 weeks CO I: 37.8 g (high-OA CRP, IL-6, TNF
palm olein)
(continued)
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION
5
 6 Q. WANG ET AL.

Sesikeran 2002; Haghighatdoost et al. 2012; Han et al. 2012;

sICAM-1, sVCAM-
1, sE-selectin,
Fibrinogen, PAI-
Teng et al. 2017; Teng et al. 2010; Voon et al. 2011). The

Fibrinogen, PAI-

CRP, IL-6, TNF,

Markers

CRP, IL-6, TNF

sP-selectin
1 activity remaining countries were four studies in the US (Lichtenstein

1 activity
et al. 2006; Miller et al. 2016; Rozati et al. 2015; Silver et al.

sICAM-1
2014), three in Canada (Baril-Gravel et al. 2015; Gillingham
et al. 2011; Lefort, Leblanc, and Surette 2017), two in Brazil
(Candido et al. 2018; de Oliveira et al. 2017), one study each

Mixed both smokers and nonsmokers were included in the study, BMI: body mass index; F: female; M: male; P: parallel; CO: crossover; I: intervention; C: control; OA oleic acid; NR: nor reported.
C: 31 g (high-LA in Australia (Foster, Petocz, and Samman 2013) and South
OA dose (source)

I: 38.4 g (olive and

I: 46.5 g (olive oil)

I: 51.6 g (high-OA
sunflower oil)

sunflower oil)

(safflower oil)
C: 15.3 g (NR)
C: 14.9 g (NR)

C: 15.3 g (NR)
C: 14.9 g (NR)

rapeseed oil)
Africa (Scholtz et al. 2004). Nonsmoking participants were

(coconut oil)
I: 29.6 g (NR)

I: 29.6 g (NR)
(palm oil)

included in 15 trials, while eight studies were attended in the

C: 27.2 g

C: 26.3 g

C: 15.2 g
subjects of mixed smokers. Overall, the duration of treatment
in individual trials ranged from 4 weeks to 24 weeks, with
most trials lasting for 4 to 8 weeks. About a third of the
articles used a crossover test design, while the remaining part
Design

used a parallel test pattern. The difference of OA dosage var-

CO

CO

CO
P

ied from 1.5 g (Foster, Petocz, and Samman 2013) to 37.1 g

(Lichtenstein et al. 2006) per day in intervention groups com-
16 weeks
Duration

pared with control groups. Only one (Silver et al. 2014) study
5 weeks

5 weeks

4 weeks

5 weeks

has reported the effect of pure oleate on inflammatory cyto-

kines. In addition, most randomized controlled trials were
conducted to study the effect of the difference in oleic acid
18/0

0/27

18/18

85/110

9/36
M/F

intake by adding edible oils with different fatty acid composi-

tions. In 21 trials, the primary forms of oleic acid supple-
ments were olive oil (Atefi, Pishdad, and Faghih 2018;
18

27

38

195

45
No.

Candido et al. 2018; de Oliveira et al. 2017; Foster, Petocz,

and Samman 2013; Haghighatdoost et al. 2012; Junker et al.
2001; Karatzi et al. 2012; Kontogianni et al. 2013; Kruse et al.
Nonsmoker

Nonsmoker

Nonsmoker

Nonsmoker
Smoking

2015; Minihane et al. 2005; Pfeuffer et al. 2011; Rozati et al.

Mixed

2015; Vafeiadou et al. 2015; Voon et al. 2011) and canola oil
(Atefi, Pishdad, and Faghih 2018; Baril-Gravel et al. 2015;
Ghafoorunissa, Laxmi, and Sesikeran 2002; Stricker et al.
24.1

26.7

23.1
BMI

2008). High-OA soybean oil (Han et al. 2012; Lichtenstein

NR
26

et al. 2006) and high-OA sunflower oil (Lefort, Leblanc, and

Surette 2017; Miller et al. 2016; Teng et al. 2017; Turpeinen,
Age

51

51

27

44

30

Basu, and Mutanen 1998) were tested in three and four trials,
respectively. One study did not explain the source of OA
(Thijssen, Hornstra, and Mensink 2005), while other studies
Subjects information

used camellia oil (Bumrungpert, Pavadhgul, and Kalpravidh

2016), rapeseed oil (Damsgaard et al. 2008; Gillingham et al.
2011), red palm oil (Scholtz et al. 2004) and high oleic palm
oil (Teng et al. 2010) as the source of OA. Oils with minimal
amounts of OA were supplemented in the control group,
CVD risk
Healthy

Healthy

Healthy

Healthy

such as sunflower oil, flaxseed oil, soybean oil, safflower oil,

sesame oil, rapeseed oil, corn oil, coconut oil, or arvensis oil.
Netherlands

Netherlands

Risk of bias and evidence certainty

Country

Malaysia
Finland

The risk of bias to appraise the quality of research is sum-

UK

marized in Table 2. We found the method for generating

the randomization sequence was low risk in 12 studies and
unclear in the remainder. Only seven studies were low risk
in allocation concealment, and the residual studies were
(Thijssen, Hornstra, and

(Thijssen, Hornstra, and

(Vafeiadou et al. 2015)

(Turpeinen, Basu, and

unclear. A multitude of experiments showed double-blind

Table 1. Continued.

Mutanen 1998)

(Voon et al. 2011)

Mensink 2005)

Mensink 2005)

design where participants and personnel were blinded if not

Study and year

specified elsewhere, and not outcome assessments. Nearly a

third of the experiments were recognized as having a high
risk of bias because of their single-blind designs. Six trials
were considered as possessing a low risk of bias in blinding
 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 7

Table 2. Quality assessment of the included studies using Cochrane.

Study
Atefi, Pishdad, and
Faghih 2018
Baril-Gravel et al. 2015
Bumrungpert, Pavadhgul,
and Kalpravidh 2016
Candido et al. 2018
Damsgaard et al. 2008
de Oliveira et al. 2017
Foster, Petocz, and
Samman 2013
Freese et al. 2004
Ghafoorunissa, Laxmi, and
Sesikeran 2002
Gillingham et al. 2011
Haghighatdoost et al. 2012
Han et al. 2012
Junker et al. 2001
Karatzi et al. 2012
Kontogianni et al. 2013
Kruse et al. 2015
Lefort, Leblanc, and
Surette 2017
Lichtenstein et al. 2006
Miller et al. 2016
Minihane et al. 2005
Pfeuffer et al. 2011
Rozati et al. 2015
Scholtz et al. 2004
Silver et al. 2014
Stricker et al. 2008
Teng et al. 2017
Teng et al. 2010
Thijssen, Hornstra, and
Mensink 2005
Turpeinen, Basu, and
Mutanen 1998
Vafeiadou et al. 2015
Voon et al. 2011
L: low risk of bias; H: high risk of bias; U: unclear risk of bias.
Random
sequence Allocation
generation concealment
L U
U U
U U
L L
L L
U U
L U
U U
U U
L L
L U
U U
U U
U U
L L
U U
U U
U U
U U
U U
U U
U L
U U
U U
L U
L L
L U
U U
U U
L U
L L
Blinding of Blinding of Selective
participants outcome Incomplete outcome
and personnel assessments outcome data reporting Other bias
U U L L L
L U L L L
H U L U L
L L L U L
L L L L L
L L U U L
L L L L L
U U L U L
U U L U L
H U L L L
H U L L L
L L L U L
U U L U L
U U U U L
H U L U L
U U L U L
L U L L L
L L L U L
U U H U L
L U L U L
L U L U L
H U L U L
H H L U L
L U U L L
L U L U L
H U L L L
H U L L L
U U L U L
L U L U L
H H L L L
U U L L L

of outcome assessments, and the remainder were rated as
having an unclear risk of bias except for two trials.
Furthermore, twelve trials provided a study protocol, and all
primary and secondary outcomes were classified as low risk
for selective reporting. None of the included studies were
ultimately identified as having other sources of bias.
Meta-analysis results
Cytokines
As presented in Figure 2A and B, the pooled effect size of
dietary OA consumption was 0.01 (95% CI:
0.10, 0.13;
P ¼ 0.849) for IL-6 and
0.05 (95% CI:
0.19, 0.10;
P ¼ 0.534) for TNF, indicating non-significance. Because the
studies for heterogeneity were not clearly defined for IL-6
and TNF (I2 ¼0.0%), we showed the results adopting the
fixed-effects model.
Acute-phase reactants
The results from 26 comparisons (21 trials) demonstrated
that the plasma concentration of CRP decreased more sig-
nificantly for OA supplementation compared with other
fatty acids (SMD¼
0.11, 95% CI
0.21,
0.01; P ¼ 0.038)
(Figure 3A). Moreover, the I2 value was 7.9%, indicating no
significant heterogeneity among the included studies. As
shown in Figure 3B, meta-analysis from six comparisons
with four studies revealed that higher OA supplementation
did not impact fibrinogen concentration (SMD ¼ 0.08, 95%
CI
0.16, 0.31; P ¼ 0.520). Likewise, the overall effect size
was
0.11 (95% CI:
0.34, 0.12; P ¼ 0.355), showing indif-
ferent effects of OA supplementation on PAI-1 activity
(Figure 3C). No heterogeneity existed among different trials
for fibrinogen and PAI-1 activity (I2 ¼0.0%).
Adhesion molecules
Both soluble intracellular adhesion molecule-1 (sICAM-1)
and soluble vascular cellular adhesion molecule-1 (sVCAM-
1) were unaffected by OA dose (Figure 4A and B). The
overall effect sizes were 0.05 (95% CI:
0.14, 0.24;
P ¼ 0.595) for sICAM-1 and
0.04 (95% CI:
0.26, 0.18;
P ¼ 0.701) for sVACM-1. A low level of heterogeneity was
observed among the seven comparisons involving sICAM-1
(I2 ¼ 0%), while moderate levels of heterogeneity was dis-
covered in sVACM-1 (I2 ¼ 46.1%).
Furthermore, only four studies included plasma sP-selec-
tin, sE-selectin, and adiponectin, respectively. As
8 Q. WANG ET AL.

Figure 2. Forest plot of the effect of OA supplementation on TNF (A) and IL-6 (B).
 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 9

Figure 3. Forest plot of the effect of OA supplementation on CRP (A), fibrinogen (B) and PAI-1 activity (C).
10 Q. WANG ET AL.

Figure 4. Forest plot of the effect of OA supplementation on sICAM-1 (A) and sVCAM-1 (B).

summarized in Table 3, no changes or heterogeneity was Subgroup analysis

detected with increasing OA intake.
The results of subgroup analysis for CRP, TNF, IL-6, and
sICAM-1 is presented in Table 4. Taken together, the
 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 11

subgroup analyses of TNF, IL-6, and sICAM-1 were not
altered among age, BMI, smoking habits, gender, duration,
OA dose, OA source, the primary fatty acid in control, the
baseline concentration of inflammatory markers, or health
status. Nevertheless, plasma CRP concentration was more
significantly reduced with OA consumption compared with
other fatty acids in the subgroups with 50 years of age par-
ticipants (SMD ¼
0.13, 95% CI:
0.25,
0.01), the
12 weeks intervention duration subgroup (SMD ¼
0.14,
95% CI:
0.25,
0.03), and the <30 BMI group (SMD ¼

0.12, 95% CI:
0.23,
0.02). In studies with female sub-
jects (SMD ¼
0.36, 95% CI:
0.64,
0.07), mixed smokers
(SMD ¼
0.24, 95% CI:
0.47,
0.01), the baseline
Table 3. Pooled effect size for inflammatory markers with limited number of
eligible studies.
Markers No. of comparisons Effect size (95% CI)
Adiponectin 4 0.13 (
0.07, 0.32)
sE-selectin 4
0.18 (
0.39, 0.02)
sP-selectin 4
0.02 (
0.25, 0.21)
concentration greater than the median (SMD ¼
0.19, 95%
CI:
0.36,
0.02), LA as the control group (SMD ¼
0.14,
95% CI:
0.28, 0.00), and healthy subjects (SMD ¼
0.21,
95% CI:
0.40,
0.02), dietary OA consumption exerted a
significant decrease in plasma CRP concentration.
Furthermore, we evaluated the relationship between
inflammatory marker changes and continuous variate using
univariate meta-regression analysis. As shown in Figure 5, the
results demonstrated an inverse association of the changes in
effect size of CRP with the baseline concentration (coefficient:

0.034, 95% CI:
0.072 to
0.004; P ¼ 0.043). Nevertheless,
Changes in other inflammatory factors had no significant lin-
ear relationship with continuous variates (data not shown).
Sensitivity analysis indicated that systematic removal of each
specific trial did not significantly change the overall results of
dietary OA consumption on inflammatory factors.
I-square
0.0% Publication bias
0.0%
0.0% As summarized in Figure 6, visual inspection of the funnel
plots did not confirm any evidence of publication bias with

Table 4. Pooled effect on selected inflammatory markers in various subgroup.

CRP TNF IL-6 sICAM-1
Subgroup N SMD (95% CI) I2 % N SMD (95% CI) I2 % N SMD (95% CI) I2 % N SMD (95% CI) I2 %
Dose difference
Median 16
0.07(
0.18, 0.05) 18.8 5
0.04(
0.24, 0.16) 0.0 9 0.02(
0.11, 0.16) 0.0 5 0.08(
0.12, 0.29) 0.0
<Median 10
0.23(
0.43,
0.04) 0 7
0.05(
0.26, 0.16) 19.4 6
0.03(
0.26, 0.21) 38.5 2
0.13(
0.61, 0.36) 0.0
Age
>50 12
0.06(
0.24, 0.12) 12.7 4
0.07(
0.42, 0.28) 0.0 2 0.04(
0.47, 0.54) 14.5 2
0.13(
0.61, 0.36) 0.0
50 14
0.13(
0.25,
0.01) 8.1 8
0.04(
0.20, 0.12) 4.9 13 0.01(
0.11, 0.13) 0.0 5 0.08(
0.12, 0.29) 0.0
BMI
30 2 0.13(
0.26, 0.52) 62.9 3
0.28(
0.60, 0.04) 19.8 2
0.12(
0.49, 0.25) 4.5
<30 23
0.12(
0.23,
0.02) 3.3 9 0.01(
0.15, 0.17) 0.0 13 0.03(
0.10, 0.15) 0.0 6 0.05(
0.15, 0.25) 0.0
NR 1
0.26(
0.88, 0.37) 1 0.09(
0.55, 0. 72)
Smoking
Nonsmoker 10
0.01(
0.16, 0.14) 22.5 7
0.12(
0.30, 0.06) 0.0 9
0.01(
0.16, 0.15) 0.0 2 0.00(
0.25, 0.26) 0.0
Mixed 8
0.24(
0.47,
0.01) 0.0 1 0.04(
0.68, 0.76) 1 0.31(
0.39, 1.01) 5 0.12(
0.18, 0.41) 0.0
NR 8
0.16(
0.32, 0.00) 0.0 4 0.11(
0.15, 0.36) 0.0 5 0.02(
0.17, 0.20) 27.7
Gender
Male 6 0.08(
0.20, 0.36) 0.0 1 0.04(
0.68, 0.76) 1 0.31(
0.39, 1.01) 2
0.13(
0.61, 0.3) 0.0
Female 5
0.36(
0.64,
0.07) 0.0 4
0.27(
0.56, 0.02) 0.0 5
0.13(
0.39, 0.14) 0.0
Both 15
0.10(
0.22, 0.01) 23.3 7 0.03(
0.14, 0.20) 0.0 9 0.04(
0.10, 0.17) 0.0 5 0.08(
0.12, 0.29) 0.0
Duration
>12 weeks 3 0.04(
0.20, 0.28) 33.6 3
0.22(
0.46, 0.01) 10.2 2
0.11(
0.36, 0.14) 0.0 1 0.06(
0.24, 0.36)
12 weeks 23
0.14(
0.25,
0.03) 1.4 9 0.06(
0.12, 0.24) 0.0 13 0.04(
0.09, 0.18) 0.0 6 0.05(
0.20, 0.30) 0.0
Intervention
Olive oil 11
0.11(
0.27, 0.05) 39.6 7
0.02(
0.20, 0.16) 0.0 6
0.03(
0.23, 0.17) 0.0 3 0.01(
0.25, 0.26) 0.0
Canola oil 4
0.20(
0.40, 0.01) 0.0 2
0.01(
0.23, 0.22) 0.0
Rapeseed oil 2 0.16(
0.22, 0.55) 0.0 2 0.24(
0.15, 0.62) 0.0 1
0.12(
0.58, 0.34)
High-OA soybean oil 3 0.12(
0.19, 0.44) 0.0
High-OA sunflower oil 2
0.14(
0.49, 0.20) 0.0 2
0.00(
0.45, 0.44) 0.0 2
0.11(
0.45, 0.23) 0.0 1 0.09(
0.55, 0.72)
High-OA palm oil 1
0.10(
0.53, 0.34) 1 0.26(
0.18, 0.69) 1 0.42(
0.02, 0.86)
NR 3
0.35(
0.70, 0.00) 7.9 2
0.38(
0.74,
0.03) 0.0 2
0.14(
0.49, 0.22) 0.0 2 0.34(
0.11, 0.80) 32.8
Main fatty acid in the placebo
SFA 3
0.02(
0.26, 0.22) 0.0 2 0.13(
0.17, 0.43) 0.0 4 0.07(
0.16, 0.30) 22.5
LA 16
0.14(
0.28, 0.00) 0.0 7
0.14(
0.33, 0.05) 0.0 6 0.00(
0.19, 0.20) 0.0 6 0.09(
0.12, 0.30) 0.0
ALA 7
0.11(
0.28, 0.06) 46.6 3 0.04(
0.30, 0.38) 0.0 5
0.02(
0.21, 0.17) 0.0 1
0.12(
0.58, 0.34)
Nulla 1
0.52(
0.98,
0.06 1
0.26(
0.72, 0.19)
Baseline concentration
>Median 12
0.19(
0.36,
0.02) 14.1 8
0.03(
0.21, 0.15) 7.6 6 0.02(
0.18, 0.23) 24.3
0.05(
0.43, 0.34) 0.0
Median 14
0.07(
0.19, 0.06) 0 4
0.07(
0.31, 0.17) 0.0 9 0.00(
0.14, 0.15) 0.0 0.08(
0.14, 0.30) 15.6
Health status
Healthy 8
0.21(
0.40,
0.02) 22.8 4 0.12(
0.11, 0.35) 0.0 4 0.11(
0.14, 0.36) 38.2 3 0.26(
0.11, 0.63) 0.0
Unhealthy 18
0.07(
0.19, 0.04) 0.0 8
0.15(
0.33, 0.03) 0.0 11
0.01(
0.15, 0.12) 0.0 4
0.02(
0.25, 0.20) 0.0
Overweight or obese 7
0.03(
0.20, 0.13) 5.7 3
0.19(
0.50, 0.13) 46.6 7
0.03(
0.19, 0.13) 0.0 1
0.08(
0.70, 0. 54)
Type 2 diabetes 3
0.59(
1.01,
0.16) 0.0 1
0.33(
1.21, 0.56) 1
0.36(
1.25, 0.52)
Dyslipidemia 4 0.04(
0.22, 0.31) 0.0 1
0.18(
0.74, 0.37) 2 0.14(
0.22, 0.50) 0.0 1
0.12(
0.58, 0.34)
Other diseases 4
0.09(
0.33, 0.15) 0.0 3
0.10(
0.36, 0.15) 0.0 1
0.04(
0.34, 0.26) 2 0.02(
0.26, 0.30) 0.0
a
The control group did not receive any supplement. SFA, saturated fatty acid; OA, oleic acid; LA, linoleic acid; ALA, a-linolenic acid; NR, not reported.
12 Q. WANG ET AL.
the effect of OA supplementation on CRP (Begg’s test:
p ¼ 0.078, Egger’s test: p ¼ 0.174), TNF (Begg’s test:
p ¼ 0.732, Egger’s test: p ¼ 0.952), IL-6 (Begg’s test
p ¼ 0.692, Egger’s test: p ¼ 0.878), or sICAM-1 (Begg’s test
p ¼ 0.368, Egger’s test: p ¼ 0.833).
Figure 5. Meta-regression plots of the association between mean changes in
blood CRP concentration with baseline concentration of CRP.
Figure 6. Funnel plots detailing publication bias in the studies selected for the analysis of OA’s effects on CRP (A), TNF (B), IL-6 (C) and sICAM-1 (D).
Discussion
This is the first meta-analysis assessing the effect of OA sup-
plementation on inflammatory biomarkers. Using 31 trials
of RCTs, this result revealed that dietary OA consumption
significantly decreased CRP. Nevertheless, OA supplementa-
tion did not significantly decrease the blood levels of inflam-
matory factors including cytokines and adhesion molecules.
Monounsaturated fatty acid (MUFA) and olive oil supple-
mentation have been associated with a reduction of risks of
CVD, type-2 diabetes, and other obesity-related diseases (
Schwingshackl et al. 2019; Schwingshackl, Strasser, and
Hoffmann 2011). Previous meta-analysis also showed that
the Mediterranean diet pattern and olive oil reduced CRP
and IL-6 levels (Nordmann et al. 2011; Schwingshackl,
Christoph, and Hoffmann 2015; Schwingshackl and
Hoffmann 2014). Oleic acid, a monounsaturated fatty acid,
is one of the major fatty acid constituents of the
Mediterranean diet pattern and olive oil (70%). However,
the effectiveness of OA supplementation on plasma inflam-
matory factors had not been previously reported.
IL-6 and TNF, the principal cytokines produced in vari-
ous tissues, play a detrimental role in cardiovascular disease
and other chronic diseases. Elevated concentrations of IL-6
and TNF are regarded as associated with increased CHD
risk (Danesh et al. 2008). Nevertheless, the evaluated pooled

findings showed no significant changes in the plasma con-
centrations of TNF or IL-6 after OA supplementation in our
study. In addition, none of the 15 included studies showed a
significant effect of OA intake on IL-6. Only one study in
which OA was supplemented in the form of oleate showed a
significant decrease in TNF levels (Silver et al. 2014), while
studies in which OA was supplemented in the form of vege-
table oil showed no significant decrease in TNF levels. The
low heterogeneity of TNF and IL-6 indicated the stability of
the meta-analysis and enhanced the rationality of our study.
Consistent with our results, in the subgroup analysis of the
meta-analysis, Schwingshackl et al. failed to observe any
beneficial effect of OA-rich olive oil on decreasing circulat-
ing IL-6 and TNF compared to other fatty acids
(Schwingshackl, Christoph, and Hoffmann 2015).
CRP is an acute reactive protein secreted by the liver and
is a sensitive nonspecific inflammatory marker that reflects
the severity of inflammation (Curb et al. 2003). Its expres-
sion is mainly regulated by interleukin-6, and partly regu-
lated by inflammatory factors such as TNF, IL-1, and IL-8
(Du Clos 2000; Heinrich, Castell, and Andus 1990;
Volanakis 2001; Woodward et al. 1999). CRP has been
accepted as the most robust and significant predictor of the
risk for CVD with several advantages such as a long half-life
and stable pentraxin structure over other inflammatory can-
didates (Ridker 2003). Oleic acid supplementation has been
demonstrated in animal and human models to reduce the
incidence of CVD and protect atherosclerosis by reducing
CRP levels (Danesh et al. 2004; El Seweidy et al. 2005).
Previous study showed that OA intake reduce serum con-
centrations of CRP (Basu, Devaraj, and Jialal 2006;
Yoneyama et al. 2007). In a prospective study, the intake of
OA was negatively associated with serum levels of CRP
(Migliori et al. 2015). A crossover clinical trial demonstrated
a six-week intervention of OA improved CRP concentrations
though did not have any beneficial effect on the other
plasma inflammatory markers (Kontogianni et al. 2013). The
results of a meta-analysis consisting of 15 RCTs indicated a
significant reduction of CRP concentrations in both healthy
and ill individuals following olive oil intake (Schwingshackl,
Christoph, and Hoffmann 2015). Likewise, our study dem-
onstrated a significant inverse association for OA supple-
mentation and the plasma CRP concentration. It has been
reported that the inhibitory effect of OA on CRP levels
might include two transcription factors: peroxisome prolifer-
ator-activated receptors (PPAR) (Borniquel et al. 2010) and
nuclear factor-kappa B (NF-jB) (Harvey et al. 2010).
Fibrinogen could tip the balance between coagulation and
fibrosis, hemostasis and thrombosis to increase the inflam-
matory status in target tissues (Adams et al. 2007; Davalos
and Akassoglou 2012). Plasma plasminogen activator inhibi-
tor-1 (PAI-1), one of the primary inhibitors of fibrinolysis,
is considered a core feature of metabolic syndrome and con-
nected with increased risk of cardiovascular events (Dellas
and Loskutoff 2005; Skurk and Hauner 2004). A residential
study found the effects of diets rich in stearic acid, oleic
acid, and linoleic acid (LA) did not significantly difference
on fibrinogen and PAI-1 activity in young healthy men
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 13
(Hunter et al. 2000). Margaret et al. concluded that substitu-
tion of saturated fatty acid (SFA) with monounsaturated
fatty acid from high-oleic-acid sunflower oil did not result
any difference in fibrinogen (Allman-Farinelli et al. 2005).
Recent in vitro studies also confirm fibrinogen and PAI-1
activity did not differ during consumption of the oleic acid
compared with the other fatty acids (Thijssen, Hornstra, and
Mensink 2005). Our results are consistent with the above
findings that dietary OA intake did not reduce the concen-
tration of fibrinogen or PAI-1 activity.
Cell adhesion molecules are a general term used to
describe the interactions and binding molecules in cell-cell
or cell-extracellular matrix interactions. sICAM-1 and
sVCAM-1, which are expressed by leukocytes and endothe-
lial cells, promote atherosclerotic processes at endothelial
surface due to an elevation of adhesion at the inflammatory
site by inducing adhesion and activation (Frank and Lisanti
2008; Habas and Shang 2018; Sarecka-Hujar, Zak, and
Krauze 2009). Studies have shown that plasma concentra-
tions of sICAM-1 and sVCAM-1 are associated with the
incidence of cardiovascular disease and may predict the risk
of future cardiovascular events (Mulvihill et al. 2002). In
this meta-analysis, neither sICAM-1 nor sVCAM-1 abun-
dance was affected by oleic acid intake. Recently, a meta-
analysis showed that olive oil can slightly reduce the
abundance of sICAM-1, but did not affect the plasma
sVCAM-1 concentration (Schwingshackl, Christoph, and
Hoffmann 2015). Pacheco et al. reported that olive oil with
high oleic acid intake was beneficially in regulating post-
prandial sICAM-1 and sVCAM-1 in patients with normo-
tensive and hypertensive hypertriglyceridemia (Pacheco et al.
2008). The results of in vitro experiments showed that oleic
acid acutely inhibited the cytokine-induced expression of
sICAM-1 and sVCAM-1, which are fully consistent with the
observations results (De Caterina, Liao, and Libby 2000).
However, previous study has shown that no differences were
observed in sICAM-1 and sVCAM-1 after the consumption
of high-oleic rapeseed oil compared with Western diet
(Gillingham et al. 2011). Compared with SFA and n-6
PUFAs, MUFAs intake to 9.5-9.6% of total energy had no
impact on cell adhesion molecules (Vafeiadou et al., 2015).
Also, Karatzi and Turpeinen reported that oleic acid supple-
mentation did not significantly reduce sICAM-1 concentra-
tion (Karatzi et al. 2013; Turpeinen, Basu, and Mutanen
1998). Due to the small number of studies included in
sICAM-1 and sVCAM-1, more studies are needed to further
assess the effects of dietary oleic acid.
Selectins (sP-selectin, sE-selectin, sL-selectin) are likely to
contribute to atherosclerosis, arterial and venous thrombosis,
ischemia-reperfusion injury, and other cardiovascular dis-
eases by mediating leukocyte adhesion and signaling at the
vascular wall (Cherian et al. 2003; McEver 2015;
Siemiatkowski et al. 2001). Accordingly, selectins have detri-
mental effects on the development of endothelial function
and the cardio-cerebral vascular system (Sprague and Khalil
2009). Conversely, adiponectin, an adipocyte-derived secre-
tory protein, could inhibit the expression of endothelial
adhesion molecules, cytokine expression in adipose tissue
14 Q. WANG ET AL.
and smooth muscle cell proliferation (Villarreal-Molina and
Antuna-Puente 2012). Adiponectin also has anti-apoptotic
and anti-oxidant effects, which play a role in athero-protect-
ive properties and anti-inflammatory effects (Maury and
Brichard 2010; Vaiopoulos et al. 2012). In the meta-analysis,
sP-selectin, sE-selectin, and adiponectin did not differ in
OA-rich olive oil compared with other fatty acids
(Schwingshackl, Christoph, and Hoffmann 2015). Our study
also did not show any effect of dietary OA intake on sP-
selectin, sE-selectin, and adiponectin. Given low number of
participants included in the RCTs evaluating these parame-
ters, more trials are needed to confirm this finding.
In our study, dietary OA intake reduced the concentra-
tion of CRP contrasting with linoleic acid (LA) as the con-
trol group, whereas OA did not decease the CRP level
contrasting with a-linolenic acid (ALA). Some studies pro-
posed that diet with abundant LA was prone to enhance the
level of CRP (Su et al. 2017). Since n-3 and n-6 PUFAs
share a metabolic pathway, increasing LA consumption
exerted a significant reduction of n-3 PUFAs and enhanced
prostaglandin E2 concentrations in animal tissues (Blair
et al. 1993; Schmitz and Ecker 2008). This subgroup analysis
revealed that different OA doses and sources from different
types of oils (olive oil, canola oil, high-OA soybean oil,
among others) did not significantly affect the overall results,
indicating that other fatty acids and minor components
might scarcely disturb inflammatory concentrations. The
subgroup of duration illustrated that OA supplementation
reduced the CRP concentration in intervention by no more
than 12 weeks. Only three studies reported the effect of oleic
acid on CRP concentration at intervention time >12 weeks,
and subgroup analysis were not significant. Data from
Miller and Vafeiadou indicated that oleic acid slightly
decreased CRP levels compare with n-6 polyunsaturated fatty
acids (Miller et al. 2016; Vafeiadou et al., 2015). Only one
study of de Oliveira proved that olive oil intake slightly
increased CRP concentration compare with a mixture of flax-
seed oil and sunflower oil in obese and overweight non-dia-
betic elderly patients (de Oliveira et al. 2017). The main cause
of this contradictory results in de Oliveira’s study appears to
be that the control group consumed large amounts of flaxseed
oil. Flaxseed oil contains a high concentration of ALA that
revealed anti-inflammatory properties (Rahimlou et al. 2019).
Some studies indicated flaxseed oil supplementation decreases
CRP levels (Lemos et al. 2012; Mirfatahi et al. 2016).
Additional studies with sufficient durations and large sample
sizes are needed to substantiate the beneficial impacts of
long-term OA consumption on CRP factors.
The subgroup analysis revealed that CRP concentration
more significantly decreased in the group where participants
had high baseline concentrations of CRP. Moreover, meta-
regression indicated that the effect size was negatively corre-
lated with baseline levels of CRP. In summary, these results
substantiated that OA supplementation significantly reduced
the CRP concentration in subjects with higher baseline con-
centrations than the median. This is “floor effect”: namely,
there is no chance for dietary OA consumption to diminish
the level of inflammatory factors when baseline
concentrations are very low. Some studies suggested that
OA reduced inflammatory factors in healthy subjects with
higher baseline concentrations than the median (Freese et al.
2004; Junker et al. 2001). There were no beneficial effects of
OA on inflammatory factors among the healthy subjects
with lower baseline concentrations than the median (Karatzi
et al. 2012; Minihane et al. 2005; Voon et al. 2011). People
with chronic diseases or their risk factors such as obesity,
hypertension and dyslipidemia had higher inflammation
markers than healthy people (Libby 2002; Packard and
Libby 2008). The stratified analysis of this meta-analysis
showed that OA intake in unhealthy subjects was associated
with a slight, though not significant, reduction in inflamma-
tory factors. The further analysis detected that OA intake
also slightly reduced the concentration of inflammatory bio-
markers in participants with different pathologies such as
overweight or obese participants, and type 2 diabetes partici-
pants. These subjects may be undergoing pharmacotherapy
that affects the baseline concentrations of inflammatory fac-
tors, although this has not been interpreted. Naugler et al.
reported that estrogen inhibited IL-6 production to reduce
liver cancer in females (Naugler et al. 2007). Additionally, pre-
vious studies reported that smoking (van Dijk et al. 2013; Xue
et al. 2019) and BMI (Elfeky et al. 2017) also enhanced blood
concentrations of inflammatory biomarkers. Nevertheless, the
inflammatory markers failed to vary among different sub-
groups of smoking and BMI except that blood CRP was
decreased in subjects with a BMI <30 and the mixed smoking
group. A recent study confirmed that gender and menopause
impacted inflammation, which could confuse the relationship
between OA and inflammation (Vetter et al., 2013). We found
that the subgroup of female subjects OA reduced CRP while it
was ineffective in the male subjects.
Our meta-analysis has several limitations. Firstly, in this
meta-analysis, the majority trials were conducted on relatively
small populations (no more than 200 subjects) and were of
relatively short duration (no more than 16 weeks). Thereby,
more precise randomized clinical trials are needed for future
intervention studies. Secondly, there are other fatty acids and
bioactive components in vegetable oils with high OA, which
may confuse the impact of OA on inflammatory mediator
concentrations. Some research provided incomplete informa-
tion such as the source of supplementation, the primary fatty
acids in the controls, and the health status of the included
subjects. These studies consequently could not be accurately
divided, which affected the results of subgroup analysis to
some extent. As two-thirds of the trials in this study were
performed in Europe and the United States, this research
must be cautiously interpreted in populations to other popu-
lations. Finally, other potential factors might affect the
strength of the results, including a high risk of bias in the
study design, and potential publication bias of the pub-
lished studies.
Conclusion
In conclusion, our systematic review and meta-analysis sug-
gested that OA supplementation exerted a significant

reduction in the blood concentration of CRP. However, this
study found that increasing OA supplementation had no sig-
nificant effects on blood concentrations of TNF, IL-6,
fibrinogen, PAI-1 activity, sICAM-1, or sVCAM-1.
Author contribution statement
X.W and Q.J designed the study. Q.W and M.C conducted
systematic research and extracted data. Q.W and R.L ana-
lyzed data and interpreted results. All authors read and
approved the final manuscript.
Disclosure statement
The authors declare no conflict of interest.
Funding
This study is supported by the program of “Collaborative innovation
center of food safety and quality control in Jiangsu Province.”
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