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\begin{document}

\title{Camelina oil in the context of a weight loss programs improves glucose
homeostasis, inflammation and oxidative stress in NAFLD patients: A
randomized, triple -blind, placebo-controlled clinical trial}



\author[1]{vali musazadeh}%
\author[1]{parvin dehghan}%
\author[2]{sevda salehghadimi}%
\author[1]{Mahdieh Abbasalizad-Farhangi}%
\affil[1]{Tabriz University of Medical Sciences}%
\affil[2]{Arak University of Medical Sciences}%


\vspace{-1em}



  
  \date{June 13, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background: Over the past few years, the benefits of co-administration
of omega-3 and antioxidants have been reported in the management of
non-alcoholic fatty liver disease (NAFLD) complications.This study
evaluated the effects of Camelina sativa oil (CSO) supplementation as
one of the richest dietary sources of omega-3 fatty acids on glucose
homeostasis,inflammation, metabolic endotoxemia, and oxidative stress in
NAFLD patients. Methods: In all, 43 subjects with NAFLD were allocated
to either an intervention (20g/d CSO) or placebo (20g/d sunflower oil)
group receiving a calorie-restricted diet for 12 weeks. Fasting serum
levels of glycemic indices, hs-CRP, endotoxin, antioxidant enzymes
activity, total antioxidant capacity (TAC), malondialdehyde (MDA),
8-iso-prostaglandin F2\selectlanguage{greek}α \selectlanguage{english}(8-iso-PGF2\selectlanguage{greek}α\selectlanguage{english}), and uric acid were measured at
baseline and post-intervention. Results: CSO intake led to a significant
decrease in insulin concentration (-17.49\%), homeostasis model
assessment of insulin resistance (HOMA-IR) (-20\%), high-sensitive
C-reactive protein (hs-CRP), (-12.94\%), lipopolysaccharide endotoxin
(-32.55\%), malondialdehyde (MDA) (-18.75\%), 8-iso-prostaglandin F2\selectlanguage{greek}α
\selectlanguage{english}(8-iso-PGF2\selectlanguage{greek}α\selectlanguage{english}) (-19.55\%) and a significant increase in the levels of
total antioxidant capacity (TAC) (31.82\%) and superoxide dismutase
activity (10.22\%) in the CSO group compared with the placebo group.
Also, there was no significant difference between the two groups in
fasting plasma glucose, quantitative insulin sensitivity check index
(QUICKI), catalase, glutathione peroxidase activity, and uric acid
level. In addition, within-group analyses showed a significant reduction
of insulin, QUICKI, hs-CRP, and endotoxin levels in the intervention
group. Conclusion: These findings indicate that CSO may improve
glycemic, inflammation, metabolic endotoxima, oxidative stress status,
and mental health in patients with NAFLD.%
\end{abstract}%



\sloppy


Camelina oil in the~context~of a~weight loss~programs \textbf{improves
glucose homeostasis, inflammation and oxidative stress in NAFLD
patients: A randomized, triple -blind, placebo-controlled clinical
trial}

\textbf{Abstract}

\textbf{Background:} Over the past few years, the benefits of
co-administration of omega-3 and antioxidants have been reported in the
management of non-alcoholic fatty liver disease (NAFLD)
complications.This study evaluated the effects of Camelina sativa oil
(CSO) supplementation as one of the richest dietary sources of omega-3
fatty acids on glucose homeostasis,inflammation, metabolic endotoxemia,
and oxidative stress in NAFLD patients.

\textbf{Methods:} In all, 43 subjects with NAFLD were allocated to
either an intervention (20g/d CSO) or placebo (20g/d sunflower oil)
group receiving a calorie-restricted diet for 12 weeks. Fasting serum
levels of glycemic indices, hs-CRP, endotoxin, antioxidant enzymes
activity, total antioxidant capacity (TAC), malondialdehyde (MDA),
8-iso-prostaglandin F2\selectlanguage{greek}α \selectlanguage{english}(8-iso-PGF2\selectlanguage{greek}α\selectlanguage{english}), and uric acid were measured at
baseline and post-intervention.

\textbf{Results:} CSO intake led to a significant decrease in insulin
concentration (-17.49\%), homeostasis model assessment of insulin
resistance (HOMA-IR) (-20\%), high-sensitive C-reactive protein
(hs-CRP), (-12.94\%), lipopolysaccharide endotoxin (-32.55\%),
malondialdehyde (MDA) (-18.75\%), 8-iso-prostaglandin F2\selectlanguage{greek}α \selectlanguage{english}(8-iso-PGF2\selectlanguage{greek}α\selectlanguage{english})
(-19.55\%) and a significant increase in the levels of total antioxidant
capacity (TAC) (31.82\%) and superoxide dismutase activity (10.22\%) in
the CSO group compared with the placebo group. Also, there was no
significant difference between the two groups in fasting plasma glucose,
quantitative insulin sensitivity check index (QUICKI), catalase,
glutathione peroxidase activity, and uric acid level. In addition,
within-group analyses showed a significant reduction of insulin, QUICKI,
hs-CRP, and endotoxin levels in the intervention group.

\textbf{Conclusion:} These findings indicate that CSO may improve
glycemic, inflammation, metabolic endotoxima, oxidative stress status,
and mental health in patients with NAFLD.

\textbf{Keywords:} Camelina; glycemic; metabolic endotoxima, oxidative
stress, inflammation, NAFLD

\textbf{What is already known about this topic?}

Some previous studies have shown the beneficial effects of camelina oil
in patients with hypercholesterolemia, and impaired glucose metabolism.
There have been no human studies investigating the effect of Camelina
oil supplementation on glucose homeostasis, inflammation, and oxidative
stress in NAFLD patients.

\textbf{What does this article add?}

This study is the first investigation in humans designed to evaluate the
effect of Camelina oil in the~context~of a~weight loss~programs improves
glucose homeostasis, inflammation and oxidative stress in NAFLD
patients. The present study was indicated that Camelina oil improved
glucose homeostasis, inflammation, and oxidative stress in patients with
NAFLD.

\textbf{1. Introduction}

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease
that characterized by the lipid~droplets accumulation in more than 5\%
of the hepatocytes. NAFLD encompasses a wide range from simple steatosis
to non-alcoholic steatohepatitis (NASH), advanced fibrosis, cirrhosis,
and hepatocellular carcinoma.\textsuperscript{1} The global prevalence
of NAFLD is estimated at nearly 25\% \textsuperscript{2}, and in Iran
was reported 33.9\%.\textsuperscript{3} The occurrence of NAFLD is
closely linked with an increased prevalence of obesity, insulin
resistance (IR), oxidative stress (OS), and cardiovascular diseases,
metabolic syndrome and Type 2 diabetes
diseases.\textsuperscript{4}According the ``two-it'' model and
``multi-parallel hit'' hypothesis, IR, increased free radical oxidation
products and decreased total antioxidant capacity result in NAFLD
progression. Furthermore, dysbiotic has been proposed as a critical risk
factor for NAFLD development .\textsuperscript{1} It has been shown that
altering the gut microbiota (GM) profile to phyla Bacteroidetes and
Firmicutes, and decreasing Akkermansia muciniphila \textsuperscript{5}
in NAFLD patients lead to metabolic endotoxemia (ME) that exacerbates
obesity, IR, OS and inflammation in these patients.

Due to lack of special pharmacologic treatments to control or improve
NAFLD, lifestyle modifications known a first-line approach for NAFLD
management.\textsuperscript{6} It is well established that having a
healthy diet and physical activity~can reduce the risk of occurrence or
progression of this disease. Recently, omega-3 fatty acids (OM3FA) and
antioxidants co-administration is considered to treatment and prevention
of NAFLD due to low OM3FA dietary intake, the high hepatic n-6: n-3
ratio and the low antioxdant levels in plasma and liver of NAFLD
patients.\textsuperscript{7} Thus, it seems that modification of dietary
fats can affect hepatic fat deposition. A meta-analysis found that OM3FA
interventions~can improve liver functions and steatosis scores in NAFLD
patients.\textsuperscript{8} OM3FA sources might be useful in
improvement of the complications of NAFLD by modify~the GM and
controlling IR, OS, inflammation, lipid metabolism, and hepatic fat
deposition.\textsuperscript{9} However, due to recent concerns~regarding
fish oil~supplements contaminated with heavy metals and consequent side
effects, and avoiding vegetarianism and veganism
for~consuming~animal-derived products, modifying OM3FA sources from
animal to plant sources~has been considered .\textsuperscript{10}

Camelina sativa (L.), known as false flax, is one of the richest dietary
sources of OM3FA, with PUFA amounts over 50\%, alpha-linolenic acid
(ALA) content of 40\% to 45\%, and linoleic acid (LA) of about 15\%,
n-3/n-6 PUFA ratio of 1.79--2.17, low SFA content (about 6\%), high
contents of phytosterols (331--442 mg/100 g), carotenoids (103--198 mg
of carotene/kg) and tocopherols (55.8--76.1
mg/100g).\textsuperscript{11} Inhibited autoxidation of extracted oil by
high levels of antioxidants in Camelina sativa oil (CSO) has led to the
superiority of this oil than other richest dietary sources of OM3FA,
such as flaxseed oil (FSO).\textsuperscript{11} Furthermore, it has been
reported that CSO has less fertilizer contamination compared to other
oils .\textsuperscript{12}

According to previous data, plant sources~of~OM3FA can improve glycemic
status \textsuperscript{13}, ME \textsuperscript{14},
inflamation\textsuperscript{15} and OS
indices.\textsuperscript{16}However, such effects have mostly been
showed in preclinical studies.\textsuperscript{17,18} Recently, limited
clinical trials have reported favorable impacts of CSO on modulation of
the lipid profile, OS, and immune system in subjects with impaired
glucose metabolism (IGM).\textsuperscript{19-22} To our knowledge, the
effects of CSO intake on glycemic, inflammation, ME, and OS status in
NAFLD patients have not been examined. Therefore, we aimed to investigat
combined effects of caloric restriction and CSO on glycemic,
inflammation, ME, and OS status in NAFLD patients.

\textbf{2. Materials and methods}

\emph{2.1 Study design and patients}

This triple-blind, placebo-controlled, randomized clinical trial was
conducted between 2019 October and 2020 March. Seventy NAFLD patients
(Body mass index (BMI): 25-35 kg/m\textsuperscript{2}) aged 20-50 years
old were engaged from Valiasr hospital of Tabriz, Iran and clinics via
advertisements and posters. The subjects were diagnosed by a physician
after an ultrasound examination on the basis of steatosis. Adherence to
a stable diet, constant physical activity level (PAL) and willingness
for participation were inclusion criteria of the study. The exclusion
criteria were a history of biliary disease, hepatitis B and C, copper
and iron storage disease; cardiovascular, gastrointestinal, and renal
disease, pancreatic, thyroid disorders, cancer, smoking; pregnancy or
lactation; post-menopausal; using antilipidemic and fatty liver inducing
medications; currently antibiotics consumption, taking antacids,
antidiarrheal, anti-inflammatory or laxative medicines and patients with
special diets or dietary limitations. Also, patients were asked to
consume minimum amount of nuts and fish and not to take antioxidants and
omega-3 supplements. At baseline, patients were given a full information
of the study and asked to sign a written informed consent. Also, they
fulfilled a demographic questionnaire containing variables including the
sex, age, PAL and the current medications of the subjects. The patients
were requested to keep their usual PALs and follow the designed diet
until the end of the intervention.

After a 2-week run-in period, patients were randomly allocated to either
intervention (CSO, jahan, Tabriz, Iran) or placebo (sunflower oil (SFO),
oila, Tehran, Iran) group based on age, sex, and BMI by block
randomization method with a block size of 4. Random allocation software
was performed to generate allocation sequence. The participants were
assigned to the study groups by a third person (entirely unrelated to
the trial) to achieve the blinding in the assessment~process. The
participants, principal researcher and statistical advisor were blind
until the end of the analysis. The participants in the study groups were
instructed to consume 15\% of the daily total fat
intake~(\textasciitilde{}20g) from the provided oil during the
intervention period. Measuring cups with the volume of 10 mL were
provided for the subjects to add two cups of oil daily to rice or salad
at the time of consumption. The rest of the required oil was provided
from meats and low-fat dairy, as well as cooking oil. A calorie
restricted diet was designed for participants in both groups (50-55\%
from carbohydrates, 30-35\% from fat and 10-15\% of energy from
protein). After a full explanation of the diet, the patients received an
exchange list to facilitate the adherence to the designed diet during
the intervention. Also, patients in both groups were asked to consume
the least amount of oil during cooking, low-fat dairy and meat and avoid
fried foods. The half of the oil bottles was provided at baseline for
participants and the remaining packages at 45 days of the study.
Patients were followed up biweekly to remind the recommendations on
oils, diet and PAL, in addition to explore any possible side effects.
Also, a checklist was provided for participants to mark after each
consumption of the prescribed oil to evaluate for cases of
non-compliance.

The sample size was calculated regarding the changes in superoxide
dismutase (SOD) level as one of the primary outcomes. A power study of
90\% and a confidence interval of 95\% \textsuperscript{23} were assumed
in the Pocock formula and calculated at least 21 subjects in each group.
Also, considering a 10\% attrition rate, the sample size increased to 23
per group.

The primary outcomes of the current study were high sensitivity- C
reactive protein (hs-CRP) malondialdehde (MDA), 8-iso-prostaglandin F2\selectlanguage{greek}α
\selectlanguage{english}(8-iso-PGF2\selectlanguage{greek}α\selectlanguage{english}), uric acid, SOD, total antioxidant capacity (TAC),
glutathione peroxidase (GSH-Px), catalase and LPS. The secondary
outcomes were insulin, and fasting plasma glucose (FPG).

\emph{2.2 Ethics}

The study protocol was approved by the ethics committee of the Tabriz
University of Medical Sciences (TBZMED) and has been registered in the
``Iranian Registry of Clinical Trials'' website with the number of
IRCT20150205020965N5.

\emph{2.3 Measurements}

\emph{2.3.1 Chemical analysis of oils}

The fatty acid compositions of CSO and SFO were determined using gas
chromatography.\textsuperscript{24} The main difference between the
fatty acid composition of used CSO and SFO in this study was the
percentage of LA (15.2\% in CSO versus 62.1\% in SFO), oleic acid
(14.20\% in CSO versus 27.80\% in SFO) and ALA (38.4\% in CSO versus
0.16\% in SFO). The percentage of other fatty acids has been compared in
Table 1.

\emph{2.3.2 Questionnaires}

The participants' height and weight were measured. BMI was computed as
the body weight (kg) divided by the square of the height (m). The
dietary intake was assessed using a 3-day food diary (2 weekdays and 1
weekend) before starting the low calorie diet and supplements and also
at the end of the study during last week. Dietary~intake composition
data were analyzed by ``Nutritionist 4'' (First Databank Inc., Hearst
Corp., San Bruno, CA, USA). The subjects' PAL was evaluated using the
International Physical Activity Questionnaire \textsuperscript{25} pre
and post intervention.

\emph{2.3.3 Biochemical measurements}

A venous blood sample (10 ml) was collected from every patient after
overnight fasting. Plasma were applied to determine insulin, FPG, MDA,
TAC, uric acid, hs-CRP, LPS, and 8-iso-PGF2\selectlanguage{greek}α. \selectlanguage{english}FPG and uric acid were
measured via the enzymatic method by an autoanalyzer using kits
(Pars-Azmoon Co., Tehran, Iran). Insulin concentration was determined
using a chemiluminescent immunoassay method. 8-iso-PGF2 (Abcam,
Cambridge, UK), and LPS levels (LAL kit endpoint-QCL1000; Cambrex
BioScience, Walkersville, Maryland, USA) were determined using an
enzyme-linked immunosorbent assay (ELISA) kit. hs-CRP serum
concentrations were measured using an immunoturbidimetric assay (Pars
Azmoon Co., Tehran, Iran). The activity levels of TAC, GSH-Px, and SOD
were measured through a colorimetric method (TAC: RANDOX kits, GSH-Px:
RANSEL kits and SOD: RANSOD kits; RANDOX Laboratory, UK) by an automatic
analyzer. MDA levels were determined by spectrofluorimeter (Kontron,
model SFM 25A, Italy).\textsuperscript{26} The method of Aebi was
applied to determine catalase activity.\textsuperscript{27}

\emph{2.3.4 Glucose homeostasis}

Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and
quantitative~insulin sensitivity~check index (QUICKI) were employed to
assess the IR via the following formula:

HOMA-IR = {[}fasting insulin (mU/L) \selectlanguage{ngerman}× fasting blood glucose (mg/dL){]} /
405

QUICKI = 1/(log (insulin, U/ml) + log (FPG, mg/dl)) \textsuperscript{28}

\emph{2.3.5 Statistical analyses}

SPSS version 24.0 was used to analyze the data. The results were showed
as mean (SD) and frequency (percent) for quantitative and qualitative
data, respectively. Intention to treat approach was used to include data
of subjects who discontinued the trial. The Kolmogorov-- Smirnov test
was used to evaluate the distribution normality of data. Un-paired
sample student T-test and Chi-square test were applied to assess between
group differences of quantitative and qualitative data, respectively.
Analysis of covariance (ANCOVA) were applied to compare the quantitative
variables between groups post intervention. Also, paired sample student
T-test was used to compare the differences within groups between
baseline and post-intervention. Percent change was calculated as {[}100
× (Intervention values -placebo values)/placebo values{]} to determine
the differences between groups. P \textless{}0.05 was considered
statistically significant.

\textbf{3. Results}

\emph{3.1 Patients}

Of the 70 patients that were recruited for trial eligibility, 43
patients (n=21 in the CSO group and n=22 in the placebo group) completed
the study. Fig. 1 shows the study flow chart and a description of the
causes for the loss to follow up. ~Overall, 90.5\% of participants were
compliant with supplements, by the end of the trial.~Any adverse effects
were reported by patients with SFO and CSO consumption. There was no
difference between groups in any of the demographic variables including
gender, age, employment, education level, marital status and PAL.

\emph{3.2 Anthropometric indices and nutrients intake}

Between group analysis were non-significant for the body weight, BMI
(Table 2), energy, macro-and micronutrients intake at baseline (Table
3). Weight and BMI showed a statistically significant reduction in
intervention group at the end of the trial, compared to placebo group
(Table 2, P\textless{} 0·05) after adjusting for confounding factors
(sex, PAL, energy intake and baseline). Within group analysis showed
that there was a non-significant reduction of body weight and BMI in the
placebo group, whereas it was significant in the intervention group
(paired T-test, P\textless{} 0·05). The mean of antioxidant
micronutrients intake was not different between placebo and intervention
groups. The dietary intake of macronutrients and energy were
significantly changed at the end of the intervention (except for protein
and fiber intake) in the intervention group compared to placebo group
(ANCOVA, P\textless{}0·05). Also, the intake of energy and
macronutrients (carbohydrate, protein, total fat and fiber) was
significantly different in the intervention and placebo groups after 12
weeks intervention compared with baseline (paired Student t-test, P
\textless{} 0.05).

\emph{3.3 Glycemic index, inflammatory biomarker, and endotoxin}

Any significant differences were observed in terms of glycaemia, LPS,
and inflammatory biomarkers between the two groups at baseline. There
was a remarkable reduction in levels of fasting insulin concentration
(-1.76 \selectlanguage{greek}μ\selectlanguage{english}U/ml, -17.49\%), HOMA-IR (-0.50, -20\%), hs-CRP (-1.25 pg/ml,
-12.94\%), and LPS (-5.59 EU/mL, -32.55\%) between the two groups (Table
4) (P \textless{} 0.05, adjusted for baseline values, sex, energy
intake, and weight changes). Decrease in FPG (-3.63 mg/dL, 3.57\%), and
QUICKI (-0.15, -4.33\%) were not statistically significant between
groups. Within group differences of insulin, QUICKI, hs-CRP and
endotoxin in the intervention group were significant (P \textless{}0.05,
paired Student t-test). All mentioned measurements, with the exception
of hs-CRP, remained unchanged in the placebo group when compared with
the baseline.

\emph{3.4 Antioxidant enzymes activity and oxidative stress status}

No significant differences were observed in antioxidant enzymes activity
and OS status between groups at baseline (Table 5). Mean levels of MDA
(-0.70 nmol/mL, -18.75\%), 8-iso-PGF2\selectlanguage{greek}α \selectlanguage{english}(-6.65 pg/ml, -19.55\%) reduced
significantly in the intervention group but not in the placebo group. A
significant elevation was observed in the mean levels of TAC (0.35
mmol/L, 31.82\%), and SOD (165.50 U/g Hb, 10.22\%) in the intervention
group compared with the placebo group. Changes in the levels of uric
acid (0.40 mg/dL, 6.66\%), GSH-Px (2.15 U/g Hb, 6.42 \%), and catalase
(6.81 U/g Hb, 10.20\%), were not statistically significant in the
intervention group compared with the placebo group (P\textless{}0.05,
adjusted for baseline values, sex, weight changes and energy intake).
TAC, SOD, GSH-Px, 8-iso-PGF2\selectlanguage{greek}α \selectlanguage{english}and MDA levels were significantly altered
in the intervention group compared with baseline, but catalase and uric
acid remained unchanged (P\textless{}0.05, paired T-test). No
significant within group differences were observed for the oxidative
stress/antioxidant parameters in the SFO group (P \textgreater{} 0.05,
paired Student \emph{t} -test).

\subsubsection*{}

{\label{section}}

\subsubsection*{}

{\label{section-1}}

\subsubsection*{}

{\label{section-2}}

\subsubsection*{}

{\label{section-3}}

\subsubsection*{}

{\label{section-4}}

\subsubsection*{4. Discussion}

{\label{discussion}}

To the best of our knowledge, our study was the first randomized
clinical trial to assess the combined effects of caloric restriction and
CSO on NAFLD penitents. Our findings showed that CSO, as a rich plant
source of OM3FA may exert beneficial effects on glycemic indices,
inflammation, ME and oxidative stress/antioxidant status in NAFLD
patients. Dietary intake of CSO significantly decreased energy,
carbohydrate, and fat intake, body weight, BMI, insulin, HOMA-IR,
hs-CRP, LPS, 8-iso-PGF2\selectlanguage{greek}α, \selectlanguage{english}MDA, and significantly increased TAC and SOD
in our study. However, changes of FPG, QUICKI, catalase, GSH-Px, and
uric acid were not significant in the intervention group

Weight management has been suggested as one of the most applicable
strategies for NAFLD treatment. It has been reported that a 5\%
reduction in BMI results in a 25\% decrease in the lipid content of the
liver.\textsuperscript{29} Our results on body weight and BMI are in
agreement with Rezaei et al. \textsuperscript{4} and with a systematic
review and meta-analysis of FSO supplementation on body weight in
overweight and obese adults.\textsuperscript{30} However, some trials
did not report the beneficial impacts of the CSO on anthropometric
indices. In a study which investigated the effect of CSO and canola oil
on anthropometric indices in postmenopausal women for six weeks, a
significant changes in WC observed in both groups and a significant
reduction was found in waist-to-hip ratio only in the CSO group. While,
weight and BMI changes were not significant.\textsuperscript{31} The
weight-decreasing effect of CSO may be attributed to a modulation of the
GM, ME, leptin, ghrelin, adiponectin, peroxisome proliferator-activated
receptors (PPARs) gene expression, gut hormones, including PYY and GLP-1
and short chain fatty acid (SCFA) production, fatty acid synthesis and
oxidation through up-regulating \selectlanguage{greek}β-\selectlanguage{english}oxidation gene~expression, like
carnitine palmitoyltransferase-1 (CPT-1) and peroxisome
proliferator-activated receptor \selectlanguage{greek}α \selectlanguage{english}(PPAR\selectlanguage{greek}α\selectlanguage{english}) and repressing~lipogenic~genes
expression such as sterol regulatory element binding proteins (SREBPs),
carbohydrate-responsive element-binding protein (ChREBP) and
PPA\textsuperscript{32} which regulate food intake and energy
expenditure.\textsuperscript{31}

The results of our study showed a significant improvement in insulin
levels and HOMA-IR after 12 weeks of supplementation with CSO. While, no
significant reduction was observed in FPG and QUICKI levels at the end
of the intervention. The effects of dietary intervention with CSO on
glycemic indices has been reported in subjects with
IGM.\textsuperscript{19} A systematic review reported a 0.2 reduction in
IR after OM3FA supplementation.\textsuperscript{33} In agreement with
the present study, Hutchins et al reported that the FSO supplementation
as another OM3FA rich plant oil reverses IR.\textsuperscript{13}However,
Schwab et al reported that CSO oil did not affect fasting, post load
plasma glucose or serum insulin concentrations in
IGM.\textsuperscript{19} Furthermore, in a study by Hajiahmadi et al.
significant improvements in FPG and insulin concentrations were found in
pre-diabetic patients who were supplemented with 2000 mg FSO for 14
weeks.\textsuperscript{34} These conflicting findings may be attributed
to designed diet, omega-6 to omega-3 ratio in diet, placebo group, basal
levels of glycemic indices, trial duration, type and dosage of
supplementation, as well as medical condition of patients.

IR as a main cause of NAFLD, augments lipid aggregation, and stimulates
inflammation in hepatocytes \textsuperscript{29}. On the other hand, it
was reported that development of IR and consequently NAFLD are
associated with dysbiosis. In the presence of dysbiosis, there is an
increased production of LPS from Gram-negative bacteria or
ME\textsuperscript{1} that exacerbates IR via enhancement of the
expression of pro-inflammatory cytokines such as tumor necrosis factor
(TNF-\selectlanguage{greek}α\selectlanguage{english}), interleukin (IL)-1, and IL-6 \textsuperscript{35}, reducing
insulin action through inhibiting phosphorylation of the insulin
receptor substrate (IRS)-1 and IRS-2 and reducing or even suppressing
the IRS-1 and IRS-2 expression.\textsuperscript{36} It was reported that
OM3FA improve ME \textsuperscript{37} via SCFAs
production.\textsuperscript{38} SCFAs as byproduct of OM3FA may
alleviate IR via inducing GLP-1 secretion from L cells in the
colon\textsuperscript{39}, activating intestinal gluconeogenesis, and
exerting beneficial effects on host glucose and energy homeostasis.
Thus, CSO supplementation may promote hypoglycaemic effects via reducing
energy intake, weight, LPS levels, and SCFAs production.

Another outcome of CSO supplementation in patients with NAFLD was
inflammation reduction via modulation of ME and inflammatory biomarkers.
ME proposed as a~triggering~factor for the systemic
inflammation.\textsuperscript{40} Limited animal studies reported
beneficial effects of OM3FA on endotoxin levels. It has been shown that
post-prandial ME caused by coconut oil decreased in pigs following fish
oil supplementation.\textsuperscript{41} In another animal study,
feeding high levels of omega-6 in mice led to increased levels of ME,
which were dramatically reduced in transgenic mice with the ability to
convert omega-6 to OM3FA.\textsuperscript{14} In a recent animal study,
dietary FSO in diabetic rats improved ME via modulating GM as well as
SCFAs. Additionally, a negative relationship was reported between ME
with Bacteroidetes and Alistipes and a positive relationship with
Blautia and Firmicutes.\textsuperscript{38} It is believed that exposure
to LPS are related to activating the NF-\selectlanguage{greek}κ\selectlanguage{english}B pathway leading to
inflammation in NAFLD patients.\textsuperscript{1,5} Probably, LPS
binding to TLR4 resulted in production of inflammatory cytokines such as
NFkB, IL-6 and interferon gamma~(IFN\selectlanguage{greek}γ\selectlanguage{english}) and
ME.\textsuperscript{42}Possibly CSO, as a source of OM3FA decreases
systemic inflammation and subsequently ME \textsuperscript{43} via
inhibiting the growth of Bilophila wadsworthia and increasing the growth
of A. muciniphila and bifidobacteria, decreasing postprandial lipaemia
involved in chylomicron-LPS complex transport, influencing lipids
transportation through the intestinal barrier cells phospholipid
membranes, increasing endogenous activity of intestinal ALP involved in
LPS production and intestinal permeability improvement, and inhibiting
the TLR4-induced signaling pathway through modulation of the G
protein-coupled receptor (GPR)-120.\textsuperscript{37} Furthermore,
anti-inflammatory effects of OM3FA may be related to the suppression of
the formation of omega-6-derived inflammatory lipid derivatives,
production of omega-3-derived endocannabinoids, ethanolamides and
oxylipins, as well as endocannabinoid system
modulation.\textsuperscript{5,44}

In the current study, another effect of CSO in patients with NAFLD was
the modulation of OS biomarkers. Our study is in agreement with a recent
preclinical study investigating the CSO effect on OS parameters in mice
with irritable bowel syndrome (IBS). The authors found that CSO
intervention caused a significant reduction in MDA levels, as well as
increases in SOD and GHP-x levels.\textsuperscript{45} The effect of CSO
on OS has been examined only in one clinical trial and reported no
remarkable changes in urinary prostanoids in patients with
IGM.\textsuperscript{22} Han et al. found that FSO consumption led to a
significant reduction in MDA levels and a significant increase of GSH
and SOD in mice.\textsuperscript{17} The underlying mechanisms of the
effect of CSO on OS is not fully explored. Several studies indicated
that ROS contributes to development of NAFLD via increasing IR, lipid
peroxidaition, inflammation and ME.\textsuperscript{46} OM3FA may reduce
OS by suppressing the~I\selectlanguage{greek}κ\selectlanguage{english}B kinase (IKK) responsible for dissociation of
nuclear factor-kappa B (NF-\selectlanguage{greek}κ\selectlanguage{english}B) from IKB-\selectlanguage{greek}α \selectlanguage{english}as a modulator of
pro-inflammatory cytokine production.\textsuperscript{47} Furthermore,
ALA is a precursor of long-chain docosahexaenoic acid. It has been shown
that docosahexaenoic acid increases the activity of glutathione
reductase, GSH-Px, and SOD and decreases MDA concentration in mice with
nonalcoholic steatohepatitis.\textsuperscript{48} Additionally,
favorable effects of intervention on OS biomarkers can be attributed to
the presence of high levels of natural antioxidants such as tocopherols,
carotenoids and phytosterols in CSO \textsuperscript{11} that may exert
inhibitory effects on lipid peroxidation and ROS production. Other
possible underlying~mechanism associated with changes~in the~GM.
Costantini~et al. reported that OM3FA intake stimulated the growth of A.
muciniphila, Bifidobacteria, Lactobacilli, Faecalibacterium, Roseburia,
and inhibited some pathogenic bacteria, such as the Enterobacteriaceae,
Clostridium, and Streptococcus.\textsuperscript{49} It was reported that
A. muciniphila alleviated OS in diabetic rats \textsuperscript{50} due
to having thiol specific antioxidant proteins such as typical 2-Cys
Peroxiredoxins as a family of thioredoxin (Trx)-scaffold enzymes and
ubiquitous.\textsuperscript{51} Bifidobacterium longum and Lactobacillus
acidophilus inhibited lipids peroxidation by scavenging
ROS\textsuperscript{52}, reducing MDA levels and increasing SOD and TAC
levels.\textsuperscript{5} Also, Clostridium perfringens, probably,
triggers OS by \selectlanguage{greek}α-\selectlanguage{english}toxin production, and activation of mitogen-activated
protein kinase/ERK~kinase/extracellular-signal-regulated kinase
(MEK/ERK), protein kinase C, and NF-\selectlanguage{greek}κ\selectlanguage{english}B
pathways.\textsuperscript{53}Short-chain fatty acids such as butyrate
reduces ROS production via suppression of IKK \textsuperscript{54},
increases in plasma antioxidant enzymes production, modulation of FOXO3A
and MT2 transcription through histone deacetylases inhibition
\textsuperscript{55}, reduction of colonic myeloperoxidase activity
\textsuperscript{56} and the MAPK/ERK, p38/MAPK and c-Jun N-terminal
kinase activation.\textsuperscript{57}Finally, CSO may protect against
IR, OS damage, ME, and inflammation by improving gut microbial dysbiosis
(Fig 2)\textbf{.}

Limitations in this study included lack of assessment of gut and fecal
microbial composition, serum fatty acids, glucose clamp, serum SCFA, and
other inflammatory/oxidative stress biomarkers. However, this study is
the triple-blind, placebo-controlled, randomized clinical design and
stratification by BMI, gender and age factors, which eliminates
inter-individual variation. Also, it was the first study to evaluate the
impact of CSO on glycemic indices, inflammatory and OS parameters, and
ME in NAFLD patients.

\textbf{5. Conclusion}

The current study found that CSO might improve NAFLD via glycemic
indices, inflammation, ME, and oxidant/antioxidant biomarkers
modulation. CSO as one of the richest dietary sources of OM3FA can be
recommended as a complementary therapy in NAFLD patients. Further trials
are required to confirm the positive results of CSO in NAFLD patients.

\textbf{Acknowledgements}

The authors would like to thank all the patients for their participation
in this study.

\textbf{Competing interests:} The authors declare that they have no
competing interests.

\textbf{Funding:} This study was funded by the Vice-chancellor for
Research and Student Research Committee of Tabriz University of Medical
Sciences, Tabriz, Iran (grant number: 65932).

\textbf{Author Contribution:}

\textbf{VM:} Drafting of the manuscript, Acquisition of data, Approval
of the article

\textbf{PD:} Contributions to concept/design, Data
analysis/interpretation, Critical revision of the manuscript, Approval
of the article

\textbf{SS:} Acquisition of data, Critical revision of the manuscript,
Approval of the article

\textbf{MA:} Critical revision of the manuscript, Approval of the
article

\textbf{DATA AVA I L A B I LIT Y S TATEMENT}

The data are available from the corresponding author on reasonable
request.

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\textbf{Table 1.} Composition of fatty acids present in Camelina oil and
Sunflower oil\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
Fatty acid & Name & Name & Camelina oil (\%) & Sunflower oil
(\%)\tabularnewline
\midrule
\endhead
14:0 & 14:0 & Myristic acid & 0.10 & 0.09\tabularnewline
16:0 & 16:0 & Palmitic acid & 5.70 & 6.2\tabularnewline
18:0 & 18:0 & Stearic acid & 2.50 & 1.74\tabularnewline
20:0 & 20:0 & Arachidic acid & 1.55 & 0.21\tabularnewline
22:0 & 22:0 & Behenic acid & 0.30 & 0.85\tabularnewline
24:0 & 24:0 & Lignoceric acid & 0.10 & 0.31\tabularnewline
Saturated fatty acids & Saturated fatty acids & & 10.20 &
9.4\tabularnewline
16:1n-7 & 16:1n-7 & Palmitoleic acid & 0.13 & 0.06\tabularnewline
18:1n-9 & 18:1n-9 & Oleic acid & 14.20 & 27.80\tabularnewline
18:1n-7 & 18:1n-7 & Cis-Vaccenic acid & 0.70 & 0.06\tabularnewline
20:1n-9 & 20:1n-9 & Eicosenoic acid & 14.40 & 0.16\tabularnewline
22:1n-9 & 22:1n-9 & Erucic acid & 3.21 & nd\tabularnewline
24:1n-9 & 24:1n-9 & Nervonic acid & 0.60 & 0.19\tabularnewline
Monounsaturated fatty acids & Monounsaturated fatty acids & & 33.20 &
28.69\tabularnewline
18:2n-6 & 18:2n-6 & Linoleic acid & 15.20 & 62.1\tabularnewline
18:3n-3 & 18:3n-3 & Alpha-linolenic acid & 38.40 & 0.16\tabularnewline
20:2n-6 & 20:2n-6 & Eicosadienoic acid & 3.50 & 0.04\tabularnewline
Polyunsaturated fatty acids & Polyunsaturated fatty acids & & 57.10 &
62.3\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 2} Baseline characteristics of the study participants\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Variables\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Placebo group (n=21)\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Placebo group (n=21)\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Intervention group (n=22)\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
P\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
P\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
P\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Age}(y) *(range)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
43.86 (6.07) (32-45)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
43.86 (6.07) (32-45)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
44.30 (4.38) (35-47)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
44.30 (4.38) (35-47)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.798\textsuperscript{+}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.798\textsuperscript{+}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Gender}, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.608\textsuperscript{++}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.608\textsuperscript{++}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
11 (52.4)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
11 (52.4)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
10 (45.5)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
10 (45.5)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
10 (47.6)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
10 (47.6)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
12 (54.5)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
12 (54.5)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Education level}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.548\textsuperscript{++}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Illiterate\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
8 (38.10)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
6 (27.30)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
6 (27.30)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
6 (27.30)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
6 (27.30)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Diploma\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
8 (38.10)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
8 (36.40)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
8 (36.40)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
8 (36.40)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
8 (36.40)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Bachelor degree\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
5 (23.80)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
8 (36.40)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
8 (36.40)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
8 (36.40)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
8 (36.40)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Employment}, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.269\textsuperscript{++}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Employed\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
11 (52.40)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
9 (40.90)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
9 (40.90)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
9 (40.90)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
9 (40.90)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Unemployed\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
10 (47.60)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
13 (59.10)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
13 (59.10)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
13 (59.10)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
13 (59.10)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{PAL}, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.301\textsuperscript{++}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Light\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
7 (33.30)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
8 (36.40)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
8 (36.40)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
8 (36.40)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
8 (36.40)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Moderate\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
11 (52.40)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
12 (54.50)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
12 (54.50)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
12 (54.50)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
12 (54.50)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Vigorous\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
3 (14.30)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
2 (9.10)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
2 (9.10)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
2 (9.10)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
2 (9.10)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Marital status}, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.421\textsuperscript{++}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Single\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
4 (19.00)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
6 (27.30)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
6 (27.30)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
6 (27.30)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
6 (27.30)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Married \textbf{Anthropometric indices}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
17 (81.00)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
16 (72.70)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
16 (72.70)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
16 (72.70)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
16 (72.70)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Height (cm)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
156.19 (3.70)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
154.65 (6.90)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
154.65 (6.90)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
154.65 (6.90)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
154.65 (6.90)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.374\textsuperscript{+}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Weight (kg) at baseline\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
82.70 (5.15)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
81.29 (3.80)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
81.29 (3.80)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
81.29 (3.80)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
81.29 (3.80)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.316\textsuperscript{+}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Weight (kg) at end of trial\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
80.30 (4.75)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
74.15 (3.05)\textsuperscript{\&}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
74.15 (3.05)\textsuperscript{\&}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
74.15 (3.05)\textsuperscript{\&}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
74.15 (3.05)\textsuperscript{\&}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.004\selectlanguage{ngerman}\textsuperscript{¥}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
BMI at baseline (kg/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
33.90 (2.65)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
34.19 (3.55)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
34.19 (3.55)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
34.19 (3.55)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
34.19 (3.55)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.797\textsuperscript{+}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
BMI at end of trial (kg/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
32.97 (2.40)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
31.19 (3.22)\textsuperscript{\&}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
31.19 (3.22)\textsuperscript{\&}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
31.19 (3.22)\textsuperscript{\&}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
31.19 (3.22)\textsuperscript{\&}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.046\selectlanguage{ngerman}\textsuperscript{¥}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}

BMI: Body mass index, PAL: physical activity level. *Data are presented
as mean (SD), \selectlanguage{english}\textsuperscript{+}Independent sample
t-test,\selectlanguage{english}\textsuperscript{++} Fisher's exact
test,\textsuperscript{\&}P\textless{}0.05, paired student t test for
comparison of data within groups \textsuperscript{Y=} P\textless{}0.05,
Analysis of covariance for comparison of data between groups after
adjusting for sex, PAL, energy intake and baseline values.

\textbf{Table 3.} Dietary intakes of patients at baseline and at the end
of the study\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
Variables & Period & Placebo group (n=21) & Intervention group
(n=22)\tabularnewline
\midrule
\endhead
Energy (kcal/d) & Initial & 2372.30 (209.70) & 2304.95
(244.80)\tabularnewline
& End & 2099.80 (199.0) \textsuperscript{a} & 1927.30
(208.80)\textsuperscript{a,b}\tabularnewline
Carbohydrate (g/d) & Initial & 322.87 (60.20) & 302.60
(45.25)\tabularnewline
& End & 267.99 (44.80) \textsuperscript{a} & 240.20
(34.40)\textsuperscript{a, b}\tabularnewline
Protein (g/d) & Initial & 88.49 (14.20) & 85.98 (12.87)\tabularnewline
& End & 98.70 (14.60) \textsuperscript{a} & 100.99 (10.40)
\textsuperscript{a}\tabularnewline
Total fat (g/d) & Initial & 77.30 (10.60) & 80.04 (12.80)\tabularnewline
& End & 69.01 (13.85) \textsuperscript{a} & 62.94
(10.50)\textsuperscript{a,b}\tabularnewline
Dietary fiber (g/d) & Initial & 12.19 (3.7) & 12.60
(2.28)\tabularnewline
& End & 13.86 (3.30) \textsuperscript{a} & 15.30 (3.82)
\textsuperscript{a}\tabularnewline
Vitamin C (mg/d) & Initial & 102.7 (21.8) & 108.9 (31.45)\tabularnewline
& End & 107.3 (25.6) & 127.4 (42.40)\tabularnewline
Vitamin E (mg/d) & Initial & 5.92 (1.46) & 6.41 (1.45)\tabularnewline
& End & 6.23 (1.83) & 5.79 (1.90)\tabularnewline
Selenium (\selectlanguage{greek}μ\selectlanguage{english}g/d) & Initial & 63.95 (15.35) & 65.50 (14.23)\tabularnewline
& End & 59.40 (15.42) & 57.65 (18.73)\tabularnewline
Cu (mg/d) & Initial & 2.3 (0.15) & 3.01 (0.25)\tabularnewline
& End & 2.7 (0.12) & 2.70 (0.23)\tabularnewline
Zn (mg/d) & Initial & 5.6 (1.14) & 6.35 (1.03)\tabularnewline
& End & 6.13 (2.12) & 5.43 (1.75)\tabularnewline
\selectlanguage{greek}β-\selectlanguage{english}Carotene (mg/d) & Initial & 3.75) 1.18) & 4.73 (1.04)\tabularnewline
& End & 4.35 (1.75) & 4.45 (1.15)\tabularnewline
Mn (mg/d) & Initial & 3.99 (1.08) & 4.01 (1.02)\tabularnewline
& End & 4.35 (2.08) & 5.03 (1.09)\tabularnewline
\bottomrule
\end{longtable}

Data are presented as mean (SD),
\textsuperscript{a}\emph{P\textless{}0.05} , paired student \emph{t}
test for comparison of data within groups. \textsuperscript{b}
\emph{P\textless{}0.05} , Analysis of covariance for comparison of data
between groups after adjusting for sex and baseline values.

\textbf{Table 4.} Changes in glycemic indices, endotoxemia, and
inflammatory biomarkers of patients at baseline and the end of the
study\textsuperscript{1}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
Variables & Period & Placebo group (n=21) & Intervention group (n=22) &
MD (95\% CI\textsuperscript{++,}) between groups\tabularnewline
\midrule
\endhead
FPG (mg/dL) & Initial & 99.70 (5.30) & 98.32 (4.06) & -1.40 (- 1.50 to
4.30)\tabularnewline
& End & 101.22 (5.15) & 97.60 (7.30) & -3.63 (-0.30 to
7.50)\textsuperscript{\#}\tabularnewline
& MD (95\% CI) within groups & 1.50 (-3.50 to 0.50) & -0.73 (-2.30 to
3.70) &\tabularnewline
Insulin (\selectlanguage{greek}μ\selectlanguage{english}U/ml) & Initial & 10.70 ( 2.60) & 10.50 (4.20) & -0.17 (-2.00
to 2.36)\tabularnewline
& End & 10.06 (1.99) & 8.30 (2.66) \textsuperscript{a,b} & -1.76 (-3.22
to -0.31)\tabularnewline
& MD (95\% CI) within groups & -0.62 (-0.04 to 1.21) & -2.22 (-0.55 to
3.90) &\tabularnewline
HOMA-IR & Initial & 2.64 (0.70) & 2.55 (1.05) & -0.09 (-0.46 to
0.64)\tabularnewline
& End & 2.50 (0.50) & 2.00 (0.70)\textsuperscript{b} & -0.50 (-0..90 to
-0.13)\tabularnewline
& MD (95\% CI) within groups & -0.13 (-0. 04 to 0.30) & -0.55 (-0.13 to
-0.96) &\tabularnewline
QUICK & Initial & 3.01 (0.12) & 2.98 (0.17) & -0.03 (-0.06 to
0.12)\tabularnewline
& End & 3.00 (0.85) & 2.87 (0.17) \textsuperscript{a} & -0.15 (-0.03 to
0.21)\tabularnewline
& MD (95\% CI) within groups & -0.01 (-0.01- to 0.05) & -0.11 (-0.03 to
-0.17) &\tabularnewline
hs-CRP (ng/ml) & Initial & 11.40 (3.15) & 10.88 (3.50) & -0.50 (-1.49 to
2.55)\tabularnewline
& End & 9.50 (2.49) & 8.27 (1.65) \textsuperscript{a, b} & -1.25 (-2.5
to -0.47)\tabularnewline
& MD (95\% CI) within groups & -1.90 (-0.65 to 3.25)\textsuperscript{a}
& -2.60 (-1.30 to -3.93) &\tabularnewline
LPS (EU/ml) & Initial & 19.59 (6.25) & 16.60 (6.60) & -2.99 (-1.60 to
10.36)\tabularnewline
& End & 18.46 (7.90) & 12.45 (6.25)\textsuperscript{a,b} & -5.59 (-1.61
to -10.36)\tabularnewline
& MD (95\% CI) within groups & -1.15 (-0.52 to 2.75) & -4.10 (-2.35 to
-5.80) &\tabularnewline
\bottomrule
\end{longtable}

CI\textsuperscript{++,} Confidence interval; FPG; Fasting plasma glucose;
HOMA-IR; Homeostatic Model Assessment for Insulin Resistance, QUICK;
quantitative~insulin sensitivity~check index, hs-CRP; high-sensitivity
C-reactive protein; LPS; Lipopolysaccharide.\textsuperscript{1} Data are
presented as mean (SD). \textsuperscript{a} P\textless{}0.05, paired
student t test for comparison of data within groups.
\textsuperscript{b}P\textless{}0.05, analysis of covariance for
comparison of data between groups after adjusting for sex, weight,
energy intake changes and baseline values.\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
Variables & Period & Placebo group\textsuperscript{1} (n=21) &
Intervention group (n=22) & MD (95\%CI\textsuperscript{++}) between
groups\tabularnewline
\midrule
\endhead
TAC (mmol/L) & Initial & 0.95 (0.10) & 0.80 (0.15) & -0.15 ( -0.56 to
0.10)\tabularnewline
& End & 1.10 (0.10) & 1.45 (0.35) \textsuperscript{a , b} & 0. 35 (0. 10
to 0.43)\tabularnewline
& MD (95\% CI) within groups & 0.15 (-0.31 to 0. 20) & 0.65 (-0.82 to
-0. 50) &\tabularnewline
SOD (U/mg Hb) & Initial & 1627.32 (142.90) & 1604.75 (97.21) &
-22.55(-52.20 to 97.35)\tabularnewline
& End & 1609.65 (154.25) & 1774.20 (105.50) \textsuperscript{a, b} &
165.50 (84.8 to 109.9)\tabularnewline
& MD (95\% CI) within groups & -17.98 (-42.57 to 78.55) & 169.45
(-218.40 to -121.20) &\tabularnewline
GSH-Px (U/g Hb) & Initial & 33.53 (3.0) & 32.96 (2.31) & 0.60 (-1.07 to
2.21)\tabularnewline
& End & 33.45 (3.34) & 35.60 (3.65) \textsuperscript{a} & 2.15 (-4.30 to
0.32)\tabularnewline
& MD (95\% CI) within groups & -0.08 (-0.70 to 0.85) & 2.64 (-3.99 to
-1.25) &\tabularnewline
Catalase (U/g Hb) & Initial & 64.20 (18.17) & 59.70 (17.20) & -4. 50
(-3.20 to 17.50)\tabularnewline
& End & 66.79 (16.60) & 73.60 (26.55) & 6.81 (-23.46 to
4.70)\tabularnewline
& MD (95\% CI) within groups & 2.59 (-7.93 to 13.15) & -13.90 (-23.65 to
4.12) &\tabularnewline
Uric acid (mg/dL) & Initial & 4.60 (1.26) & 4.75 (1.23) & 0.15 (-0.91 to
0.62)\tabularnewline
& End & 4.50 (1.33) & 4.80 (1.20) & 0.40 (-1.10 to 0.45)\tabularnewline
& MD (95\% CI) within groups & -0.10 (-0.14 to 0..40) & 0.15 (-0.39 to
0.26) &\tabularnewline
MDA (nmol/mL) & Initial & 3.85 (0.84) & 3.64 (1.42) & -0.25 (-0.56 to
0.93)\tabularnewline
& End & 3.68 (0.68) & 2.99 (1.16) \textsuperscript{a , b} & -0.70 (-0.25
to -1.20)\tabularnewline
& MD (95\% CI) within groups & -0.17 (-0.23 to 0.56) & -0.65 (-0.50 to
-1.21) &\tabularnewline
8-iso-PGF2\selectlanguage{greek}α \selectlanguage{english}(pg/ml) & Initial & 33.60 (7.03) & 30.15 (4.50) & -3.30
(-11.80 to 6.50)\tabularnewline
& End & 31.20 (5.15) & 25.10 (4.15) \textsuperscript{a , b} & -6.65
(-8.45 to -5.40)\tabularnewline
& MD (95\% CI) within groups & -2.4.0 (-9.15 to 8.20) & -4.90 (-8.05 to
-4.60) &\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 5.} Changes in oxidative stress status and antioxidant
biomarkers of patients at baseline and the end of the
study\textsuperscript{1}

CI++: confidence interval; TAC: serum total antioxidant capacity; SOD:
superoxide dismutase; GSH-Px: glutathione peroxidase; MDA:
malondialdehyde, 8-iso-PGF2\selectlanguage{greek}α: \selectlanguage{english}8-iso-prostaglandin
F2\selectlanguage{greek}α,\selectlanguage{english}\textsuperscript{1}Data are presented as mean
(SD).\textsuperscript{a} P\textless{}0.05, paired T-test for comparison
of data between within groups. \textsuperscript{b} P\textless{}0.05,
Analysis of covariance for comparison of data between groups after
adjusting for sex, weight and energy changes and baseline values.

\textbf{Figure legends:}

Fig 1: Flow chart of the study

Fig 2: Graphical abstract (underlying mechanism of the effect camelina
sativa oil on inflammation, oxidative stress, insulin resistance, and
metabolic endotoxemia)

ALP= Alkaline phosphatase,DC=Dendritic cell, eCB= Endocannabinoid,IR=
insulin resistance, GLP-1=Glucagon-like peptide-1, GLP-2=Glucagon-like
peptide-2, LPS= Lipopolysaccharide ME=metabolic endotoxemia,Ros=
Reactive Oxygen Species, SCFA=Short chain fatty acid

\textbf{Hosted file}

\verb`Fig1 (3).doc`  available at \url{https://authorea.com/users/421448/articles/527480-camelina-oil-in-the-context-of-a-weight-loss-programs-improves-glucose-homeostasis-inflammation-and-oxidative-stress-in-nafld-patients-a-randomized-triple-blind-placebo-controlled-clinical-trial}\selectlanguage{english}
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\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Graphical-abstract7/Graphical-abstract7}

\end{center}
\end{figure}

\selectlanguage{english}
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