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Relationship of Plasma Polyunsaturated Fatty Acids to Circulating Inflammatory Markers

  • IRCCS INRCA Istituto Nazionale di Ricovero e Cura per Anziani
  • ASL Azienda Sanitaria Locale toscana centro, Firenze,Italy

Abstract and Figures

Persons with high intake of polyunsaturated fatty acids (PUFAs) have lower cardiovascular morbidity and mortality. The protective effect of PUFAs is mediated by multiple mechanisms, including their antiinflammatory properties. The association of physiological PUFA levels with pro- and antiinflammatory markers has not been established. In 1123 persons (aged 20-98 yr), we examined the relationship between relative concentration of fatty acids in fasting plasma and level of inflammatory markers. Adjusting for age, sex, and major confounders, lower arachidonic and docosahexaenoic acids were associated with significantly higher IL-6 and IL-1ra and significantly lower TGFbeta. Lower alpha-linolenic acid was associated with higher C-reactive protein and IL-1ra, and lower eicosapentaenoic acid was associated with higher IL-6 and lower TGFbeta. Lower docosahexaenoic acid was strongly associated with lower IL-10. Total n-3 fatty acids were associated with lower IL-6 (P = 0.005), IL-1ra (P = 0.004), and TNFalpha (P = 0.040) and higher soluble IL-6r (P < 0.001), IL-10 (P = 0.024), and TGFbeta (P = 0.0012). Lower n-6 fatty acid levels were significantly associated with higher IL-1ra (P = 0.026) and lower TGFbeta (P = 0.014). The n-6 to n-3 ratio was a strong, negative correlate of IL-10. Findings were similar in participants free of cardiovascular diseases and after excluding lipids from covariates. In this community-based sample, PUFAs, and especially total n-3 fatty acids, were independently associated with lower levels of proinflammatory markers (IL-6, IL-1ra, TNFalpha, C-reactive protein) and higher levels of antiinflammatory markers (soluble IL-6r, IL-10, TGFbeta) independent of confounders. Our findings support the notion that n-3 fatty acids may be beneficial in patients affected by diseases characterized by active inflammation.
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Relationship of Plasma Polyunsaturated Fatty Acids to
Circulating Inflammatory Markers
Luigi Ferrucci, Antonio Cherubini, Stefania Bandinelli, Benedetta Bartali, Annamaria Corsi,
Fulvio Lauretani, Antonio Martin, Cristina Andres-Lacueva, Umberto Senin, and Jack M. Guralnik
Longitudinal Studies Section (L.F.), Clinical Research Branch, National Institute on Aging, Baltimore, Maryland 21225;
Department of Clinical and Experimental Medicine (A.Ch., U.S.), Institute of Gerontology and Geriatrics, Perugia University
Medical School, 06100 Perugia, Italy; Department of Geriatric Rehabilitation (S.B.), Tuscany Regional Health Agency
(A.Co., F.L.), 50125 Florence, Italy; Division of Nutritional Sciences (B.B.), Cornell University, Ithaca, New York 14853;
Human Nutrition Research Center on Aging (A.M.), Tufts University, Boston, Massachusetts 02111; Department of Nutrition
and Food Science (C.A.-L.), CeRTA, University of Barcelona, 08028 Barcelona, Spain; and Laboratory of Epidemiology,
Demography, and Biometry (J.M.G.), National Institute on Aging, Bethesda, Maryland 20892
Aims: Persons with high intake of polyunsaturated fatty acids
(PUFAs) have lower cardiovascular morbidity and mortality. The
protective effect of PUFAs is mediated by multiple mechanisms, in-
cluding their antiinflammatory properties. The association of phys-
iological PUFA levels with pro- and antiinflammatory markers has
not been established.
Methods and Results: In 1123 persons (aged 20 –98 yr), we exam-
ined the relationship between relative concentration of fatty acids in
fasting plasma and level of inflammatory markers. Adjusting for age,
sex, and major confounders, lower arachidonic and docosahexaenoic
acids were associated with significantly higher IL-6 and IL-1ra and
significantly lower TGF
. Lower
-linolenic acid was associated with
higher C-reactive protein and IL-1ra, and lower eicosapentaenoic acid
was associated with higher IL-6 and lower TGF
. Lower docosa-
hexaenoic acid was strongly associated with lower IL-10. Total n-3
fatty acids were associated with lower IL-6 (P 0.005), IL-1ra (P
0.004), and TNF
(P 0.040) and higher soluble IL-6r (P 0.001),
IL-10 (P 0.024), and TGF
(P 0.0012). Lower n-6 fatty acid levels
were significantly associated with higher IL-1ra (P 0.026) and lower
(P 0.014). The n-6 to n-3 ratio was a strong, negative correlate
of IL-10. Findings were similar in participants free of cardiovascular
diseases and after excluding lipids from covariates.
Conclusions: In this community-based sample, PUFAs, and espe-
cially total n-3 fatty acids, were independently associated with lower
levels of proinflammatory markers (IL-6, IL-1ra, TNF
, C-reactive
protein) and higher levels of antiinflammatory markers (soluble IL-
6r, IL-10, TGF
) independent of confounders. Our findings support
the notion that n-3 fatty acids may be beneficial in patients affected
by diseases characterized by active inflammation. (J Clin Endocri-
nol Metab 91: 439 446, 2006)
HERE IS EVIDENCE that a diet rich in polyunsaturated
fatty acids (PUFAs) and, in particular, the omega-3
family (n-3), is associated with lower cardiovascular mor-
bidity and mortality and reduced risk of sudden death, in-
dependent of other known cardiovascular risk factors (1–5).
Studies have suggested that the protective effects of n-3
PUFA are mediated by multiple mechanisms, including their
antiinflammatory properties (6).
Preclinical studies have shown that fatty acids modulate
the inflammatory response by multiple mechanisms, includ-
ing transcriptional down-regulation of proinflammatory cy-
tokines and the vascular surface expression of endothelial
leukocyte adhesion molecules (7, 8). In particular, in exper-
imental and animal models, n-3 fatty acids inhibit the pro-
duction of IL-1 and TNF
(7). An antiinflammatory effect of
n-3 fatty acids is supported by the beneficial effect of n-3
fatty-acid supplementation in patients affected by diseases
characterized by active inflammation, such as rheumatoid
arthritis and Crohn’s disease (9). In small groups of healthy
volunteers, dietary supplementation with n-3 fatty acids was
associated with reduced levels of IL-1
, thromboxane
, and
prostaglandin E2 (10, 11) but not C-reactive protein (CRP) (12).
A recent study showed that dietary intake of n-3 and
omega-6 (n-6) fatty acids in American men and women was
inversely associated with plasma levels of soluble TNF
receptors 1 and 2 but not with other cytokines (13). This
observation is important because it suggests that physiolog-
ical levels of fatty acids modulate inflammation. However,
studies on dietary intake should be complemented by studies
that investigate the relationship between fatty acid plasma
levels and serum levels of multiple inflammatory markers. In
fact, although some studies found a good correlation be-
tween dietary intake of fatty acids and blood levels (14),
others did not confirm this finding, reporting only a modest
association (15), likely due to the fact that circulating fatty
acid levels reflect the interplay among dietary intake, ab-
sorption, and metabolism.
Using data from a representative sample of the general
population, we tested the hypothesis that circulating levels
First Published Online October 18, 2005
Abbreviations: AA, Arachidonic acid; ALA,
-linolenic acid; BMI,
body mass index; CRP, C-reactive protein; DHA, docosahexaenoic acid;
EPA, eicosapentaenoic acid; FAME, fatty acid methyl esters; HDL, high-
density lipoprotein; IL-1ra, IL-1 receptor antagonist; InCHIANTI, In-
vecchiare in Chianti, aging in the Chianti area; LA, linoleic acid; LDL,
low-density lipoprotein; n-3, omega-3 family; n-6, omega-6 family;
PPaR, peroxisome proliferator activated receptor; PUFA, polyunsatu-
rated fatty acid; sIL-6r, soluble IL-6 receptor.
JCEM is published monthly by The Endocrine Society (http://www., the foremost professional society serving the en-
docrine community.
0021-972X/06/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 91(2):439 446
Printed in U.S.A. Copyright © 2006 by The Endocrine Society
doi: 10.1210/jc.2005-1303
on February 24, 2006 jcem.endojournals.orgDownloaded from
of selected PUFAs are associated with lower concentrations
of proinflammatory cytokines and, possibly, higher levels of
antiinflammatory cytokines. This information is important in
furthering our understanding of the mechanisms by which
fatty acids modulate cardiovascular risk and other clinical
conditions characterized by a proinflammatory state.
Subjects and Methods
Study population and collection of blood samples.
Invecchiare in Chianti, aging in the Chianti area (InCHIANTI) is an
epidemiological study conducted in two small towns of Tuscany, Italy.
The rationale, design, and data collection methods of InCHIANTI are
described elsewhere (16). In brief, in August 1998, 1270 persons aged 65
yr or older were randomly selected from the population registry of the
two sites. Additionally, men and women randomly sampled from the
age strata 20 –29, 30 –39, 40 49, 50–59, and 60 64 yr were sequentially
invited to participate in the study, until at least 30 men and 30 women
in each decade, ages 20 69 yr, had been enrolled.
Of the 1714 eligible persons, 640 men and 813 women (84.8%) agreed
to participate and were interviewed. Of those, 595 men and 748 women
(92.4%) provided blood samples. Data on plasma fatty acid and serum
cytokine composition were obtained for 1180 participants (87.9%). Be-
cause poor cognitive status is associated with inflammatory conditions
and strongly affects dietary intake (17), we also excluded 57 participants
in whom we established a dementia diagnosis, based on the Diagnostic
and Statistical Manual of Mental Disorders, version III-R criteria (18).
Thus, the final study population included 1123 participants, none of
whom had dietary supplementation of fatty acids.
The study protocol complies with the Declaration of Helsinki and was
approved by the Italian National Institute of Research and Care on
Aging Ethical Committee. Participants received an extensive description
of the study and signed an informed participation consent that included
permission to conduct analyses on the biological specimens collected
and stored.
Laboratory analysis
Blood samples were collected in the morning after a 12-h fast. Ali-
quots of serum and plasma were immediately obtained and stored at
80 C. The samples used to measure circulating levels of cytokines and
fatty acids had not been previously thawed.
Fatty acids were measured using a fasting plasma sample. A known
amount of heptadecanoic acid (17:0) (Sigma Chemical Co., St Louis, MO)
was added to each sample as an internal standard, and total lipids were
extracted from 0.15 ml of plasma (19). In a pilot study, we had found that
no traces of heptadecanoic acid were detectable in 25 plasma samples
from InCHIANTI participants. Fatty acid methyl esters (FAME) were
prepared through transesterification using Lepage and Roy’s method
(20), modified according to Rodriguez-Palmero et al. (21). Separation of
FAME was carried out on an HP-6890 gas chromatograph (Hewlett-
Packard, Palo Alto, CA) with a 30-m fused silica column (HP-225;
Hewlett-Packard). FAMEs were identified by comparison with pure
standards (NU Chek Prep, Inc., Elysian, MA). For quantitative analysis
of fatty acids as methyl esters, calibration curves for FAME (ranging
from C14:0 to C24:1) were prepared by adding six increasing amounts
of individual FAME standards to the same amount of internal standard
(C17:0; 50
g). The correlation coefficients for the calibration curves of
20 fatty acids were in all cases higher than 0.998 in the range of con-
centrations studied. Fatty acid concentration was expressed as a per-
centage. Fatty acid percent area/area was also calculated. The coefficient
of variation for all fatty acids was on average 1.6% for intraassay and
3.3% for interassay.
In the present analysis, we examined data on the concentration of
PUFAs, which are characterized by two or more double bonds in the
hydrocarbon chain. The n-3 and n-6 families of fatty acids account for
more than 95% of total PUFAs and are named from the position of the
first double bond, located on the third or sixth carbon, respectively, from
the terminal methyl group (22). The total n-6 fatty acids included linoleic
(LA) (C18:2-n6), eicosadienoic (C20:2n6), dihomo-g-linolenic (C20:3n6),
and arachidonic (AA) (C20:4n6) acids, whereas the total n-3 fatty acids
-linolenic (ALA) (C18:3n3), eicosapentaenoic (EPA) (C20:
5n3), and docosahexaenoic (C22:6-n3) (DHA) acids.
Serum levels of IL-6, soluble IL-6 receptor (sIL-6r, 80 kDa), IL-1
, IL-1
receptor antagonist (IL-1ra), and TNF
were measured by ELISAs using
commercial kits (BIOSOURCE International, Camarillo, CA). TGF
IL-10 levels were measured in duplicate using highly sensitive quanti-
tative sandwich assays (Quantikine HS, R&D Systems, Minneapolis,
MN). The lowest detectable concentrations were 0.1 pg/ml for IL-6, 8
pg/ml for sIL-6r, 0.01 pg/ml for IL-1
, 0.09 pg/ml for TNF
, 4 pg/ml
for IL-1ra, 7 pg/ml for TGF
, and 1.5 pg/ml for IL-10. The interassay
coefficient of variation was 4.5% for IL-1ra and less than 8.0% for the
other cytokines.
CRP was measured in duplicate using an ELISA colorimetric com-
petitive immunoassay that used purified protein and polyclonal anti-
CRP antibodies. The minimum detectable concentration was 0.03 mg/
liter and the interassay coefficient of variation was 5.0%. Total
cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycer-
ides were assessed using commercial enzymatic tests (Roche Diagnos-
tics, Mannheim, Germany).
Participants were classified as nonsmokers or former smokers vs.
current smokers based on self-report. Weight was measured using a
high-precision mechanical scale. Standing height was measured to the
nearest 0.1 cm. Body mass index (BMI) was calculated as weight (kilo-
grams)/height (square meters). Average daily intake of energy (kilo-
calories) and carbohydrates, proteins, total lipids and unsaturated, and
monosaturated and polyunsaturated fatty acids (grams) were estimated
by administering the European Prospective Investigation into Cancer
and Nutrition food frequency questionnaire, which has been extensively
validated in the Italian population (23).
Study participants responded to an extensive questionnaire on ha-
bitual physical activity and were classified as sedentary if they reported
being completely inactive or performing low-intensity physical activity,
such as short walking or light housekeeping activities totaling less than
2 h/wk.
A physician evaluated all participants. Diseases were ascertained
according to standard, preestablished criteria that combined informa-
tion from self-reported physician diagnoses, current pharmacological
treatment, medical records, clinical examinations, and blood tests. Dis-
eases included in the current analysis were coronary heart disease (in-
cluding angina and myocardial infarction), congestive heart failure,
cerebrovascular disease (including transient ischemic attack and stroke),
diabetes, and hypertension. Diagnostic algorithms were modified ver-
sions of those created for the Women’s Health and Aging Study (24). An
ankle-arm index of 0.9 or less was considered indicative of peripheral
arterial disease (25). Participants were asked to report all drugs taken at
least once over the last 15 d. Using this information, we created a
dichotomous variable indicating whether the participant received treat-
ments that may affect circulating levels of fatty acids and/or inflam-
matory markers, including statins, other drugs aimed at reducing cir-
culating lipids, steroids, nonsteroidal antiinflammatory drugs, and
angiotensin-converting enzyme inhibitors. This condition is defined in
the text as potentially confounding drug treatment.
Statistical analysis
Continuous variables are reported as mean sd and categorical
variables as percentages. Log-transformed values of cytokines, except
for TGF
, were used in the analysis.
The relationships of specific fatty acids with potential covariates were
explored by computing age- and sex-adjusted partial Pearson correla-
tions. Further analyses were performed to test the mutually independent
effects of total n-3 and n-6 fatty acids on inflammatory markers, after
adjusting for age; sex; education; intake of energy, proteins, and car-
bohydrates; physical activity; BMI; smoking; low-density lipoprotein
(LDL) cholesterol; HDL cholesterol; triglycerides; hypertension; diabe-
tes; coronary heart disease; congestive heart failure; stroke; peripheral
arterial disease; and potentially confounding drug treatment. All anal-
yses were performed using the SAS statistical package (version 9.1; SAS
Institute, Inc., Cary, NC) with a statistical significance level set at P
440 J Clin Endocrinol Metab, February 2006, 91(2):439446 Ferrucci et al. PUFA Levels Correlate with Low Inflammation
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The principal characteristics of the study population are
reported in the first column of Table 1. Only data on total n-3
and n-6 PUFAs are shown. Both total n-3 and n-6 were
negatively correlated with age (n-3: r ⫽⫺0.13; n-6: r ⫽⫺0.33)
but not sex (n-3: r 0.02; n-6: r 0.03). Independent of age
and sex, total n-3 PUFAs were positively correlated with
education and HDL cholesterol and negatively correlated
with triglycerides. Total n-6 PUFAs were positively corre-
lated with total, LDL, and HDL cholesterol and negatively
correlated with most of the other cardiovascular risk factors
and cardiovascular diseases (Table 1). LA was positively and
independently correlated with LDL cholesterol. LA (r
0.31), AA (r 0.28), EPA (r 0.23), and DHA (r 0.14) were
positively correlated with HDL cholesterol. LA (r 0.51) was
positively correlated (r 0.51), whereas AA (r ⫽⫺0.34), EPA
(r ⫽⫺0.21), and DHA (r ⫽⫺0.20) were negatively correlated
with triglycerides. Other correlations of specific fatty acids
with the variables reported in Table 1 were small (0.09) and
generally not statistically significant. In particular, neither
n-3 nor n-6 fatty acids were independently correlated with
parameters of dietary intake.
The mean plasma concentration of total fatty acids was
3200 724 mg/liter (range 1295– 6885), which is compatible
with those reported in a group of middle-aged American
women and blood donors (26, 27). The concentration tended to
be higher at older ages (r 0.08, P 0.0023) with no substantial
difference between men and women (men, 3155 777 vs.
women, 3236 677 mg/liter, P 0.07). As expected, the plasma
concentration of total fatty acids was positively correlated with
total cholesterol (r 0.59, P 0.0001) and triglycerides (r 0.71,
P 0.0001) and negatively correlated with HDL cholesterol (r
0.07, P 0.025). Total fatty acids were not independently
correlated with any of the inflammatory markers considered in
this study. n-3 and n-6 fatty acids accounted for 3.4 and 33.1%
of total fatty acids. The percentage of n-3 and n-6 fatty acids on
total fatty acids was significantly lower in older participants,
respectively, by 0.002% per year (P 0.0001) for n-3 and 0.008%
per year (P 0.0001) for n-6, without substantial difference
between men and women.
Of the plasma n-3 fatty acids, 13.6 6.1% were ALA,
18.8 5.0% were EPA and 67.7 4.9% were DHA. Of the
n-6 fatty acids, 75.3 5.0% were LA and 24.4 4.9% were
AA. Levels of inflammatory markers according to quartiles
of specific fatty acids are reported in Table 2. All mean values
and statistical tests are adjusted for age and multiple con-
founders. Lower AA and DHA were associated with higher
IL-6 and IL-1ra and lower TGF
. Lower DHA was also as-
sociated with lower IL-10. Lower ALA was associated with
higher CRP and IL-1ra, and lower EPA was associated with
higher IL-6, lower TGF
, and lower IL-10. Participants in the
two lower quartiles of LA had significantly lower sIL-6r than
those in the two upper quartiles. AA/EPA ratio was not
associated with any of the different inflammatory markers.
After removing lipids as covariates from these models, these
results were substantially unchanged, except that the inverse
association of IL-1ra with LA (adjusted values across quar-
tiles: 149, 129,and 127 pg/ml; P 0.0003) and EPA (143, 132,
128, and 130; P 0.0076) became stronger and highly statisti-
cally significant (cf. Table 2). Restricting the analysis to the 432
TABLE 1. Characteristics of the study population (n 1123) and their correlation with n-3 and n-6 fatty acids
Mean SD or n (%)
Age and sex adjusted partial correlations r (P value)
With total n-3 FA
With total n-6 FA
Age (yr) 68.2 15.4
65 246 (21.9)
65–74 504 (44.9)
75–84 276 (24.6)
85 97 (8.6)
Sex (women) 620 (55.2)
Years in school 6.6 4.2 0.14 (0.0001) 0.05 (0.13)
BMI (kg/m
) 27.5 4.4 0.04 (0.13) 0.14 (0.0001)
Energy intake (kcal/d) 2027 621 0.07 (0.03) 0.02 (0.47)
Carbohydrate intake (g/d) 261 87 0.06 (0.03) 0.01 (0.69)
Protein intake (g/d) 79 23 0.05 (0.10) 0.02 (0.46)
Total lipids intake (g/d) 69 23 0.05 (0.08) 0.01 (0.86)
Saturated FA intake (g/d) 23 9 0.05 (0.09) 0.02 (0.45)
Monounsaturated FA intake (g/d) 35 12 0.02 (0.46) 0.03 (0.29)
Polyunsaturated FA intake (g/d) 7 2 0.05 (0.11) 0.01 (0.82)
Total cholesterol (mg/dl) 215 40 0.00 (0.95) 0.11 (0.001)
LDL cholesterol (mg/dl) 134 35 0.02 (0.58) 0.18 (0.0001)
HDL cholesterol (mg/dl) 56 15 0.14 (0.0001) 0.38 (0.0001)
Triglycerides (mg/dl) 123 65 0.21 (0.0001) 0.58 (0.0001)
Current smoker 179 (16) 0.03 (0.36) 0.07 (0.030)
Sedentary 186 (17) 0.06 (0.06) 0.09 (0.004)
Coronary heart disease 58 (5.2) 0.01 (0.69) 0.06 (0.020)
Stroke 21 (1.9) 0.02 (0.46) 0.08 (0.003)
Congestive heart failure 62 (5.5) 0.07 (0.02) 0.09 (0.004)
Hypertension 500 (45.5) 0.04 (0.21) 0.08 (0.005)
Diabetes 78 (7.0) 0.01 (0.81) 0.03 (0.24)
Peripheral artery disease 139 (12.6) 0.04 (0.15) 0.08 (0.010)
FA, Fatty acids.
Log-transformed values were used for the correlation analysis.
Ferrucci et al. PUFA Levels Correlate with Low Inflammation J Clin Endocrinol Metab, February 2006, 91(2):439446 441
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TABLE 2. Multivariate analysis of the relationship between specific n-3 and n-6 fatty acids and inflammatory markers
LA (quartiles), %
AA (quartiles), %
ALA (quartiles), %
Quartiles limits 22.33 22.33–24.95 24.96–27.51 27.51
P for
6.82 6.82–7.97 7.98 –9.28 9.28
P for
0.304 0.3040.381 0.382– 0.493 0.493
P for
Median 20.5 23.5 26.2 29.4 5.95 7.34 8.58 10.19 0.264 0.344 0.427 0.640
IL-6 (pg/ml) 1.32 1.23 1.28 1.28 0.38 1.44
1.28 1.15 0.0024 1.35 1.28 1.31 1.20 0.12
sIL-6r (ng/ml) 83
90 97 0.06 84
80 87 96 0.1452 87 87 90 92 0.50
(pg/ml) 0.13 0.14 0.13 0.14 0.60 0.13 0.14 0.14 0.13 0.52 0.14 0.12 0.14 0.13 0.41
IL-1ra (pg/ml) 140 127 129 131 0.26 141
126 126 0.0008 143
127 132 128 0.0248
(pg/ml) 4.8 4.7 4.7 4.8 0.67 4.8 5.0 4.5 4.7 0.29 5.1 4.4 4.7 4.8 0.53
IL-10 (pg/ml) 3.3 3.6 4.8 3.5 0.91 3.4 3.7 4.4 3.5 0.98 3.3 3.7 3.8 3.9 0.17
(ng/ml) 11.20
11.90 12.00 12.60 0.38 10.60
11.40 12.80 12.90 0.0003 11.8 11.7 11.5 12.7 0.35
CRP (mg/liter) 2.70 2.50 2.50 2.40 0.90 2.50 2.70
2.30 0.60 3.0
2.6 2.3 2.4 0.0047
EPA (quartiles), %
DHA (quartiles), %
AA/EPA ratio (quartiles)
Quartiles limits 0.491 0.491–0.585 0.586 0.707 0.707
P for
1.77 1.77–2.23 2.24–2.75 2.75
P for
11.40 11.40–13.20 13.21–15.95 15.95
P for
Median 0.422 0.543 0.647 0.800 1.46 2.00 2.47 3.18 9.82 12.28 14.50 18.16
IL-6 (pg/ml) 1.37
1.24 1.16 0.0033 1.43
1.30 1.25 1.18 0.0075 1.22 1.34 1.31 1.25 0.51
sIL-6r (ng/ml) 86
88 89 94 0.39 85
87 91 94 0.19 89 88 84
95 0.75
(pg/ml) 0.13 0.14 0.14 0.13 0.85 0.13 0.14 0.13 0.13 0.61 0.13 0.14 0.14 0.14 0.44
IL-1ra (pg/ml) 138 132 129 131 0.20 143
130 135 125 0.0021 131 136 133 133 0.59
(pg/ml) 5.2 4.6 4.5 4.7 0.13 4.8 5.1 4.7 4.5 0.06 4.9 4.4 4.8 4.8 0.69
IL-10 (pg/ml) 3.0 3.7 4.0 4.1 0.07 2.9 3.8 3.6 4.7 0.003 4.4 3.5 3.9 3.3 0.11
(ng/ml) 11.40
13.10 0.0071 10.90
13.20 0.0004 11.6 12.3 11.5 12.4 0.79
CRP (mg/liter) 2.60 2.60 2.40 2.50 0.97 2.80
2.40 2.60 2.30 0.17 2.5 2.6 2.6 2.4 0.55
ref, Reference quartile.
Mean values and statistics for the association of specific fatty acids with selected inflammatory markers are adjusted for age, sex, education, daily intake of energy, carbohydrates,
proteins and lipids, physical activity, BMI, smoking, LDL cholesterol, HDL cholesterol, triglycerides, hypertension, diabetes, coronary heart disease, congestive heart failure, stroke,
peripheral artery disease, and potentially confounding drug treatment.
P 0.01, compared with the reference quartile.
P 0.05, compared with the reference quartile.
442 J Clin Endocrinol Metab, February 2006, 91(2):439446 Ferrucci et al. PUFA Levels Correlate with Low Inflammation
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men and 569 women free of prevalent cardiovascular disease,
all the associations that were statistically significant in Table 2
remained statistically significant, and in addition, the inverse
relationship between LA and sIL-6r and between DHA and
that were borderline statistically significant became sta-
tistically significant (respectively, P 0.020 and P 0.040).
Figure 1 shows median serum levels of inflammatory mark-
ers according to n-3 and n-6 quartiles. Adjusting for age and sex,
lower total n-3 and n-6 PUFAs were associated with higher IL-6,
IL1-ra, TNF
, and CRP and lower IL-6r, IL-10, and TGF
In most cases, the associations were highly statistically signif-
icant, with an evident dose-response relationship.
In subsequent models predicting inflammatory markers, we
simultaneously entered both total n-3 and total n-6 PUFAs as
well as multiple potential confounders and tested n-6 to n-3
ratio as predictor. From these models, we estimated the mean
values of inflammatory markers, according to n-3 and n-6 quar-
tiles and n-6 to n-3 ratio quartiles, which are reported and
statistically compared in Table 3. Lower total n-3 PUFAs were
still strongly and significantly associated with higher IL-6, IL-
1ra, and TNF
and lower total sIL-6r, IL-10, and TGF
but no
longer with higher CRP. Lower n-6 PUFAs were independently
associated with higher IL-1ra and lower TGF
but no longer
with the other inflammatory markers. The n-6 to n-3 ratio was
positively associated with IL-6 and IL-1ra and, based on P
value, was the strongest negative correlate of IL-10 and TGF
These findings were confirmed in analyses performed sepa-
rately in men and women, in participants 65 yr and older and
after restricting the study population to the 1001 participants
free of coronary artery disease, congestive heart failure, stroke,
and peripheral arterial disease.
Our findings are consistent with the hypothesis that n-3
fatty acids have antiinflammatory properties (6, 7, 11, 28).
IL-6 and TNF
are generally considered proinflammatory
cytokines and the potent antiinflammatory properties of
IL-10 and TGF
are well known (29, 30). The negative as-
sociation of total n-3 fatty acids with IL-1ra (a competitive
inhibitor of the proinflammatory cytokine IL-1) and the pos-
itive association with sIL-6r (that in certain conditions en-
hances the biological activity of IL-6) requires discussion. At
a molecular level, IL-1ra is a natural antagonist of the proin-
flammatory cytokine IL-1 (31), and in animal models of
chronic inflammation, the administration of IL-1ra prevents
tissue damage (32). Despite this, as a circulating biomarker,
IL-1ra is considered an acute-phase protein and a more re-
liable measure of proinflammatory state than IL-1 (33). Sim-
ilar triggers induce the production of IL-1 and IL-1ra, but IL-1
is produced locally and only small quantities spill in the serum,
whereas IL-1ra is produced by the liver in large quantities and
fully released into the circulation. For example, in experimental
endotoxemia in humans, IL-1 increases in the circulation only
by a factor of 2–2.5, whereas IL-1ra increases by a factor of 10 –20
(32, 34). This may also explain why we did not find any asso-
ciation between fatty acids and IL-1
in our study.
The role of sIL-6r in inflammation is still unclear. In gen-
FIG. 1. Median serum levels of inflammatory markers according to total n-3 and n-6 PUFAs quartiles. Comparisons between groups and tests
for trend are based on age- and sex-adjusted nonparametric ANOVA. The thresholds for quartile definition were 2.72, 3.27, and 3.93 for total
n-3 fatty acids and 30.4, 33.13, and 36.26 for total n-6 fatty acids.
Ferrucci et al. PUFA Levels Correlate with Low Inflammation J Clin Endocrinol Metab, February 2006, 91(2):439446 443
on February 24, 2006 jcem.endojournals.orgDownloaded from
eral, a specific IL-6 receptor is expressed by the membranes
of hepatocytes, monocytes/macrophages, and some leuko-
cytes. However, the sIL-6r/IL-6 complex can stimulate a
much wider range of cell types that have the gp130 protein,
the inner portion of the IL-6 receptor, on their membrane.
Recent literature suggests that this mechanism is active only
when plasma levels of soluble gp130 are low, which is prob-
ably a rare condition. When high levels of gp130 and sIL-6r
are present, a hexameric complex is created (2*IL-6 2*sIL-6r
2*gp130), which tends to precipitate and has no biological
activity (35). Thus, in this condition, sIL-6r levels are anti-
inflammatory (36). IL-6 and sIL-6r have shown opposite bi-
ological activity in several instances. Recently we reported
that IL-6 is associated with insulin resistance, whereas sIL-6r
has the opposite effect (37).
Similarly to Pischon et al. (13), we found some evidence that
n-6 fatty acids may be antiinflammatory with no evidence of the
proinflammatory activity previously suggested by many au-
thors. However, our data suggest that the immunomodulatory
effect of PUFAs may be influenced by the n-6 to n-3 ratio, which
in our study was the strongest negative correlate of IL-10 and
, two powerful antiinflammatory cytokines. Pischon et al.
found no significant association between plasma PUFA con-
centrations and serum CRP levels, and in our study only ALA
was an independent negative correlate of CRP. This particular
finding is somewhat puzzling and difficult to interpret because
the production of CRP is mainly regulated by IL-6 (38), and
ALA was not a significant independent correlate of IL-6. In-
terestingly, in a recent trial, supplementation of ALA vs. LA for
2 yr significantly reduced serum CRP but had no effect on other
inflammatory markers (39).
Our findings show that plasma levels of AA and omega-3
PUFAs, which probably reflect higher dietary intake, are asso-
ciated with lower serum concentrations of certain proinflam-
matory cytokines and lower concentrations of certain antiin-
flammatory cytokines. Therefore, these findings support the
view that AA and n-3 PUFAs may modulate the inflammatory
response by acting both on the proinflammatory and antiin-
flammatory arms of the cytokine network. Such a modulatory
effect on multiple signaling pathways suggests a direct regu-
latory effect on gene expression. Interestingly, short-term in-
fusion of n-3 lipid emulsion markedly suppresses monocytic
generation of TNF
, IL-1, IL-6, and IL-8 in response to endo-
toxin (40).
The mechanism by which AA and n-3 fatty acids may
inhibit the production of proinflammatory cytokines has
been intensively investigated. Fatty acids can bind to the
peroxisome proliferator activated receptors (PPaR)
, which regulate the transcription of target genes (7,
41). PPaRs can also repress gene transcription by interfering
with signaling molecules, such as nuclear factor-
B, there-
fore inhibiting the production of proinflammatory cytokines
(42, 43). De Caterina and colleagues (8, 44) found that poly-
unsaturated fatty acids have antiinflammatory properties
and hypothesized that they exert this effect because they
have an unsaturated double bond, which, regardless of the
n-3 or n-6 position, inactivates reactive oxygen species and
prevents their interaction with nuclear factor-
B. This hy-
pothesis is consistent with our findings suggesting that n-3
and n-6 fatty acids have both antiinflammatory properties.
TABLE 3. Multivariate analysis of the relationship between total n-3 and n-6 fatty acids and inflammatory markers
Total n-3 fatty acids,
% (quartiles)
(mean SD, 3.4 1.0)
P for
Total n-6 fatty acids,
% (quartiles)
(mean SD, 33.1 4.6)
P for
n-6/n-3 fatty acids,
% (quartiles)
SD, 10.5 3.1)
P for
Quartiles limits 2.7 2.7–3.3 3.4–3.9 3.9
30 30–33 34–36.3 36
8.4–10.2 10.2–12.1 12.1
Median 2.3 3.0 3.5 4.5 28.0 31.6 34.7 38.2 7.3 9.3 11.0 13.8
IL-6 (pg/ml) 1.38
1.29 1.24
1.14 0.0048 1.26 1.29 1.29 1.20 0.56 1.13
1.29 1.24 1.39 0.0057
sIL-6r (ng/ml) 79
91 97 0.0003 88 85 90 88 0.74 89 87 88 86 0.53
(pg/ml) 0.13 0.14 0.13 0.13 0.53 0.13 0.13 0.14 0.13 0.56 0.13 0.13 0.13 0.14 0.93
IL-1ra (pg/ml) 140
131 130 121 0.0044 143 128 128 123 0.0258 122
132 142 0.0007
(pg/ml) 5.1
4.6 4.9 4.3 0.0404 4.8 4.9 4.6 4.5 0.32 4.3 4.7 5.0 4.9 0.08
IL-10 (pg/ml) 2.6 4.1 4.2 4.7 0.0236 4.2 4.0 3.1 3.3 0.07 4.5
3.9 2.9 0.0002
(ng/ml) 11.1
12.0 13.1 0.0012 10.6 12.0 12.3 12.7 0.014 13.1 12.1 11.2 11.0 0.0005
CRP (mg/liter) 2.51 2.40 2.54 2.24 0.35 2.53 2.28 2.55 2.32 0.77 2.30 2.45 2.45 2.48 0.46
ref, Reference quartile.
Mean values and statistics for the association of n-3 and n-6 fatty acids with selected inflammatory markers are mutually independent. All mean values and statistical tests
are adjusted for age, sex, education, daily intake of energy, proteins, lipids and carbohydrates, physical activity, BMI, smoking, LDL cholesterol, HDL cholesterol, triglycerides,
hypertension, diabetes, coronary heart disease, congestive heart failure, stroke, peripheral artery disease, and potentially confounding drug treatment.
P 0.01, compared with the reference quartile.
P 0.05, compared with the reference quartile.
444 J Clin Endocrinol Metab, February 2006, 91(2):439446 Ferrucci et al. PUFA Levels Correlate with Low Inflammation
on February 24, 2006 jcem.endojournals.orgDownloaded from
The most important limitation of this study is the cross-
sectional nature of our analysis. Although the consistency of the
effect across multiple inflammatory markers is suggestive of
causality, the correlation reported in this study does not prove
the link between PUFAs and inflammatory markers but sug-
gests that the physiological concentration of PUFAs reflects the
severity of inflammation independently of other risk factors. In
addition, although our analysis was adjusted for a number of
potential confounders, we cannot exclude the possibility that
other factors affect both n-3 fatty acids and cytokine concen-
trations. The diet of the Tuscany population is particularly poor
of polyunsaturated fatty acids (45). In the InCHIANTI study,
the average estimated daily intake of PUFAs was 7.4 g, which
is lower than the intake reported for other populations (46) and
even compared with other Italian populations (47). On the
contrary, the intake of monounsaturated fatty acids in our pop-
ulation tended to be high (50% of total lipids), likely the result
of the large consumption of olive oil in Italy and, in particular,
in the Tuscany region. The generalizability of our findings to
other populations with different dietary intake should be con-
firmed by other studies.
Our finding that n-3 and n-6 account for a significantly
lower percentage of total fatty acids in older persons may
explain the mild proinflammatory state that is often found in
the elderly and is not completely accounted for by cardio-
vascular risk factors and morbidity (48). If this hypothesis is
correct, nutritional intervention may contrast this age-related
trend to a proinflammatory state.
This study also has several strengths. To our knowledge,
this is the first investigation of the relationship between
plasma concentrations of fatty acids and multiple proinflam-
matory and antiinflammatory cytokines based on a repre-
sentative sample of the general population. Different fatty
acids were directly measured in plasma and not estimated
from dietary reports. Because no participants were using
dietary supplements, our findings are based on physiological
plasma concentrations; this information is more precise and
provides a more objective measure of fatty acid exposure,
which depends on both intake and metabolism. Finally, in-
formation on multiple potential confounders, including di-
etary intake, was available for all participants.
Because serum levels of specific fatty acids can be easily
modified by a different selection of foods in the diet or dietary
supplementation, physicians should consider dietary interven-
tions to suppress production of proinflammatory compounds
as part of the prevention and treatment of diseases in which
inflammation exerts adverse effects on clinical progression.
The authors are indebted to Chiara Ceccucci for integrating fatty acids
peaks in the chromatograms and for data entry.
Received June 16, 2005. Accepted October 7, 2005.
Address all correspondence and requests for reprints to: Luigi Fer-
rucci, M.D., Ph.D., Longitudinal Studies Section, Clinical Research
Branch, National Institute on Aging, National Institutes of Health, Har-
bor Hospital, 5th Floor, 3001 Hanover Street, Baltimore, Maryland 21225.
This work was supported as a targeted project by the Italian Ministry
of Health (ICS110.1/R597.71) and an unrestricted grant by Bracco Im-
aging SpA, Italy (to A.Ch.). C.A.-L. was supported by the Ramon Cajal
program by the Ministry of Science and Technology, Spain.
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446 J Clin Endocrinol Metab, February 2006, 91(2):439446 Ferrucci et al. PUFA Levels Correlate with Low Inflammation
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... Insulin resistance is associated with increased oxidative stress and manifests in lower 20:4n6 levels (44), suggesting that increasing carbohydrate load in individuals with MetS is associated with oxidative stress, lower 20:4n6, and increased polyunsaturated fatty acid anabolism. Increased proportions of 20:4n6 and total polyunsaturated and less SFAs in membranes increase membrane fluidity and correlate with increased insulin sensitivity (44) and decreased inflammation (21,45). Many of the same studies that reported increased risks for MetS, CVD, and morality associated with circulating SFAs and 16:1n7 also showed similar associated risks with increased DGLA and low 20:4n6 (13,15,34). ...
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Lignosus rhinocerotis, a polypore found in the tropical forests of Malaysia is traditionally used by the locals to treat various diseases. The objectives of the study were to quantify linoleic acid and β-glucan, characterize polysaccharide structure as well as to evaluate the cytotoxicity effects of L. rhinocerotis extracts. The linoleic acid and β-glucan concentrations in six different extracts of L. rhinocerotis were quantified using HPLC and β-glucan assay kit, respectively and the polysaccharide structure were analyzed using FTIR and XRD. The proliferation rate of human bronchial epithelial BEAS-2B cells treated with the L. rhinocerotis extracts were also analyzed. The highest linolic acid content and β-glucan composition were found in petroleum ether extract and hexane residue, respectively. Cold water and petroleum ether extracts showed cytotoxic effect with 30% reduction of cell viability at 72 hours at the concentration of 62.5-250 µg/mL while the other extracts are not cytotoxic. Quantification of linoleic acid and β-glucan as well as characterization of polysaccharide structure in L. rhinocerotis extracts have been successfully determined. The observed effects on BEAS-2B cells are likely attributable to the immunomodulatory properties exhibited by the active compounds of linoleic acid and β-glucan. Abstrak Lignosus rhinocerotis merupakan polipor yang terdapat di hutan tropika Malaysia telah digunakan secara tradisi oleh penduduk tempatan untuk merawat pelbagai penyakit. Kajian ini bertujuan untuk mengukur tahap asid linoleik dan β-glukan, mencirikan struktur polisakarida serta menilai kesan sitotoksisiti ekstrak L. rhinocerotis. Tahap asid linoleik dan β-glukan di dalam enam ekstrak L. rhinocerotis yang berlainan masing-masing diukur dengan kaedah HPLC dan kit ujian mezayme yis dan cendawan β-glukan. Struktur polisakarida juga dianalisa menggunakankan kaedah FTIR dan XRD. Titisan sel epitelium bronkus manusia Abdullah et al.: QUANTIFICATIONS OF LINOLEIC ACID AND β-GLUCAN IN Lignosus rhinocerotis EXTRACT AND ITS CYTOTOXICITY ANALYSIS IN HUMAN LUNGS EPITHELIAL BEAS-2B CELLS 866 BEAS-2B dikultur dan dirawat dengan ekstrak L. rhinocerotis dan ujian kesitotoksikan telah dijalankan. Petroleum eter menghasilkan jumlah asid linoleik yang paling tinggi, manakala ekstrak residu heksana menghasilkan komposisi β-glukan tertinggi. Ekstrak air sejuk dan petroleum eter menunjukkan kesan sitotoksik ringan pada kepekatan 62.5-250.0 µg/mL dengan penurunan kadar kebolehhidupan sel adalah tidak melebihi 30% manakala kebanyakan ekstrak lain tidak sitotoksik. Tahap asid linoleik dan β-glukan serta pencirian struktur polisakarida di dalam ekstrak L. rhinocerotis telah berjaya ditentukan. Kesan ekstrak ini terhadap titisan sel epitelium bronkus manusia BEAS-2B juga telah berjaya dikaji dan berkemungkinan disebabkan oleh sifat imunomodulator yang ditunjukkan oleh sebatian aktif, iaitu asid linoleik dan β-glukan.
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... As the precursor to arachidonic acid, linoleic acid with their metabolites may mediate inflammation (Shen et al. 2018) as metabolized by lipoxygenase (LOX) to derivatives called hydroxyoctadecadienoic acids (HODEs) and further to oxo-HODEs and epoxy-HODEs, that involves in inflammation ( Vangaveti et al. 2016). According to an Italian epidemiological study, plasma linoleic acid concentrations possess the most elevated pro-inflammatory IL-6 and c-reactive protein (CRP) concentrations and the least anti-inflammatory IL-10 and TGF-β ones (Ferrucci et al. 2006). Accordingly, linoleic acid may take part in pro-and anti-inflammatory pathways. ...
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Objective Welding fume exposure is inevitable of welding workers and poses a severe hazard to their health since welding is a necessary industrial process. Thus, preclinical diagnostic symptoms of worker exposure are of great importance. The aim of this study was to screen serum differential metabolites of welding fume exposure based on UPLC–QTOF-MS/MS.Methods In 2019, 49 participants were recruited at a machinery manufacturing factory. The non-target metabolomics technique was used to clarify serum metabolic signatures in people exposed to welding fume. Differential metabolites were screened by OPLS-DA analysis and Student's t-test. The receiver operating characteristic curve evaluated the discriminatory power of differential metabolites. And the correlations between differential metabolites and metal concentrations in urine and whole blood were analyzed utilizing Pearson correlation analysis.ResultsThirty metabolites were increased significantly, and 5 metabolites were decreased. The differential metabolites are mainly enriched in the metabolism of arachidonic acid, glycero phospholipid, linoleic acid, and thiamine. These results observed that lysophosphatidylcholine (20:1/0:0) and phosphatidylglycerol(PGF1α/16:0) had a tremendous anticipating power with relatively increased AUC values (AUC > 0.9), and they also presented a significant correlation of Mo concentrations in whole blood and Cu concentrations in urine, respectively.Conclusion The serum metabolism was changed significantly after exposure to welding fume. Lysophosphatidylcholine (20:1/0:0) and phosphatidylglycerol (PGF1α/16:0) may be a potential biological mediator and biomarker for laborers exposure to welding fume.
... Similarly, a significant inverse relationship was observed between total RBC-MUFAs and CRP levels in the current study. These findings are similar to previous cross-sectional studies, which have reported an anti-inflammatory relationship between MUFAs and CRP [22,29]. This relationship may have been driven by the individual MUFAs C18:1n-7 (vaccenic acid) and C24:1n-9 (nervonic acid), which were inversely associated with CRP levels in the adjusted models. ...
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Evidence suggests that diet can play a role in modulating systemic inflammation. This study aims to examine the relationship between fatty acids (FAs) (self-reported dietary intake and red blood cell (RBC) membrane fatty acid concentrations), three diet quality scores, and the plasma concentrations of inflammatory markers (interleukin-6, IL-6; tumour necrosis factor alpha, TNF-α; and C-reactive protein, CRP) in a group of Australian adults (n = 92). Data were collected on their demographic characteristics, health status, supplement intake, dietary intake, RBC-FAs and plasma inflammatory markers over a nine-month period. Mixed-effects models were used to determine the relationship between RBC-FAs, dietary intake of FAs, diet quality scores and inflammatory markers to determine which variable most strongly predicted systemic inflammation. A significant association was identified between dietary saturated fat intake and TNF-α (β = 0.01, p < 0.05). An association was also identified between RBC membrane saturated fatty acids (SFA) and CRP (β = 0.55, p < 0.05). Inverse associations were identified between RBC membrane monounsaturated fatty acids (MUFAs) (β = −0.88, p < 0.01), dietary polyunsaturated fatty acids (PUFAs) (β = −0.21, p < 0.05) and CRP, and the Australian Eating Survey Modified Mediterranean Diet (AES-MED) score and IL-6 (β = −0.21, p < 0.05). In summary, using both objective and subjective measures of fat intake and diet quality, our study has confirmed a positive association between saturated fat and inflammation, while inverse associations were observed between MUFAs, PUFAs, the Mediterranean diet, and inflammation. Our results provide further evidence that manipulating diet quality, in particular fatty acid intake, may be useful for reducing chronic systemic inflammation.
... For instance, inverse associations were found between consumption of fruits and vegetables and circulating levels of CRP, IL6 and TNFα [15]. Some nutrients have also been associated with lower levels of inflammation (measured by CRP, adiponectin, TNFα, IL6, interleukin 1 receptor antagonist (IL1RA) and IL10 levels), such as carbohydrates [16], n-3 polyunsaturated fatty acids [17,18], or fiber [19]. On the other hand, red and processed meat intake has been reported to be positively associated with higher levels of leptin in men and women, and of CRP in women, and with lower levels of adiponectin in women [20]. ...
Background: Since the first version of the dietary inflammatory index (DII®) developed in the past decade, several other versions have been developed. However, to date no study has attempted to compare these versions with respect to their associations with biomarkers of inflammation. Objective: We aimed to investigate the relationship between four dietary inflammatory scores [DII, two energy-adjusted derivatives (E-DII and E-DIIr), and the Inflammatory Score of the Diet (ISD)], and circulating levels of several inflammatory markers and adipokines. Methods: This study included 17 637 participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with at least one marker of inflammation measured in blood. Associations between the four scores and C-reactive protein (CRP), interleukin (IL)6, IL10, IL1RA, tumor necrosis factor-α (TNFα), soluble tumor necrosis factor receptor-1 (sTNFR1), sTNFR2, leptin, soluble leptin receptor (sLeptin R), adiponectin, and High Molecular Weight (HMW) adiponectin were evaluated using multivariable linear regressions adjusted for potential confounders. Results: Positive associations were observed between the four dietary inflammatory scores and levels of CRP, IL6, sTNFR1, sTNFR2 and leptin. However, only the DII and the ISD were positively associated with IL1RA levels and only the DII and the E-DIIr were positively associated with TNFα levels. The proportion of variance of each biomarker explained by the scores was lower than 2%, which was equivalent to the variance explained by smoking status but much lower than that explained by body mass index. Conclusions: Our results suggest that the four dietary inflammatory scores were associated with some biomarkers of inflammation and could be used to assess the inflammatory potential of diet in European adults but are not sufficient to capture the inflammatory status of an individual. These findings can help to better understand the inflammatory potential of diet, but they need to be replicated in studies with repeated dietary measurements.
... These agreed with those of Li et al., 2011 47 who reported that lower levels of the two PUFAs in PDR patients may be associated with higher levels of circulating proinflammatory markers such as IL-1ra and IL-6 and lower anti-inflammatory marker TGFb. 48 Diabetic retinopathy is associated with proinflammatory cytokines, and downregulation of omega-6 PUFAs may potentiate these effects and increase the risk of developing the condition. 6 As regard Sema3A levels, we found that both PDR and NPDR groups had significantly higher serum levels than NDR group. ...
Diabetic retinopathy (DR) is a typical microvascular complication of diabetes mellitus (DM) and it remains one of the leading causes of vision loss worldwide. Studies postulated that a distinct metabolic signature of DR exists and can be resolved from that of diabetes alone. Serum Semaphorin3A (Sema3A) levels have also been found to be correlated with the phenotypes of diabetic retinopathy. We aimed to analyze and identify serum metabolites and serum Sema3A levels that could be useful biomarkers of DR progression. This cross-sectional study included 45 type 2 diabetes (T2D) patients. Diabetic patients were divided into three groups based on the status of their complications: non-DR (NDR, n=15), non-proliferative DR (NPDR, n=15), and proliferative DR (PDR, n=15) groups. Serum metabolomic profiles of these patients were determined by using high-performance liquid chromatography-mass spectrometry (HPLC-MS), and serum Sema3A levels measured by ELISA. Metabolomics analysis revealed a set of metabolites that were altered in the serum of PDR patients as compared with NPDR and NDR groups. Among these metabolites total asymmetric dimethylarginine (ADMA) and Kynurenine were potential predictors of PDR patients. Significantly higher serum levels of Sema3A in PDR patients as compared with NPDR and NDR groups (p < 0.001), their serum levels were positively correlated with the central macular thickness (r= 0.952, p < 0.001) and negatively correlated with the superficial macular density (r=-0.952, p < 0.001). In conclusion, the metabolite signatures identified in this study and serum Sema3A levels could be proposed as biomarkers for DR development and progression in T2D patients. However, Sema3A was superior to metabolomics in the prediction of the severity of DR.
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Objectives This meta-analysis aims to evaluate the effect of n-3 polyunsaturated fatty acids (PUFAs) as a part of parenteral nutrition in patients undergoing liver surgery. Design Systematic review and meta-analysis. Data sources PubMed, the Cochrane Central Register of Controlled Trials, Springer link, Web of Science, China National Knowledge Infrastructure and VIP Database. Eligibility criteria We included randomised controlled trials (RCTs) and evaluated the outcomes of liver function, inflammatory reaction, the influence of certain markers of the immune system, and specific clinical indexes for patients undergoing liver surgery and receiving parenteral nutrition with n-3 PUFAs. Data extraction and synthesis The Cochrane Collaboration’s tool was used to assess the risk of bias for each study. Findings were summarised in Grades of Recommendation, Assessment, Development and Evaluation evidence profiles and synthesised qualitatively. Results Eight RCTs, including 748 patients (trial: 374; control: 374), were included in the meta-analysis. Compared with patients in the control group, the patients in the n-3 PUFA group who underwent liver surgery had significantly lower aspartate aminotransferase (mean difference, MD −42.72 (95% CI −71.91 to –13.52); p=0.004), alanine aminotransferase (MD −38.90 (95% CI −65.44 to –12.37); p=0.004), white cell count (MD −0.93 (95% CI −1.60 to –0.26); p=0.007) and IL-6 (MD −11.37 (95% CI −14.62 to –8.13); p<0.00001) levels and a higher albumin level (MD 0.42 (95% CI 0.26 to 0.57); p<0.00001). They also had fewer infection complications (OR 0.44 (95% CI 0.28 to 0.68); p=0.0003) and a shorter duration of hospital stay (MD −2.17 (95% CI −3.04 to –1.3); p<0.00001) than the controls. However, there were no significant differences in terms of total bilirubin, TNF-α, IL-2, IgA, IgG, IgM and CD3, biliary leakage and mortality between the two groups. Conclusions We found that n-3 PUFAs can benefit patients undergoing liver surgery by improving liver function and certain clinical indexes and decreasing related inflammation factors. However, there are limited RCTs on the application of n-3 PUFAs for patients undergoing liver surgery. Further evidence of the benefit of n-3 PUFAs in these patients warrants further exploration.
Natural variations in the 13C:12C ratio (carbon-13 isotopic abundance [δ13C]) of the food supply have been used to determine the dietary origin and metabolism of fatty acids, especially in the n-3 polyunsaturated fatty acid (PUFA) biosynthesis pathway. However, n-6 PUFA metabolism following linoleic acid (LNA) intake remains under investigated. Here, we sought to use natural variations in the δ13C signature of dietary oils and fatty fish to analyze n-3 and n-6 PUFA metabolism following dietary changes in LNA and eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) in adult humans. Participants with migraine (aged 38.6 ± 2.3 y, 93% female, BMI 27.0 ± 1.1 kg/m2) were randomly assigned to one of three dietary groups for 16 weeks: 1) low omega-3, high omega-6 (H6), 2) high omega-3, high omega-6 (H3H6), or 3) high omega-3, low omega-6 (H3). Blood was collected at baseline, 4, 10, and 16 weeks. Plasma PUFA concentrations and δ13C were determined. The H6 intervention exhibited increases in plasma LNA δ13C signature over time; meanwhile, plasma LNA concentrations were unchanged. No changes in plasma arachidonic acid δ13C or concentration were observed. Participants on the H3H6 and H3 interventions demonstrated increases in plasma EPA and DHA concentration over time. Plasma δ13C-EPA increased in total lipids of the H3 group and phospholipids of the H3H6 group compared to baseline. Compound-specific isotope analysis supports a tracer-free technique that can track metabolism of dietary fatty acids in humans, provided that the isotopic signature of the dietary source is sufficiently different from plasma δ13C.
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Omega-3 fatty acids may be protective against bipolar disorder (BD), whereas omega-6 fatty acids and an increased omega-6:omega-3 ratio may increase the risk of BD. This causal relationship has not yet been established. We attempted to prove the existence of these causal relationships in this study. Datasets on omega-3, omega-6, and omega-6:omega-3 ratios were obtained from the UK Biobank. The EBI database was used to obtain the BD dataset. SNPs associated with fatty acids were identified as instrumental variables (IVs) that met the criteria of P < 5 × 10-8, LD (R2 > 0.01), and kb < 10 000. The main analytical method in this study was the inverse variance weighted (IVW) method. Furthermore, we employ a variety of methods for sensitivity analysis. According to the IVW analysis, higher omega-3 levels were associated with a lower risk of BD (OR = 0.884, 95%CI: 0.796-0.982, P < 0.05). An increase in the omega-6:omega-3 ratio was associated with an increased risk of BD (OR = 1.172, 95%CI: 1.046-1.314, P < 0.05), but no causal relationship between omega-6 levels and BD risk was unearthed. Our MR findings suggest that the ratio of omega-3, omega-6:omega-3 is associated with the risk of BD. It is important to be concerned about the risk of BD in individuals with low serum omega-3 intake and a high omega-6:omega-3 ratio.
Conference Paper
Alzheimer disease is one of the leading causes of death among older individuals. Unexplained weight loss and cachexia are frequent clinical findings in patients with Alzheimer disease. Thus, it has been postulated that Alzheimer disease may be associated with dysfunction in body weight regulation. This brief review examines the interrelations among energy intake, energy expenditure, and body composition in Alzheimer disease. We explored whether abnormally high daily energy expenditures, low energy intakes, or both contribute to unexplained weight loss and a decline in nutritional status. Specifically, we considered studies that examined energy intake, body composition, and daily energy expenditure and its components. The application of doubly labeled water and indirect calorimetry to understand the etiology of wasting has increased our knowledge regarding the relation among energy expenditure, physical activity levels, and body composition in Alzheimer disease patients. Although the number of studies are limited, results do not support the notion that a hypermetabolic state contributes to unexplained weight loss in Alzheimer disease, even in cachectic patients. Recent findings are presented suggesting an association between abnormally elevated levels of physical activity energy expenditure and elevated appendicular skeletal muscle mass and energy intake in Alzheimer disease patients. Clinical strategies aimed at developing lifestyle and dietary interventions to maintain adequate energy intake, restore energy balance, and maintain skeletal muscle mass should be a future area of investigation in Alzheimer disease research.
Background: The ankle brachial index (ABI) is a noninvasive, reliable measure of lower-extremity ischemia. However, the relationship between ABI and lower-extremity function has not been well studied. Objective: To describe the association between the ABI and lower-extremity function. Design: Cross-sectional study. Setting: 3 academic medical centers in the Chicago area. Participants: 740 men and women (460 with peripheral arterial disease). Measurements: Accelerometer-measured physical activity over 7 days, 6-minute walk, 4-m walking velocity, standing balance, and ABI. Results: 33% of participants with peripheral arterial disease had intermittent claudication. Fewer than 40% of participants with an ABI less than 0.40 walked continuously for 6 minutes compared with more than 95% of participants with an ABI between 1.00 and 1.50. Compared with an ABI of 1.10 to 1.50, an ABI less than 0.50 was associated with shorter distance walked in 6 minutes (beta-regression coefficient = -523 ft [95% Cl, -592 to -454 ft]; P < 0.001), less physical activity (beta = -514.8 activity units [Cl, -657 to -373 activity units]; P < 0.001), slower 4-m walking velocity (beta = -0.21 m/s [Cl, -0.27 to -0.15 m/s]; P < 0.001), and less likelihood of maintaining a tandem stand for 10 seconds (odds ratio, 0.37 [Cl, 0.18 to 0.76]; P = 0.007), after adjustment for typical confounders. Associations between ABI and function were stronger than associations between leg symptoms and function. Conclusions: The ABI, a noninvasive test that can be performed in a medical office, is more closely associated with leg function in persons with peripheral arterial disease than is intermittent claudication or other leg symptoms. These data support the use of the ABI to identify abnormal lower-extremity function.
Long chain fatty acids, derived either from endogenous metabolism or by nutritional sources play significant roles in important biological processes of membrane structure, production of biologically active compounds, and participation in cellular signaling processes. Recently, the structure of dietary fatty acids has become an important issue in human health because ingestion of saturated fats (containing triglycerides composed of saturated fatty acids) is considered harmful, while unsaturated fats are viewed as beneficial. It is important to note that the molecular reason for this dichotomy still remains elusive. Since fatty acids are important players in development of pathology of cardiovascular and endocrine system, understanding the key molecular targets of fatty acids, in particular those that discriminate between saturated and unsaturated fats, is much needed. Recently, insights have been gained on several fatty acid-activated nuclear receptors involved in gene expression. In other words, we can now envision long chain fatty acids as regulators of signal transduction processes and gene regulation, which in turn will dictate their roles in health and disease. In this review, we will discuss fatty acid-mediated regulation of nuclear receptors. We will focus on peroxisome proliferators-activated receptors (PPARs), liver X receptors (LXR), retinoid X receptors (RXRs), and Hepatocyte Nuclear Factor alpha (HNF-4α), all of which play pivotal roles in dietary fatty acid-mediated effects. Also, the regulation of gene expression by Conjugated Linoleic Acids (CLA), a family of dienoic fatty acids with a variety of beneficial effects, will be discussed.Keywords: Fatty acid; Nuclear receptor; Gene; Transcription
Peroxisome proliferator-activated receptors (PPARs) are key players in lipid and glucose metabolism and are implicated in metabolic disorders predisposing to atherosclerosis, such as dyslipidaemia and diabetes
Long chain fatty acid fractionation has become a valuable tool in the management of patients maintained on total parenteral nutrition. While many clinicians prefer to use absolute concentrations to monitor a patient's fatty acid status, reference ranges are not available. Previous reference range studies reported values in terms of percentages only and calculated ranges parametrically. However, due to the non-Gaussian distributions of some serum fatty acids, it is necessary to calculate reference ranges non-parametrically. Serum from blood donors (n = 130) were collected and analyzed for total fatty acids by gas-liquid chromatography. Results for each of the fatty acids were calculated both as a concentration and as a percentage of the total fatty acids measured. © 1994 Wiley-Liss, Inc.
Interleukin-6 mediates pleiotropic functions in various types of cells through its specific receptor (IL-6-R), the cDNA of which has already been cloned. We report here that an 80 kd single polypeptide chain (IL-6-R) is involved in IL-6 binding and that IL-6 triggers the association of this receptor with a non-ligand-binding membrane glycoprotein, gp130. The association takes place at 37 degrees C within 5 min and is stable for at least 40 min in the presence of IL-6, but does not occur at 0 degree C. Human IL-6-R can associate with a murine gp130 homolog and is functional in murine cells. Mutant IL-6-R lacking the intracytoplasmic portion is functional, suggesting that the two polypeptide chains interact to involve their extracellular portion. In fact, a soluble IL-6-R lacking the transmembrane and intracytoplasmic domains can associate with gp130 in the presence of IL-6 and mediate its function. These findings indicate that the complex of IL-6 and IL-6-R can interact with a non-ligand-binding membrane glycoprotein, gp130, extracellularly and can provide the IL-6 signal.