The Journal of Nutrition
Nutrition and Disease
Ruminant-Produced trans-Fatty Acids Raise
Plasma HDL Particle Concentrations in Intact
and Ovariectomized Female Hartley Guinea
Beth H. Rice,4,8Jana Kraft,4Fre ´de ´ric Destaillats,5Dale E. Bauman,6and Adam L. Lock7*
4Department of Animal Science, University of Vermont, Burlington, VT;5Nestle ´ Research Center, Vers-chez-les-Blanc, Lausanne,
Switzerland;6Department of Animal Science, Cornell University, Ithaca, NY; and7Department of Animal Science, Michigan State
University, East Lansing, MI
Cardiovascular disease (CVD) is the leading cause of death among women worldwide, and risk for developing CVD
increases postmenopause. Consumption of trans-fatty acids (tFA) has been positively associated with CVD incidence and
mortality.The current studywas designedto assessthe effectsof dietshigh in industrially produced(IP)-tFA, frompartially
hydrogenated vegetable oils (PHVO), and ruminant-produced (RP)-tFA, from butter oil (BO), on risk factors for CVD. Thirty-
two female Hartley guinea pigs, one-half of which were ovariectomized (OVX) to mimic the postmenopausal condition,
were fed hypercholesterolemic diets containing 9% by weight PHVO or BO (n = 8/diet and ovariectomy) for 8 wk. The
plasma and hepatic lipids did not differ between IP- and RP-tFA groups or between intact and OVX guinea pigs. The BO
diet resulted in higher concentrations of plasma total and small HDL particle subclass concentrations than the PHVO diet
regardless of ovariectomy status. The intact BO group had higher concentrations of large HDL particles than the intact
PHVO group. HDL mean particle size tended to be larger (P = 0.07) in the PHVO groups compared with the BO groups
regardless of ovariectomy status. There was a trend toward an interaction between diet and ovariectomy status for LDL
mean particle size, which tended to be larger in OVX guinea pigs fed PHVO (P = 0.07). In summary, consumptionof IP- and
RP-tFA resulted in differential effects on HDL particle subclass profiles in female guinea pigs. The effect of tFA
consumption and hormonal status on HDL particle subclass metabolism and the subsequent impact on CVD in females
warrants further investigation. J. Nutr. doi: 10.3945/jn.112.160077.
Cardiovascular disease (CVD)9is the leading cause of mortality
among men and women in the United States (1). In the last 2
decades, deaths attributable to CVD have been declining in men,
but not in women, with more women dying annually from CVD
than men (2). Many deaths caused byCVD occur in women with
no prior symptoms of disease (3), which indicates that early
detection of risk factors is essential to morbidity and mortality
prevention (2). Prior to menopause, women have a significantly
lower risk of experiencing a cardiovascular event (4). This may
be because transition into menopause is associated with an
increased fat mass and a redistribution of fat from the periphery
to the abdomen, both of which emerge with estrogen deficiency
(5). These changes in adiposity are associated with dyslipidemia
and increased risk of CVD postmenopause (6).
The consumption of trans-fatty acids (tFA) has been associ-
ated with an increased risk of CVD in both men and women (7).
There are 2 predominant sources of dietary tFA in the food
supply: industrially produced (IP)-tFA formed during the man-
ufacture of partially hydrogenated vegetable oils (PHVO) and
ruminant-produced (RP)-tFA that are synthesized via the bac-
terial metabolism of MUFA and PUFA in the rumen and found in
ruminant-derived milk and meat products (8,9). The majority of
tFA present in both sources are 18-carbon fatty acids with a
single double bond (18:1) (8). The relative amount of trans-18:1,
1Supported in part by the University of Vermont and Cornell University
Agricultural Experiment Stations, Michigan State University AgBioResearch,
and the Vermont Genetics Network through grant no. P20 RR16462 from the
Institutional Development Award Networks of Biomedical Research Excellence
Program of the National Center for Research Resources, a component of the
2Author disclosures: J. Kraft, D. E. Bauman, and A. L. Lock, no conflicts of
interest. B. H. Rice is employed by the Dairy Research Institute and declares no
other interests. F. Destaillats is employed by the Nestle ´ Research Center and
declares no other interests.
3Supplemental Tables 1 and 2 are available from the ‘‘Online Supporting
Material’’ link in the online posting of the article and from the same link in the
online table of contents at http://jn.nutrition.org.
8Present address: Dairy Research Institute, Rosemont, IL 60018.
9Abbreviations used: BO, butter oil; CVD, cardiovascular disease; IP, industrially
produced; OVX, ovariectomized; PHVO, partially hydrogenated vegetable oil; RP,
ruminant-produced; TC, total cholesterol; tFA, trans-fatty acids; TRANSFACT,
trans-Fatty Acids Collaboration.
* To whom correspondence should be addressed. E-mail: firstname.lastname@example.org.
ã 2012 American Society for Nutrition.
Manuscript received February 22, 2012. Initial review completed April 4, 2012. Revision accepted June 14, 2012.
Copyright (C) 2012 by the American Society for Nutrition
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The Journal of Nutrition. First published ahead of print July 18, 2012 as doi: 10.3945/jn.112.160077.
at DAIRY MANAGEMENT INC on July 19, 2012
however, differs greatly between the 2 sources, with PHVO
containing up to 60% trans-18:1, whereas ruminant-derived fats
contain ~2–4% trans-18:1 (8). The distribution of trans-18:1
fatty acid isomers also varies between sources, with PHVO
typically containing a Gaussian distribution centered on trans-
6–8, trans-9, or trans-10 18:1 (8). By comparison, in ruminant-
derived fats, the predominant isomer is trans-11 18:1, also
known as vaccenic acid (10). Although the consumption of
trans-18:1 from PHVO is associated with increased risk
of developing CVD (11), there is a growing body of scientific
evidence indicating possible differences in health outcomes
between tFA sources (9). One potential factor explaining such
differences is the varying total amount and distribution of trans-
18:1 fatty acid isomers present in IP-tFA and RP-tFA. This is
supported by our recent study in which we reported that
different IP-tFA sources (PHVO) containing the same total tFA
content but different trans-18:1 profiles had divergent effects on
cholesterol and lipoprotein metabolism in hamsters (12).
In the Trans-Fatty Acids Collaboration (TRANSFACT)
study, it was reported that when consumed in equal amounts,
IP-tFA from PHVO and RP-tFA from butter oil (BO) induced
divergent effects on risk factors for CVD (13). Results also
indicated that gender might play a role in the effects of IP- and
RP-tFA intake on risk factors for CVD; RP-tFA raised plasma
HDL- and LDL-cholesterol and large HDL and LDL particles in
women, but not men, compared with IP-tFA. Using these same
test fats, we showed that when fed at a high level, IP- and RP-tFA
had similar effects on traditional plasma cholesterol risk factors
for CVD in male Hartley guinea pigs (14). In the guinea pig,
however, RP-tFA, but not IP-tFA, resulted in increased levels of
plasma total and small HDL particles, a particle profile that has
been hypothesized to be associated with a decreased risk of CVD
(14). Guinea pigs are an appropriate and often-used model for
testing the effects of dietary interventions on established CVD
risk factors because they have reverse cholesterol transport and
metabolize lipoproteins similarly to humans (15).
Based on the aforementioned results, we hypothesized that a
diet rich in IP-tFA from PHVO would have detrimental effects
on risk factors associated with CVD compared with a diet rich in
RP-tFA. Because the transition into menopause is associated
with a significantly higher risk of experiencing a cardiovascular
event (4), we hypothesized that effects observed would differ
between intact and ovariectomized (OVX) female guinea pigs.
OVX guinea pigs have been previously used as models for
menopause (16) and intact and OVX guinea pigs have been
utilized in nutritional studies pertaining to CVD risk (15,17).
The objective of the current study was to compare plasma lipids,
lipoprotein concentrations and distribution, and hepatic lipids in
intact and OVX female Hartley guinea pigs that were fed IP-tFA
from PHVO and RP-tFA from BO.
Materials and Methods
Experimental design. The University of Vermont Animal Care and Use
Hartley guinea pigs (n = 32; weighing 250–300 g), one-half of which
were OVX, were purchased from Charles River Laboratories. Guinea
pigs were housed in pairs according to ovariectomy status in a controlled
environment (22?C, 55% humidity) with a 12-h-light/-dark cycle.
Guinea pigs consumed ad libitum a commercial standard diet (Guinea
Pig Diet 50Z3; Nutrazu) until 8 wk of age.
Guinea pigs were randomly assigned by ovariectomy status (intact or
OVX) to the PHVO or BO diet groups (n = 8/diet and ovariectomy). A
mixture of commercial standard diet and designated experimental diet
(50:50 by weight) was fed for a 2-wk lead-in time, followed by the start
of the 8-wk experimental period. Over the course of the lead-in and
experimental periods, feed and refusals were weighed daily and guinea
pigs were allowed free access to water. During the experimental period,
guinea pigs were pair-fed to the mean of the OVX-PHVO group to
ensure intake and weight gain remained consistent between them.
At the conclusion of the experiment, guinea pigs were feed deprived
overnight. The following day they were anesthetized with isoflurane and
blood was collected from the left ventricle into tubes containing EDTA
(BD). Guinea pigs were killed by exsanguination. The liver was
immediately removed, weighed, and stored at 220?C.
Diet formulation. Both the PHVO and BO test fats were previously
used in the TRANSFACT clinical study (13) and in our prior investi-
gation of tFA sources and CVD risk factors in male guinea pigs (14). The
manufacture of the test diets has been described in detail elsewhere (18).
The tFA content of the BO was ~4- to 7-fold higher than that typically
present in milk fat, which allowed for the direct comparison on a gram-
to-gram basis the effect of RP- with IP-tFA.
The composition of experimental guinea pig diets is shown in
Supplemental Table 1 and was previously reported (14). Diets were
prepared and pelleted by Teklad Custom Research Diets (Harlan
Laboratories). When mixed, the experimental diets were calculated to
contain 18.1% protein, 31.8% carbohydrate, and 12.1% total fat. The
experimental fats, PHVO and BO, supplied 9% of the total fat in their
respective diets. Protein, carbohydrate, and fat were calculated to account
for 23.5, 41.2, and 35.3% of total energy in the diets. Cholesterol was
added to the diets to induce hyperlipidemia and enhance detectable effects
of the treatments (15). The PHVO diet was supplemented with 0.25%
cholesterol by weight, whereas the BO diet had 0.23% added cholesterol
by weight to account for the level of cholesterol already present in this fat
The PHVO and BO diets were similar in total SFA, MUFA, PUFA,
and trans-18:1 amounts (Table 1). The amount of IP- and RP-tFA in the
current study (1.3% of energy) was similar to that used for the moderate
RP-tFA group(1.5%of energy) in a clinical study (19),a levelthat can be
achieved through a high intake of dairy products and meat from
ruminants (19). The PHVO diet was higher in trans-6–8, trans-9, and
trans-10 18:1 fatty acids, whereas the BO diet was higher in trans-11
18:1 (Table 1). The sum of trans-6–8, trans-9, and trans-10 18:1 fatty
acids in the PHVO diet was equal to the quantity of trans-11 18:1 in the
BO diet. Thus, the equality in total trans-18:1 fatty acid amount allowed
Fatty acid composition of experimental diets1
g/100 g of total fatty acids
g/100 g of total trans-18:1 isomers
1Values are means of 3 replicate GLC analyses. ND, not detected, ,0.01 g/100 g fatty
2 of 5 Rice et al.
at DAIRY MANAGEMENT INC on July 19, 2012
the effects of the trans-18:1 isomer distribution to be compared among
Plasma lipid and lipoprotein particle analysis. Plasma was isolated
and the concentrations of total cholesterol (TC), TG, LDL-cholesterol,
and HDL-cholesterol were determined using enzymatic assays (WAKO
Diagnostics) as previously described (14). HDL, IDL, LDL, and VLDL
particle sizes and concentrations were measured by H+NMR spectros-
copy (Liposcience) as previously described (14).
Hepatic cholesterol and TG analysis. Hepatic lipids were extracted
using the method of Bligh and Dyer (20). TC, free cholesterol, and TG
concentrations were determined from a 600-mg aliquot of total hepatic
lipids using enzymatic assays (WAKO Diagnostics) as previously de-
scribed (14). Cholesterol esters were calculated as the difference of free
cholesterol from TC.
Statistical analysis. Data were analyzed using JMP 8.0 statistical
discovery software. The test for unequal variances was used to ensure
normal distribution. Two-way ANOVA, by fit model, was used to
determine the effects of diet (PHVO and BO), ovariectomy (intact and
OVX), and the interaction of diet 3 ovariectomy. Differences between
means in the intact and OVX groups due to intake of PHVO or BO were
determined by Tukey?s post hoc test. Treatment effects were declared
significant at P # 0.05 and tendencies for treatment effects at P # 0.10.
Data are reported as mean 6 SD. One guinea pig from the intact PHVO
group died during the study. Therefore, the statistical analyses were
based on n = 31 (n = 8/diet and ovariectomy, except the intact PHVO
group, where n = 7).
52 g) did not differ among treatment groups during the experi-
Plasma cholesterol and TG concentrations. Plasma choles-
terol concentrations, including TC, HDL-cholesterol, and LDL-
cholesterol, as well as plasma TG did not differ among treatment
groups regardless of ovariectomy (Table 2).
Plasma lipoprotein particle concentrations and sizes.
VLDL, IDL, and LDL particle subclass concentrations did not
differ among groups (Table 2). Total and small HDL particle
concentrations were more than 5-fold higher in the BO groups
than in the PHVO groups (P < 0.001). There was an interaction
between diet and ovariectomy for large HDL particle concen-
trations, which was higher in intact BO-fed guinea pigs than in
intact PHVO-fed guinea pigs (P < 0.05). Large HDL particle
concentrations did not differ in OVX guinea pigs fed PHVO or
BO and neither differed from intact guinea pigs.
and distribution of intact or OVX guinea pigs fed a PHVO or BO diet for 8 wk1
Plasma lipid, lipoprotein cholesterol concentrations, and lipoprotein particle size
Plasma Variable PHVOBOPHVOBO Diet Ovariectomy Interaction
Lipids and ratios
VLDL cholesterol, mmol/L
NMR lipoprotein particle measures
Total VLDL particles
Total LDL particles
Total HDL particles
Particle size, nm
0.71 6 0.40
8.1 6 4.2
0.25 6 0.12
4.3 6 2.3
1.5 6 0.9
1.5 6 0.4
0.70 6 0.30
7.9 6 3.9
0.25 6 0.10
3.9 6 2.1
1.6 6 1.0
1.5 6 0.9
0.95 6 0.38
8.8 6 5.3
0.31 6 0.17
4.5 6 2.6
1.3 6 0.4
2.2 6 1.6
0.82 6 0.18
8.2 6 3.6
0.25 6 0.20
4.1 6 1.6
1.9 6 0.9
1.6 6 0.8
88.5 6 51.5
1.8 6 1.9
17. 7 6 9.2
69.1 6 43.3
240 6 126
62.6 6 36.0
1.3 6 1.0
15.6 6 11.2
45.7 6 24.8
152 6 92
92.1 6 60.6
2.6 6 2.7
17.1 6 9.9
72.5 6 52.1
226 6 120
70.2 6 28.8
1.5 6 1.0
17.2 6 7.9
51.5 6 21.4
183 6 57
1.10 6 0.47
0.21 6 0.09
0.12 6 0.07
0.53 6 0.27
1.03 6 0.42
0.25 6 0.08
0.13 6 0.04
0.50 6 0.24
1.16 6 0.52
0.31 6 0.11
0.13 6 0.07
0.50 6 0.27
1.08 6 0.32
0.25 6 0.13
0.13 6 0.03
0.53 6 0.15
0.37 6 0.56b
0.10 6 0.16b
0.29 6 0.59b
2.43 6 0.91a
0.30 6 0.13a
2.13 6 0.97a
0.45 6 0.23b
0.19 6 0.12ab
0.26 6 0.32b
2.10 6 1.07a,0.001
0.20 6 0.09ab
1.90 6 1.08a,0.001
42.6 6 8.0
20.5 6 0.5
10.8 6 1.3
42.9 6 19.6
20.7 6 0.5
9.9 6 0.8
51.3 6 8.3
21.0 6 0.6
10.4 6 1.5
47.8 6 8.0
20.5 6 0.4
9.8 6 0.8
1Values are mean 6 SD, n = 8/diet and ovariectomy, except intact PHVO, n = 7. Means in a row without a common letter differ, P # 0.05.
BO, butter oil; ND, not detected; OVX, ovariectomized; PHVO, partially hydrogenated vegetable oil; TC, total cholesterol.
Dietary trans-18:1, ovariectomy, and cardiovascular disease risk3 of 5
at DAIRY MANAGEMENT INC on July 19, 2012
Mean lipoprotein particle sizes among the groups were not
different (Table 2). The mean HDL particle size tended to be
larger in guinea pigs fed PHVO than in guinea pigs fed BO
regardless of ovariectomy (P = 0.07). Furthermore, there was a
trend toward an interaction between diet and ovariectomy for
LDL mean particle size, with OVX-PHVO guinea pigs having
larger LDL mean particle sizes compared with the other groups
(P = 0.07).
Hepatic cholesterol and TG concentrations. Hepatic cho-
lesterol and TG concentrations did not differ among groups
regardless of ovariectomy (Supplemental Table 2).
The current study demonstrated that diets containing ~1.3%
of energy as trans-18:1 from different sources had divergent
effects on HDL particle subclass concentrations and distribution
in female guinea pigs. The differences in plasma HDL particle
subclass concentrations in intact and OVX guinea pigs fed IP-
and RP-tFAwere significant despite the similarity in plasma total
HDL-cholesterol concentration between these groups.
The inverse association between HDL-cholesterol and CVD
risk has been attributed to the role of HDL in reverse cholesterol
transport (21). Although guinea pigs have lower total concen-
trations of HDL-cholesterol than humans, the similarity in the
distribution of VLDL-, LDL-, and HDL-cholesterol is markedly
similar to humans, with guinea pigs carrying the majority of
cholesterol as LDL (22). Therefore, the changes in lipoprotein
metabolism detected in guinea pigs lend insight into the mech-
anisms by which dietary and hormonal changes may influence
lipoprotein remodeling and atherogenic status in humans.
Ovariectomy is a useful tool to mimic human ovarian
hormone loss comparable with the situation in postmenopausal
women (16). In prior investigations, it was reported that OVX
guinea pigs fed high-fat diets had a more atherogenic plasma
lipoprotein profile than intact guinea pigs (16,17). The profile of
plasma lipoproteins, however, did not differ between intact and
OVX guinea pigs in the current investigation. In previous
studies, other fat sources with different fatty acid profiles (lard
and corn oil as opposed to BO and PHVO) and higher fat
contents (15% as opposed to 12% of energy) were utilized
(16,17). Additionally, previous investigations utilized 0.33%
cholesterol in diets as opposed to the 0.25% in the current study
(17,23). These factors and others such as total diet composition,
age of guinea pigs, and duration of experiment may have
contributed to the differences in plasma lipid profiles reported
between the current and previous investigations.
The effects on HDL particle subclasses induced by RP-tFA in
the current study are not unlike those previously reported in
male guinea pigs fed the same treatment diets (14). When male
guinea pigs were fed PHVO and BO for 8 and 12 wk, the BO
treatment also resulted in higher total and small HDL particles
compared with the PHVO treatment (14). In the current study,
plasma large HDL particles were higher in the female guinea
pigs fed BO compared with those fed PHVO, but this effect was
seen only in intact guinea pigs, indicating an interaction between
tFA source and ovariectomy. In contrast, no differences in large
HDL particle concentration were detected between the PHVO
and BO treatments in the previous study conducted in male
guinea pigs (14). The TRANSFACT clinical study (13) utilized
the same experimental fats as those used in the current study.
These fats were incorporated into foods administered to men and
premenopausal women, withthe BO treatment resulting in higher
concentrations of large HDL subclass particles than the PHVO
treatment in women, but not in men (13). In a clinical trial in men
consuming 1.5% ofdaily energyintake as RP-tFA, a neutral effect
on plasma lipids and other CVD risk factors was reported (19). In
a recent clinical study in women, which evaluated the same daily
intake of RP-tFA, no significant effect on plasma TC, LDL-C, or
TG was reported. There was a small but significant reduction in
HDL-cholesterol among overweight or obese women fed the RP-
the effects of IP- and RP-tFA on HDL particle subclass metab-
olism between males and females.
The effects of diet on HDL particle subclass distribution is of
particular importance, because it has been reported that plasma
classes of HDL lipoproteins are better predictors of coronary
events than plasma HDL-cholesterol concentrations (25), par-
ticularly in postmenopausal women (26). Recently, plasma small
HDL particle concentrations were positively associated and
plasma large HDL particle subclass concentrations inversely
associated with the degree of coronary atherosclerosis in a
cohort of postmenopausal women with established CVD (26).
This raises the question as to whether or not the HDL subclass
distribution induced by the BO treatment in the current study
was more or less atherogenic than that of the PHVO. Whereas
small HDL particles have been associated with CVD (26–32), an
intervention trial showed an inverse association between plasma
concentrations of both small and total HDL particles and risk of
new CVD events in patients receiving oral, lipid-lowering drug
therapy (25). In a review on HDL particle subclass distribution
and its effect on atherogenicity, it was noted that small HDL
particles typically possess antiatherogenic properties but may
become dysfunctional and contribute to atherogenesis when
coupled with a decrease in total HDL particles (31). In the
currentinvestigation, the increased concentrations of smallHDL
particles induced by the BO treatment were accompanied by
greater total HDL particles. Therefore, the effect of the BO
treatment on plasma small HDL particle subclass distribution
may not have been indicative of an atherogenic effect. Changes
in activity of cellular proteins and rate-limiting enzymes critical
to reverse cholesterol transport may affect cholesterol efflux
such that HDL particle numbers are increased while the amount
of HDL-cholesterol remains the same (21). Further investigation
of the effect of tFA on HDL particle subclass distribution is
In the current study, counter to the hypothesized result, the
PHVO diet did not result in a more detrimental plasma lipid
profile than the BO diet. A recent study in male F1B hamsters
revealed that PHVO containing the same total tFA content but
different trans-18:1 profiles resulted in divergent plasma lipo-
protein and subclass profiles (12). A prior study in golden Syrian
hamsters demonstrated that PHVO consumption resulted in a
more atherogenic plasma lipid profile compared with consump-
tion of trans-9 18:1 as a single fatty acid (33). These results
suggest that specific trans-18:1 isomer profiles or tFA in PHVO
other than trans-18:1 isomers (e.g., trans-18:2 isomers) may be
responsible for the effects of PHVO on various CVD risk factors.
Notably, the most abundant trans-18:1 isomer in the PHVO
used in the current study was trans-9 18:1. It is possible that if
the PHVO used in the current study was derived from other
parent oils or was manufactured under hydrogenation condi-
tions leading to a different tFA profile, it may have affected
plasma lipid concentrations differently.
In conclusion, diets high in RP- and IP-tFA as well as
ovariectomy modulated HDL particle subclass concentrations
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at DAIRY MANAGEMENT INC on July 19, 2012
and distribution in female Hartley guinea pigs. Compared with
IP-tFA, consumption of RP-tFA resulted in higher total andsmall
HDL particle subclass concentrations regardless of ovariectomy
and higher large HDL particle subclass concentrations in intact
female guinea pigs. These results indicate the premenopausal
condition may play an important role in metabolic responses to
dietary sources of tFA. Further research into the effects of RP-tFA
on HDL particle subclass metabolism in females is warranted.
B.H.R., J.K., and A.L.L. designed the research; B.H.R. and J.K.
conducted the research, analyzed the data, and wrote the
mauscript; F.D. and D.E.B. provided essential materials; F.D.,
D.E.B., and A.L.L. contributed to the review and editing of the
manuscript; and A.L.L. had primary responsibility for the final
content. All authors read and approved the final manuscript.
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at DAIRY MANAGEMENT INC on July 19, 2012