Critical Review

Guinea Pigs as Models for Cholesterol and Lipoprotein Metabolism

Maria Luz Fernandez1
Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut 06269-4017

ABSTRACT Guinea pigs carry the majority of their plasma cholesterol in LDL, making them a unique animal model
with which to study hepatic cholesterol and lipoprotein metabolism. In this review, the benefits and advantages of
using this particular model are discussed. How dietary factors such as soluble fiber, cholesterol and fatty acids that

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vary in saturation and chain length affect hepatic cholesterol homeostasis and influence the synthesis, intravascular
processing and catabolism of lipoproteins is reviewed. In addition, alterations in hepatic cholesterol metabolism
and plasma lipoproteins as affected by treatment with cholestyramine or 3-hydroxyl-3-methylglutaryl coenzyme A
reductase inhibitors, exercise, marginal intake of vitamin C, ovariectomy (a model for menopause) and similarities
to the human situation are addressed. A review of guinea pigs as models for early atherosclerosis development is
also presented. J. Nutr. 131: 10 –20, 2001.

KEY WORDS: ● Guinea pigs ● lipoprotein metabolism ● hepatic cholesterol metabolism ● soluble fiber
● atherosclerosis.

The goal of this review is to provide insight into the
benefits and advantages of using guinea pigs to explain how
hepatic cholesterol and lipoprotein metabolisms are affected
by dietary factors, drug treatment, marginal intake of Vitamin
C, exercise, gender, development and menopause.
There is some controversy as to whether guinea pigs (Cavia
porcellus) should be classified as rodents (Martignetti et al.
1993, Noguchi et al. 1994). Although this issue is not relevant
to the present discussion, there is one aspect of guinea pigs
that makes them stand out from other rodents: the fact that
they carry the majority of their cholesterol in LDL (Fernandez
and McNamara 1989). This outstanding difference raises the
question as to whether guinea pigs have other similarities to
humans in cholesterol and lipoprotein metabolism. Research-
ers at our laboratory and other investigators have found that
guinea pig cholesterol metabolism does indeed have some
analogies to human cholesterol metabolism that merit discus-
sion.
Some of these similarities include the following:
1. Guinea pigs have high LDL-to-HDL ratios (Fernandez
et al. 1990a).
2. They have higher concentrations of free than of ester-
ified cholesterol in the liver (Angelin et al. 1992).
1
To whom correspondence should be addressed.
E-mail: maria-luz.fernandez@uconn.edu
2
Abbreviations used: ACAT, acyl coenzyme A cholesteryl acyltransferase;
apo, apolipoprotein; Bmax, maximal binding; CETP, cholesterol ester transfer
protein; CE, cholesteryl ester; CO, corn oil; Cyp7, cholesterol 7␣-hydroxylase; FC,
free cholesterol; FCR, fractional catabolic rate; GG, guar gum; HC, high concen-
tration of dietary cholesterol; HDL-C, HDL-cholesterol; HL, hepatic lipase; HMG-
CoA, 3-hydroxy-3-methylglutaryl coenzyme A; LC, low concentration of dietary
cholesterol; LDL-C, LDL cholesterol; LCAT, lecithin-cholesterol acyltransferase;
LPL, lipoprotein lipase; MONO, monounsaturated fatty acids; PC, phosphatidyl-
choline; PE, pectin; PK, palm kernel oil; PPP, prickly pear pectin; PSY, psyllium;
PUFA, polyunsaturated fatty acids; SAT, saturated fatty acids; TAG, triacylglyc-
erol; VLDL-C, VLDL cholesterol.
3. They have plasma cholesteryl ester transfer protein
(CETP)2 (Ha et al. 1982), lecithin-cholesterol acyl-
transferase (LCAT) (Douglas and Pownell 1991) and
lipoprotein lipase (LPL) (Olivecrona and Bengsston-
Olivecrona 1993) activities for intravascular processing
of plasma lipoproteins.
4. They exhibit comparable moderate rates of hepatic
cholesterol synthesis (Reihner et al. 1990) and catab-
olism (Reihner et al. 1991).
5. Similar to humans, the binding domain for the LDL
receptor differentiates between normal and familial
binding defective apolipoprotein (apo)B-100 (Corsini
et al. 1992).
6. Apo B mRNA editing in the liver is negligible (⬍1%)
compared with 18 –70% in other species (Greeve et al.
1993).
7. They require dietary vitamin C (Sauberlich 1978).
8. Females have higher HDL concentrations than males
(Roy et al. 2000).
9. Ovariectomized guinea pigs have a plasma lipid profile
similar to that of postmenopausal women (Roy et al.
2000).
10. During exercise in guinea pigs, plasma triacylglycerol
(TAG) decreases and plasma HDL cholesterol
(HDL-C) increases (McNamara et al. 1993).
11. Guinea pigs respond to dietary interventions (Fernan-
dez and McNamara 1992b, 1992a and 1995a, He and
Fernandez 1998a) and drug treatment (Berglund et
al.1989, Hikada et al. 1992) by lowering plasma LDL
cholesterol (LDL-C)
Hepatic cholesterol metabolism
In contrast to rats (Swann et al. 1975), guinea pigs have
moderate rates of hepatic cholesterol synthesis (Fernandez et

0022-3166/01 $3.00 © 2001 American Society for Nutritional Sciences.

Manuscript received 17 July 2000. Initial review completed 3 October 2000.

10
 GUINEA PIGS AND LIPOPROTEIN METABOLISM
TABLE 1
Hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
reductase activity and hepatic free cholesterol concentrations
in guinea pigs fed 15% corn oil and varying concentrations of
dietary cholesterol or 0.25% cholesterol diet and varying
concentrations of citrus pectin1
HMG-CoA Hepatic free
Dietary treatment reductase activity cholesterol
pmol 䡠 min⫺1 䡠
mg protein⫺1 mmol/g
Dietary cholesterol,2 %
0 39 ⫾ 19a 4.4 ⫾ 0.3c
0.08 10 ⫾ 8b 7.5 ⫾ 0.8bc
0.17 4 ⫾ 1b 12.7 ⫾ 1.0b
0.33 7 ⫾ 1b 17.8 ⫾ 3.9a
Pectin,3 %
0 2.7 ⫾ 0.4b 17.0 ⫾ 4.0a
5 3.6 ⫾ 0.5b 13.7 ⫾ 2.8ab
12.5 31.2 ⫾ 5.0a 5.8 ⫾ 0.4b
1 Values are presented as means ⫾ SD, n ⫽ 4 –9 per group. Values
in a column with different superscript letters are significantly different as
determined by one-way ANOVA and the Newman-Keuls post hoc test
(P ⬍ 0.01).
2 Adapted from Lin et al. 1992.
3 Adapted from Fernandez et al. 1994a.
al. 1990a, McNamara 1984), esterification (Fernandez et al.
1995a) and catabolism (Fernandez 1995). However, hepatic
HMG-CoA reductase, acyl coenzyme A cholesterol acyltrans-
ferase (ACAT) and cholesterol 7␣-hydroxylase (Cyp7) activ-
ities are modulated by diet, drug treatment and gender in
guinea pigs.
HMG-CoA reductase (EC 1.1.1.34). Dietary modifica-
tions that alter hepatic free cholesterol (FC) modulate the
activity of the regulatory enzyme of cholesterol synthesis,
HMG-CoA reductase. The first compensatory response to
moderate concentrations of dietary cholesterol equivalent to
an absorbed amount of half of the daily synthesis rate in guinea
pigs is a significant down-regulation of HMG-CoA reductase
activity (Lin et al. 1992). Further, HMG-CoA reductase is
up-regulated when hepatic cholesterol concentrations are re-
duced as a result of the action of dietary soluble fiber in the
intestinal lumen (Fernandez et al. 1994a). Results from these
studies suggest that there might be a threshold of hepatic
cholesterol concentrations and that when this is achieved, the
immediate response is an up-regulation of cholesterol synthesis
by increases in HMG-CoA reductase activity. In contrast,
dietary fat saturation has only moderate effects on hepatic
cholesterol synthesis in guinea pigs (Fernandez and McNamara
1994, Ibrahim and McNamara 1988). The effects of dietary
cholesterol and dietary pectin on HMG-CoA reductase activ-
ity in response to changes in hepatic FC concentrations are
presented in Table 1.
ACAT (EC 2.3.2.26). ACAT is the intracellular enzyme
responsible for catalyzing the esterification of cholesterol in
various tissues, including the liver. We have observed that
dietary interventions (Fernandez et al. 1994a) and drug treat-
ment (Conde et al. 1996) modulate this enzyme activity. A
very significant dose-response in ACAT activity to dietary
pectin associated with parallel decreases in hepatic cholesterol
has been demonstrated in guinea pigs fed increasing doses of
citrus pectin (Fernandez et al. 1994a). There was a positive
correlation (r ⫽ 0.82) between hepatic FC and ACAT activ-
11
ity, demonstrating that substrate availability is a major deter-
minant of ACAT activity. Similarly, atorvastatin treatment
reduced hepatic microsomal FC, which resulted in a parallel
decrease in ACAT activity (Conde et al. 1996) (Fig. 1).
Other dietary treatments that lower hepatic FC in microsomes
(Vidal-Quintanar et al. 1997) or hepatic cholesterol (Ramji-
ganesh et al. 2000) have also been correlated with a decrease
in ACAT activity.
Dietary fat saturation and cholesterol amount alter hepatic
ACAT activity in guinea pigs (Sun et al. 1999). Monounsat-
urated (MONO) fatty acids resulted in the highest ACAT
activity compared with saturated (SAT) or polyunsaturated
(PUFA) fatty acids. Increasing concentrations of dietary cho-
lesterol resulted in parallel increases in hepatic ACAT activity
and microsomal FC. After modification of microsomal lipid
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composition with FC/phosphatidylcholine (PC) treatment,
ACAT activities remained significantly related to the FC-
to-PC molar ratio (Sun et al. 1999), confirming previous
findings that FC or FC/PC is a major regulator of ACAT
activity (Vidal-Quintanar et al. 1997).
Cyp7 (EC 1.14.13.7). The conversion of hepatic cho-
lesterol to bile acids represents the major regulatory pathway
by which the body eliminates excess cholesterol. Cholesterol
hydroxylation at the 7␣ position is the initial and rate-limiting
step in this process. Cyp7 presents a feedback inhibition by
hepatic flux of bile acids in rats, guinea pigs and rabbits
(Nguyen et al. 1999).
The activity of Cyp7 is up-regulated by soluble fiber in
guinea pigs (Fernandez 1995), possibly as a compensatory
response to interruption of the enterohepatic circulation of
bile acids. In the hamster, psyllium (PSY) intake increases
Cyp7 activity and mRNA abundance (Horton et al. 1994). In
addition, significant decreases in plasma LDL-C have been
observed in both hamsters and guinea pigs after PSY intake
(Fernandez 1995, Horton et al. 1994). These results suggest
that soluble fiber has multiple sites of action in the liver and
plasma compartment that contribute to the lowering of plasma
LDL-C. The first modulating step in the whole process could
be the up-regulation of Cyp7. In contrast, dietary cholesterol
has no effect on hepatic Cyp7 in guinea pigs (Fernandez 1995,
Fernandez et al. 1995a) or hamsters (Horton et al. 1995).
The LDL receptor. The LDL receptor plays a central role
in the metabolism of cholesterol in humans and animals
(Brown and Goldstein 1986). The expression of the LDL
FIGURE 1 Decreases in hepatic acyl-CoA cholesteryl acyltrans-
ferase (ACAT) activity and microsomal free cholesterol (FC) in guinea
pigs fed increasing doses of the HMG-CoA reductase inhibitor atorva-
statin. There was a significant dose-response (r ⫽ ⫺0.96, P ⬍ 0.001) for
changes in ACAT activity and (r ⫽ ⫺0.82, P ⬍ 0.01) for changes in
microsomal free cholesterol. Adapted from Conde et al. (1996).
12 FERNANDEZ
FIGURE 2 Correlation between plasma LDL cholesterol (LDL-C)
concentrations and LDL receptor number (Bmax) in female guinea pigs
fed control (cnt), pectin (pe), guar gum (gg) and psyllium (psy) diets in
combination with low and high levels of dietary cholesterol. A signifi-
cant negative correlation (r ⫽ ⫺0.70, P ⬍ 0.01) was found. Adapted
from Fernandez et al. (1995b).
receptor gene in the liver is regulated by a feedback mecha-
nism that involves hepatic cholesterol. When the demand for
cholesterol increases, the liver cells express high concentra-
tions of LDL receptor mRNA, and when cholesterol accumu-
lates in the cell, the activity and expression of the LDL
receptor are suppressed. In guinea pigs, an important mecha-
nism that regulates plasma LDL-C in response to diet or drug
treatment is the LDL or apoB/E receptor.
Intake of PUFA compared with SAT increases hepatic LDL
maximal binding (Bmax) in vitro (Fernandez et al. 1992a,
1992b and 1993, Fernandez and McNamara 1989) and recep-
tor-mediated LDL fractional catabolic rate (FCR) in vivo
(Fernandez et al. 1992a, 1992b and 1993), suggesting that
up-regulation of apoB/E receptors is a significant mechanism
by which PUFA decrease plasma LDL-C concentrations. Sim-
ilarly, when intake of soluble fiber [either pectin (PE), PSY or
guar gum (GG)] was compared with a control diet that con-
tained cellulose, a significant increase in hepatic LDL recep-
tors was observed, as well as increased rates of LDL turnover
(Fernandez 1995). In agreement with these observations, a
significant negative correlation was found between plasma
LDL-C and hepatic LDL Bmax in female guinea pigs fed dif-
ferent sources of fiber with low and high cholesterol diets (r
⫽ ⫺0.70, P ⬍ 0.01; Fernandez et al. 1995b) (Fig. 2).
Lipoprotein metabolism and processing in the intravascular
compartment
VLDL. Dietary fat saturation (Abdel-Fattah et al. 1995),
soluble fiber (Fernandez et al. 1997a) and simple carbohydrate
intake (Fernandez et al. 1995c) influence the secretion rate of
VLDL and affect the composition of nascent VLDL in guinea
pigs. Soluble fiber intake results in a slower secretion of VLDL
apoB, and the nascent particles are larger. In contrast, both a
high SAT diet and a diet high in sucrose result in a faster
secretion rate of smaller VLDL particles rich in CE compared
with a PUFA diet or a diet rich in complex carbohydrates
(Abdel-Fattah et al. 1995, Fernandez et al. 1995c).
In agreement with studies in humans (Grundy 1996),
guinea pigs fed diets rich in complex carbohydrates have lower
plasma TAG and VLDL cholesterol concentrations than those
fed diets rich in simple carbohydrates (Fernandez et al. 1996a).
Hepatic VLDL TAG secretion rates were not affected by
carbohydrate type after the intravenous injection of Triton
WR 1339, a detergent that blocks the action of LPL, which
results in TAG accumulation in plasma. However, the rate of
apoB secretion was 1.9-fold higher in sucrose-fed animals (P
⬍ 0.02), which explains the higher concentrations of plasma
TAG observed in guinea pigs fed simple carbohydrates (Fer-
nandez et al. 1995c and 1996b).
CETP and LCAT (2.3.1.43). Dietary soluble fiber (Fer-
nandez et al. 1997), intake of complex carbohydrates (Fernan-
dez et al. 1995b) and drug treatment (Conde et al. 1996) result
in significant alterations in the composition of plasma lipopro-
teins, which may be related to altered CETP activity. Guinea
pigs treated with 1, 3, 10, 20 and 40 mg atorvastatin/d had
lower CETP activity than those fed the control diet (0 mg
atorvastatin) (Conde et al. 1996). The lower CETP activity in
guinea pigs fed soluble fiber was related to the lower concen-
tration of CE in VLDL, which has a lower rate of conversion
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into LDL and is removed faster from plasma (Fernandez et al.
1997a).
LCAT plays a major role in the esterification process in the
plasma compartment. When guinea pigs are fed diets low in
cholesterol, the secreted nascent VLDL has a negligible
amount of CE (Abdel-Fattah et al. 1995). In contrast, the
mature VLDL derived from guinea pigs fed low cholesterol has
⬃10% CE (Fernandez et al. 1998). In agreement with our
observations, Barter et al. (1977) found that the composition
of guinea pig VLDL resembles that of LDL, which suggests
that, like humans, guinea pig CE in VLDL is mostly derived
from LCAT activity. Guinea pigs fed 35 or 45% total calories
from fat had higher LCAT activity than those fed 10 or 19%
total calories from fat, which correlated with the higher
VLDL-C concentrations observed in the former compared
with the latter groups (Fernandez et al. 1995d). Thus, CE in
VLDL from guinea pigs may be derived from two sources:
LCAT activity and CETP-mediated CE transfer. However,
ACAT activity may also contribute to the formation of CE in
VLDL (Fernandez and McNamara 1994), as discussed later.
LPL (3.1.1.34) and hepatic lipase (HL) (3.1.1.3). The
lipase gene family is made up of three genes that share struc-
tural similarities and are derived from a common ancestral
gene (Hide et al. 1992). This family includes LPL, HL and the
digestive enzyme pancreatic lipase. In humans, LPL activity
corresponds to two thirds of post– heparin lipase activity
whereas HL constitutes approximately one third (Olivecrona
and Bengstton-Olivecrona 1993). Although earlier studies re-
ported the absence of HL in guinea pigs (Yamada et al. 1979),
Wallinder et al. (1981) demonstrated lipase activity in guinea
pig postheparin plasma with the characteristics of HL. In later
studies, HL activity was shown to be up-regulated in guinea
pigs fed high cholesterol diets (Heller 1983). In guinea pigs,
similar to humans, HL activity is lower than LPL activity (Yin
et al. 1999).
A major step in the metabolism of TAG-rich lipoproteins is
hydrolysis of most of their TAG by LPL. A characteristic
feature of LPL is that apoC-II enhances the activity of this
enzyme (Jackson et al. 1977). Earlier studies postulated that
guinea pigs lacked apoC-II in plasma (Shirai et al. 1983);
however, Wallinder et al. (1979) demonstrated the presence of
an activator for LPL in guinea pig VLDL that hydrolyzed this
lipoprotein rapidly. Later, Andersson et al. (1991) conclu-
sively demonstrated the presence of apoC-II in plasma and,
with a human apoC-II cDNA probe, they identified the
mRNA species in guinea pig liver. Andersson et al. (1997) also
demonstrated that the low stimulation of LPL by guinea pig
plasma was due to lower absolute concentrations of apoC-II
and the presence of apoC-II containing LDL that had an
inhibitory effect on LPL activity. In contrast, apoC-III has an
important role in the inhibition of LPL. The cDNA of guinea
 GUINEA PIGS AND LIPOPROTEIN METABOLISM
pig apoC-III was cloned and sequenced (Yin and Olivecrona
1999). The two most conserved areas of guinea pig apoC-III
were found in residues 16 –33 and 50 – 69, which have been
predicted to form amphipathic helices assumed to play impor-
tant roles in the inhibition of LPL.
LPL activity is modulated in guinea pigs by food depriva-
tion (Sem and Olivecrona 1986) and by dietary fat being
higher in the dietary regimens that result in lower concentra-
tions of plasma LDL-C. For example, a diet rich in PUFA
resulted in higher LPL activity compared with a diet rich in
SAT (Cryer et al. 1978). Similarly, rapeseed oil intake resulted
in lower plasma LDL-C concentrations compared with intake
of either olive oil or palm oil, and lower LDL-C also correlated
with higher LPL activity (Fernandez et al. 1996b).
LDL. Various animal models have been used to determine
the effects of diet on lipoprotein concentration and metabo-
lism. Caution must be exercised in the interpretation of some
of these studies because animal species can vary greatly in the
distribution of plasma cholesterol among lipoproteins and be
totally different from humans (Nicolosi 1997). However, di-
etary modifications (Kris-Etherton and Yu-Poth 1997) and
drug treatment (Nawrocki et al. 1995) that alter LDL-C con-
centrations in humans result in similar alterations in guinea
pigs (Fernandez et al. 1999). Because guinea pigs carry the
majority of their cholesterol in LDL, this is not a surprising
finding. How dietary modifications and drug treatment affect
cholesterol and lipoprotein metabolism in guinea pigs is dis-
cussed later.
Earlier studies by Chapman et al. (1972) reported evidence
that LDL particles are formed from serum lipoproteins and are
not secreted directly into the plasma pool by the liver. Later,
Abdel-Fattah et al. (1995) used Triton WR 1339 to measure
the effects of dietary fat saturation on VLDL secretion and
demonstrated that LDL apoB specific radioactivity was un-
changed over time. These results are consistent with the
complete blockage of the conversion of VLDL to LDL and the
absence of any direct secretion of LDL apoB in guinea pigs.
Smaller LDL subfractions have been shown to disappear
from circulation faster in guinea pigs (Fernandez 1995, Fer-
nandez et al. 1992a and 1993, Swinkels et al. 1988). Swinkels
et al. (1988) isolated two human LDL subfractions with den-
sities of 1.023–1.034 and 1.036 –1.041 kg/L, respectively.
When they were injected into guinea pigs, a faster receptor-
mediated uptake was observed for the smaller fraction. Simi-
larly, we have reported faster clearance rates of smaller LDL
induced by PUFA (Fernandez et al. 1992a and 1993) or
soluble fiber intake (Fernandez 1995). In contrast, cholestyra-
mine and lovastatin treatment, which results in smaller LDL
with significant compositional changes compared with LDL
derived from control guinea pigs, had a slower FCR than did
control LDL (Berglund et al. 1989, Witztum et al. 1985).
HDL. HDL are present in low concentrations in guinea
pig plasma (Fernandez et al. 1994b, Fernandez and McNamara
1991, He and Fernandez 1998b). ApoAI is the major apoli-
poprotein in guinea pig HDL (Fernandez and McNamara
1990, Guo et al. 1977). Although there are some differences in
composition, guinea pig apoA-I is as potent as human apoA-I
for activating purified LCAT derived from human plasma
(Guo et al. 1977). Few dietary and drug manipulations have
been shown to alter plasma HDL-C concentrations in guinea
pigs. Intake of 0.33% dietary cholesterol, which is equivalent
to absorbed dietary cholesterol that is 200% of the daily
endogenous cholesterol synthesis in these animals, signifi-
cantly increased plasma HDL-C (Lin et al. 1995). Simvastatin
treatment (Matsunaga et al. 1991), exercise (McNamara et al.
1993) and replacement of marginal with adequate intakes of
13
vitamin C (Montano et al. 1998) have also been shown to
increase plasma HDL-C concentrations in guinea pigs.
Effects of dietary factors on cholesterol and lipoprotein
metabolism
Dietary fat. Effects of fatty acids varying in chain length
and degree of saturation on cholesterol and lipoprotein me-
tabolism have been studied in guinea pigs. Diets high in PUFA
[corn oil (CO)] lower plasma LDL-C concentrations compared
with highly SAT palm kernel oil (PK), which is rich in
short-chain fatty acids, or SAT lard, which is rich in long-
chain fatty acids (Abdel-Fattah et al. 1995, Fernandez et al.
1992a and 1993). Numerous aspects of lipoprotein metabolism
modulated by dietary fatty acids accounted for the observed
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changes in plasma LDL-C. For instance, guinea pigs fed the PK
diet had the highest apoB secretion rate (Abdel-Fattah et al.
1995). The PK group also exhibited the slowest LDL FCR in
vivo. In contrast, guinea pigs fed the CO diet had the fastest
LDL FCR and the highest number of hepatic LDL receptors
(Fernandez et al. 1993). Intake of CO also resulted in the
smallest mature VLDL particle, as measured by electron mi-
croscopy (Abdel-Fattah et al. 1998).
In addition, significant differences in LDL composition
have been observed in guinea pigs fed PK, lard or CO diets,
which may have metabolic implications. Guinea pigs fed SAT
have CE-enriched LDL, which are associated with higher
concentrations of LDL-C. In contrast, guinea pigs fed PUFA
diets have small CE-poor LDL particles with 1.5 times faster
LDL turnover in plasma than the larger LDL from guinea pigs
fed SAT fat (Fernandez et al. 1993).
The effects on hepatic enzyme activity of fatty acids that
vary in saturation and chain length have been evaluated in
guinea pigs (Fernandez and McNamara 1994c). Guinea pigs
fed the PK diet had the highest plasma LDL-C, followed by
those fed palm oil rich in palmitic acid. CO intake resulted in
the lowest plasma LDL-C concentrations. HMG-CoA reduc-
tase activity varied among groups and was independent of
plasma LDL-C. In contrast, ACAT activity exhibited a posi-
tive correlation with plasma LDL-C concentrations. Two pos-
sibilities may account for these correlations: 1) ACAT activity
determines rates of incorporation of CE into VLDL, which is
subsequently converted into LDL; and 2) ACAT activity
changes with the rate of hepatic cholesterol influx. In support
of the first possibility, hypercholesterolemic diets are related to
the production of a greater number of larger LDL particles in
African green monkeys (Carr et al. 1992) and in guinea pigs
(Fernandez et al. 1993). The greater number of CE molecules
incorporated into newly secreted lipoproteins has been corre-
lated with increased ACAT and with a greater number of
atherosclerotic lesions in African green monkeys (Carr et al.
1992). In support of the second possibility, dietary fat satura-
tion and chain length affect LDL absolute catabolic rate (Fer-
nandez et al. 1992a and 1992b). In a steady-state condition,
LDL flux equals total catabolic rate and, assuming 80% LDL
uptake by the liver, guinea pigs having the greatest influx
(PK-fed animals) also had the highest ACAT activity. Similar
results supporting both theories have been reported for guinea
pigs fed low (2.5%) or high (25%) fat diets (Romero and
Fernandez 1996). A comparison of different parameters of
cholesterol and lipoprotein metabolism, which account for the
hypocholesterolemic effects of PUFA versus SAT diets, is
presented in Table 2.
These studies demonstrate that the mechanisms by which
different fatty acids alter lipoprotein concentration and com-
position, and possibly atherosclerotic events, are related to
14 FERNANDEZ
TABLE 2
Effects of a polyunsaturated fatty acid diet (corn oil), a diet high in short-chain fatty acids (palm kernel oil) and a diet high in long-
chain fatty acids (lard) on hepatic cholesterol and lipoprotein metabolism1
Parameter Corn oil
LDL-C,2 mmol/L 0.98 ⫾ 0.16c
LDL FCR,3,4 pools/h 0.112 ⫾ 0.009a
LDL Bmax,3,5 ␮g/mg 5.07 ⫾ 0.53a
VLDL apoB secretion rate,4 mg 䡠 kg⫺1 䡠 h⫺1 1.14 ⫾ 0.63b
VLDL FCR6 0.65 ⫾ 0.08a
LDL-1 size,5 nm 18.3 ⫾ 1.0a
LDL-2 size,5 nm 17.1 ⫾ 0.9a
VLDL size,6 nm 49 ⫾ 5b
ACAT activity,2 pmol 䡠 min⫺1 䡠 mg protein⫺1 4.8 ⫾ 1.7a
1 Values are expressed as means ⫾ SD, n ⫽ 6 – 8. Values in a row with different superscript letters are significantly different as determined by
one-way ANOVA and the Newman-Keuls post hoc test (P ⬍ 0.01).
2 Adapted from Fernandez et al. 1994b.
3 FCR, fractional catabolic rate; Bmax, maximal binding.
4 Adapted from Abdel-Fattah et al. 1995.
5 Adapted from Fernandez et al. 1993.
6 Adapted from Abdel-Fattah et al. 1998.
specific effects of these fatty acids on hepatic cholesterol
homeostasis, VLDL secretion, alterations in the intravascular
compartment and LDL catabolic rates. In addition, the cho-
lesterolemic response of guinea pigs to dietary fatty acids is
similar to reports from clinical studies (Nicolosi 1997), and is
in agreement with proposed mechanisms reported in studies in
humans (Cortese et al. 1983, Turner et al. 1981).
Dietary cholesterol. Earlier reports of the deleterious ef-
fects of dietary cholesterol on guinea pigs, including hemolytic
anemia characterized by accelerated destruction of the eryth-
rocytes (Puppione et al. 1971) and death before considerable
plaques developed, precluded the use of guinea pigs as models
of cholesterol and lipoprotein metabolism. In addition, these
reports focused on the appearance of abnormal lipoproteins
and changes in lipid metabolism, which were postulated to be
species specific (Guo et al. 1982, Meng et al. 1979, Ostwald
and Shannon 1964, Sarted et al. 1972). These carefully con-
trolled studies failed to stress that the amount of cholesterol
provided to guinea pigs was 1–2%, which, based on our careful
calculations, is equivalent to 7500 –15,000 mg cholesterol/d in
humans. Thus, remarks concerning these earlier studies have
to be taken with caution and interpretation of the results must
be made with the consideration that these experiments cannot
possibly have any clinical relevance.
The effects of dietary cholesterol on plasma lipids, lipopro-
tein composition, hepatic LDL receptors and HDL metabolism
have been evaluated in guinea pigs fed 0.08, 0.17 or 0.33%
dietary cholesterol, which is equivalent to 600-2500 mg cho-
lesterol/d in humans (Lin et al. 1992, 1994 and 1995). These
concentrations of dietary cholesterol correspond to an amount
of absorbed cholesterol equal to half, one time and two times
the endogenous cholesterol synthesis in guinea pigs (Lin et al.
1992). Increasing the concentration of dietary cholesterol
resulted in a dose-dependent increase in plasma cholesterol
associated with the LDL fraction, which was independent of
the dietary fat level. HMG-CoA reductase activity was signif-
icantly down-regulated with an absorbed amount equivalent to
half the endogenous cholesterol synthesis (0.08% dietary cho-
lesterol) as a first compensatory mechanism. The amount of
cholesterol in the liver was also increased in a dose-dependent
manner as the concentration of dietary cholesterol increased
(Lin et al. 1992) (Table 1). The hepatic LDL receptor number
was measured by incubating increasing concentrations of 125I-
Lard Palm kernel oil
1.24 ⫾ 0.23b 2.04 ⫾ 0.23a
0.087 ⫾ 0.008b 0.073 ⫾ 0.016b
3.91 ⫾ 0.81b 3.43 ⫾ 0.79b
1.53 ⫾ 0.83b 3.11 ⫾ 0.84a
1.22 ⫾ 0.37b 0.98 ⫾ 0.02a
20.5 ⫾ 2.3b 21.9 ⫾ 2.6c
18.4 ⫾ 0.6a 19.2 ⫾ 1.5b
78 ⫾ 7a 69 ⫾ 10a
6.0 ⫾ 1.5a 11.6 ⫾ 3.7b
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LDL with hepatic membranes, and the number of receptors
was decreased as the amount of dietary cholesterol increased
(Lin et al. 1994).
In addition, guinea pigs can be hyporesponders or hyperre-
sponders to dietary cholesterol (Fernandez et al. 1990b), dem-
onstrating that the responses to dietary cholesterol are highly
individualized, in agreement with clinical studies (McNamara
et al. 1987). Our laboratory has also demonstrated that guinea
pigs present early atherosclerotic development and fatty streak
accumulation after 12 wk when challenged with amounts of
dietary cholesterol in the range of 2000 mg/d consumption by
humans (Cos et al. 2000).
Dietary soluble fiber. The effectiveness of several types of
soluble fiber in reducing plasma LDL-C concentrations and
their specific effects on hepatic cholesterol and lipoprotein
metabolisms have been studied in guinea pigs. Prickly pear
(Opuntia sp.), a plant commonly grown in Mexico, has been
traditionally used for diabetes treatment and as a hypocholes-
terolemic agent. Studies were carried out with pectin isolated
from this plant (PPP) to test its potential properties in lower-
ing plasma cholesterol (Fernandez et al. 1990b, 1992b and
1994d). Guinea pigs were fed hypercholesterolemic diets con-
taining 0, 1 or 2.5% PPP, and plasma lipids and some meta-
bolic parameters were compared. Plasma LDL-C was 33%
lower in guinea pigs fed the PPP diet compared with the
control group. The hepatic apoB/E receptor was 60% higher in
guinea pigs fed the PPP diets, which was in agreement with the
twofold faster receptor-mediated LDL FCR observed in guinea
pigs fed this type of fiber. Although a 46% reduction in hepatic
free cholesterol was observed, HMG-CoA reductase and
ACAT activities were not altered by PPP (Fernandez et al.
1994d).
In another study, guinea pigs were fed increasing concen-
trations of pectin (PE) (0, 2.5, 5, 7.5, 10 and 12.5%) with low
(LC, 0.04%) or high (HC, 0.25%) concentrations of dietary
cholesterol (Fernandez et al. 1994a). Guinea pigs fed LC had
lower concentrations of plasma LDL-C at 10 and 12.5% PE
compared with controls. In contrast, guinea pigs fed HC ex-
hibited a PE dose–related decrease in plasma LDL-C and a PE
dose– dependent increase in hepatic LDL receptors. HMG-
CoA reductase activity was suppressed by high dietary choles-
terol and only intake of 12.5% PE reversed this suppression.
Guinea pigs fed 12.5% PE with HC diets had a complete
 GUINEA PIGS AND LIPOPROTEIN METABOLISM 15

reversal of hyperlipidemia because plasma LDL-C and hepatic TABLE 4

cholesterol concentrations were similar to those of animals fed
LC. Plasma lipids and other variables of lipoprotein metabolism in
In other fiber studies, guinea pigs were fed either GG sedentary and exercised guinea pigs
(Fernandez et al. 1995e) or PSY (Fernandez et al. 1995a).
Compared with the control diet, intake of GG resulted in Parameter Sedentary Exercised
lower plasma LDL-C, a lower LDL cholesteryl ester-to-protein Total cholesterol, mmol/L 0.93 ⫾ 0.11 0.72 ⫾ 0.04
ratio, and lower hepatic cholesterol concentrations and VLDL ⫹ LDL-cholesterol, mmol/L 0.70 ⫾ 0.11 0.40 ⫾ 0.06
ACAT activity, whereas both HMG-CoA reductase activity HDL cholesterol mmol/L 0.21 ⫾ 0.03b 0.34 ⫾ 0.04a
and hepatic LDL receptors were up-regulated (Fernandez et al. Triacylglycerol, mmol/L 0.81 ⫾ 0.07a 0.54 ⫾ 0.02b
1995d). Plasma LDL-C concentrations were 30 and 54% lower Total cholesterol/HDLC 4.6 ⫾ 1.2a 2.3 ⫾ 0.7b
and hepatic cholesterol was reduced an average of 25%, but Heart lipoprotein lipase activity,
mnol 䡠 min⫺1 䡠 g⫺1 1500 ⫾ 400b 2800 ⫾ 300a
hepatic HMG-CoA reductase activity was 120% higher due to Adipose lipoprotein lipase activity,
PSY intake. In addition, PSY reduced hepatic ACAT activity mnol 䡠 min⫺1 䡠 g⫺1 420 ⫾ 58b 630 ⫾ 38a
and up-regulated LDL receptors and Cyp7 (Fernandez 1995).

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Some of the parameters contributing to the lowering of plasma 1 Values are presented as means ⫾ SD for 6 in each group. Values
LDL-C by PSY are presented in Table 3. Similar to reports in in the same row with different superscript letters are significantly dif-
humans (Everson et al. 1992), PSY did not affect cholesterol ferent (P ⬍ 0.05) as determined by Student’s t test.
absorption but, rather, induced fecal bile acid secretion, as
suggested by increased hepatic Cyp7 activity (Fernandez
1995). In addition, decreased susceptibility of LDL to oxida- patic cholesterol homeostasis are correlated with decreases in
tion has been reported in guinea pigs fed soluble fiber (either the number of secreted VLDL, faster VLDL removal from the
PE or PSY) compared with guinea pigs fed a control diet plasma compartment, decreased conversion of VLDL to LDL
(Vergara-Jimenez et al. 1999), suggesting that the smaller and increases in LDL apoB FCR. In addition, CETP activity is
CE-poor LDL particles induced by fiber intake are less suscep- reduced (Fernandez et al. 1997a). All of these alterations in
tible to oxidation. PE and PSY in combination with high fat hepatic cholesterol metabolism result in the known effect of
diets have also been shown to reduce the apoB secretion rate soluble fiber of reducing plasma LDL-C.
and to increase LDL turnover (Vergara-Jimenez et al. 1998).
Although the extent of the hypocholesterolemic response
to dietary soluble fiber may vary depending on the fiber source, Exercise and lipoprotein metabolism
there are some general aspects of hepatic and cholesterol The beneficial effect of exercise on plasma lipoproteins,
metabolism that are consistent for all soluble fiber sources. which results in decreases in plasma TAG and increases in
Soluble fiber intake reduces hepatic cholesterol pools gener- HDL-C, is well documented (Sustin and Haskel 1994).
ated by the decreased delivery of cholesterol to the liver Guinea pigs that ran on a rodent treadmill at a rate of 33.3 rpm
through the chylomicron remnant or by up-regulation of Cyp7 for 30 – 40 min for a 6-wk period exhibited lower plasma TAG
as a response to the interruption of enterohepatic circulation and higher HDL-C concentrations than did sedentary animals
of bile acids (Fernandez 1995). This generates a negative (Table 4).
balance of hepatic cholesterol, which results in up-regulation Prolonged exercise lowers fasting plasma TAG concentra-
of HMG-CoA reductase and hepatic apoB/E receptors and tions (Sayard and Bouchard 1990). Exercise training increases
down-regulation of ACAT activity. These alterations in he- LPL activity in plasma and in parenchymal cells, suggesting
that exercise has a role in increasing the capacity to clear
TAG from circulation and that LPL is involved in the resto-
TABLE 3 ration of muscle TAG stores reduced by exercise (Oscai et al.
1990). In addition, adipose tissue has increased LPL activity
Variables of lipoprotein metabolism in guinea pigs affected by after exercise (Savard and Bouchard 1990). In agreement with
psyllium intake human studies, exercised guinea pigs have been shown to have
greater LPL activity in both heart and adipose tissue (Mc-
Variable1 Control2 Psyllium Namara et al. 1993) (Table 4).
LDL cholesterol,2 mmol/L 1.76 ⫾ 0.31a 1.19 ⫾ 0.26b
Significant regression and less progression of coronary ath-
Hepatic LDL receptor,2 erosclerosis have been documented for patients treated with
␮g/mg protein 4.06 ⫾ 0.03b 4.78 ⫾ 0.36a diet and exercise compared with usual-care control patients
LDL FCR,2,3 pools/h 0.073 ⫾ 0.005b 0.103 ⫾ 0.015a (Schlierf et al. 1995). These results were correlated with
Cholesterol 7␣-hydroxylase significant decreases in plasma LDL-C and TAG in the treated
activity,2 group. We have demonstrated that plasma lipid changes due to
pmol 䡠 min⫺1 䡠 mg⫺1 1.19 ⫾ 0.17b 3.06 ⫾ 0.70a
CETP activity,4
exercise in guinea pigs are similar to those in humans and that
␮mol 䡠 L⫺1 䡠 h⫺1 49 ⫾ 36a 21 ⫾ 15b these animals develop atherosclerosis (Cos et al. 2000). Based
(LDL oxidation) TBARS,5 on these observations, the guinea pig could be an appropriate
nmol MDA/non-HDL model to further evaluate the beneficial effects of exercise in
protein 5.98 ⫾ 3.68a 3.02 ⫾ 2.05b the treatment of coronary heart disease.
1 Values represent means ⫾ SD, n ⫽ 6. Values in a row with different
superscript letters are significantly different as determined by Student’s Drug treatment studies
t test (P ⬍ 0.01).
2 Adapted from Fernandez 1995. Guinea pigs have been used as models to study the effects of
3 FCR, fractional catabolic rate. drugs on plasma cholesterol and to clarify the hypocholester-
4 Adapted from Fernandez et al. 1997a. olemic mechanisms of some drugs, including cholestyramine
5 Adapted from Vergara-Jimenez et al. 1999. (Witztum et al. 1985), probucol (Hikada et al. 1992), ACAT
16 FERNANDEZ
inhibitors (Krause et al. 1993), HMG-CoA reductase inhibi-
tors such as pravastatin (Matsunaga et al. 1994), simvastatin
(Conde et al. 1999a and 1999b), lovastatin (Berglund et al.
1989, Krause et al. 1994, Krause and Newton 1991) and
atorvastatin (Conde et al. 1996, 1999a and 1999b).
Cholestyramine has a potent hypocholesterolemic effect in
guinea pigs, reducing plasma LDL-C concentrations by 55–
75% (Fernandez et al. 2000). Witztum et al. (1985) measured
cholestyramine effects on LDL size and composition and how
these affected LDL FCR. Their findings suggest that LDL from
cholestyramine-treated guinea pigs, which were smaller in size,
had a slower turnover in plasma than did LDL derived from
controls. The plasma LDL-C lowering by cholestyramine was
due to increases in the LDL receptor in treated guinea pigs,
suggesting that compositional changes in LDL have profound
metabolic consequences.
Guinea pigs treated with reductase inhibitors exhibited
significant decreases in plasma LDL-C concentrations (Conde
et al. 1996 and 1999a, Matsunaga et al. 1994). Most of these
reductase inhibitors have shown that increases in the LDL
receptor represent a major mechanism for the observed hypo-
cholesterolimia (Berglund et al. 1989, Conde et al. 1996 and
1999a, Matsunaga et al. 1994). Lovastatin therapy has been
shown to increase hepatic LDL receptor activity in guinea
pigs, and the compositional changes induced by treatment
with this reductase inhibitor had a significant effect on the
removal of LDL from plasma (Berglund et al. 1989). LDL from
lovastatin-treated guinea pigs had a slower LDL turnover com-
pared with control LDL. When these studies were repeated in
subjects with hyperlipidemia, results similar to those reported
for guinea pigs were found: a decrease in particle affinity for
the receptor and increases in receptor activity (Berglund et al.
1998). In our studies with atorvastatin, treatment with this
reductase inhibitor decreased secretion of apoB and increased
hepatic apoB/E receptors (Conde et al. 1996 and 1999a). Our
results are in total agreement with the reported mechanisms of
LDL-C lowering in hyperlipidemic individuals treated with
lovastatin (Berglund et al. 1998), confirming the suitability of
guinea pigs for mimicking metabolic alterations in plasma
lipoproteins induced by drug treatment.
Gender and hormonal status
Results from the Framingham Heart Study have shown that
high plasma TAG and low plasma HDL-C concentrations are
highly associated with cardiovascular disease risk in women,
whereas for men the major risk factor is elevated concentra-
tions of plasma LDL-C (Castelli et al. 1988). Studies have
shown that responses to dietary factors may differ between
men and women (Cobb et al. 1993). In addition, postmeno-
pausal women have significantly greater risk factors for heart
disease due to increased plasma LDL-C, apoB and TAG con-
centrations (Bonithon-Kopp et al. 1990). Based on these ob-
servations, it is important to have an animal model with
gender-associated responses to diet that are similar to humans.
In addition, this model should present similar detrimental
changes in the lipoprotein profile in the absence of estrogen, as
occurs in postmenopausal women.
Female guinea pigs are more responsive to dietary choles-
terol than are males (Fernandez et al. 1995e), which is in
agreement with reported observations in humans (Clifton et
al. 1995). In addition, in females, fiber does not alter the
regulatory enzymes of hepatic cholesterol metabolism, as is the
case in males (Fernandez et al. 1995b). However, a slower
apoB secretion rate and a faster LDL FCR were observed in
females as compared with males (Shen et al. 1998), indicating
important differences in the gender response to dietary treat-
ments. In addition, we have observed that female guinea pigs
have higher HDL-C concentrations than do males (Roy et al.
2000).
In a recent study using male, female and ovariectomized
guinea pigs, several important findings emerged that reinforce
the suitability of ovariectomized guinea pigs to mimic human
menopause. Ovariectomized guinea pigs had higher concen-
trations of plasma TAG than did either males or females,
higher concentrations of LDL-C and a more detrimental li-
poprotein profile overall (Roy et al. 2000). In addition, ovari-
ectomized guinea pigs exhibited a higher susceptibility of LDL
to oxidize compared with intact females. It has been shown
that estrogen exerts a protective effect against free radical
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formation (Sack et al. 1994), which might explain the higher
susceptibility of LDL to oxidize in the ovariectomized guinea
pigs. Gender and hormonal status effects on early atheroscle-
rosis development were also evaluated in guinea pigs. Male
guinea pigs had the greatest fatty streak accumulations in
aortas, followed by ovariectomized animals; females had the
least lesion involvement (P ⬍ 0.001) (Cos et al. 2000).
Developmental studies
Guinea pigs are appropriate models for developmental stud-
ies because they experience rapid growth during the third
trimester and can be weaned at 2 d of age. Guinea pigs develop
fatty livers during fetal life. Small lipoproteins can be observed
in the hepatic Golgi in the 52-d-old guinea pig fetus and, at
68 d, the fetus contains large lipoproteins in the secretory
vesicles, which provide further evidence for active synthesis,
assembly and secretion of TAG-rich lipoproteins (Bohmer et
al. 1972). There is a significant accumulation of hepatic TAG
in the fetus, which is accounted for by the rate of placental
fatty acid transfer (Bohmer and Havel 1975).
Bile acid pools are low in most mammals during birth,
including guinea pigs, and reach adult concentrations at the
time of weaning (Li et al. 1979). Feeding 0.25% cholesterol to
pregnant guinea pig dams resulted in a significant decrease in
the total bile acid pool in the neonate, a significant reduction
in chenodeoxycholic acid and an increase in the proportion of
bile acids in the neonatal liver. These are important findings
relevant to earlier reports in which feeding chenodeoxycholic
acid to guinea pigs reduced the activity of Cyp7, suggesting
that in this species chenodeoxycholic acid exerts a feedback
inhibition for the synthesis of this bile acid from cholesterol
(Hassan et al. 1983). In contrast, in rats the activity of fetal
and neonatal Cyp7 was increased after feeding of 1% choles-
terol (Naseem et al. 1980), indicating important differences
between animal models in the handling of pharmacological
doses of dietary cholesterol.
Studies have been carried out to determine prenatal inter-
ventions on maternal and fetal cholesterol homeostasis in
guinea pigs. The dams were fed a nonpurified diet supple-
mented with 1.1% cholestyramine or 0.25% cholesterol. Ma-
ternal hepatic cholesterol synthesis increased 3.5-fold with
cholestyramine treatment and decreased 87% with cholesterol
intake (Yount and McNamara 1991). In contrast, the fetus
had moderate changes in cholesterol synthesis modulated by
time of gestation rather than by dietary manipulations. These
studies indicate that responses to dietary treatment do not vary
between pregnant and nonpregnant dams and that the fetus is
relatively insensitive to maternal dietary or drug treatments.
 GUINEA PIGS AND LIPOPROTEIN METABOLISM
Ascorbic acid and cardiovascular disease
Guinea pigs are the most appropriate model in which to
study the role of vitamin C in hepatic lipid metabolism,
plasma lipids and progression of atherosclerosis because they
are one of the few species that has a dietary requirement for
ascorbic acid (Turley et al. 1976). Epidemiological studies
have shown a negative correlation between intake of vitamin
C and plasma cholesterol concentrations (Cerna and Ginter
1978). In addition, the Basel protective study documented
that low plasma carotene and ascorbate concentrations corre-
lated with a higher risk for coronary heart disease (Gey et al.
1993). Studies in guinea pigs have shown that inadequate
intake of vitamin C leads to hypercholesterolemia (Montano
et al. 1998) and hypertriglyceridemia (Yokota et al. 1981) and
that it may influence the pathogenesis of atherosclerosis (Gin-
ter 1978) and possibly increase oxidative stress (Liu and Le
1997).
Ascorbic acid deficiency is associated with reductions in
hepatic microsomal cytochrome P450, which leads to reduc-
tions of Cyp7 activity (Greene et al. 1985). In agreement with
earlier studies (Holloway et al. 1981), a significant reduction
was observed in Cyp7 activity in guinea pigs fed marginal
amounts of vitamin C (Fernandez et al. 1997b, Holloway et al.
1981). Reductions in the active form of HMG-CoA reductase
have also been reported (Montano et al. 1998). These reduc-
tions were correlated with higher concentrations of CE in
guinea pigs fed marginal amounts of vitamin C, suggesting that
the homeostatic response of the liver to maintain the free
cholesterol pool occurs by suppressing cholesterol synthesis
and increasing hepatic cholesterol stores.
A potential mechanism for the increases in plasma LDL-C
observed in cases of an inadequate supply of vitamin C could
be the down-regulation of LDL receptors. Marginal intake of
vitamin C has been related to a lower number of hepatic LDL
receptors (Montano et al. 1998) and slower LDL FCR com-
pared with guinea pigs fed an adequate amount of vitamin C
(Fernandez et al. 1997b, Ginter and Jurcovicoca 1977). Sim-
ilarly, an increase in the LDL receptor number was observed in
cultured arterial smooth muscle cells incubated with ascorbate
(Auslinkas et al. 1983).
A consistent finding associated with vitamin C deficiency is
elevated concentrations of plasma TAG. It has been postu-
lated that a deficiency of vitamin C reduces carnitine synthe-
sis, thus causing more accumulation of TAG in the liver due
to a reduced transport of fatty acids to the mitochondria for
␤-oxidation (Hylse et al. 1978). This accumulation of TAG
results in an increased TAG secretion rate. Marginal intake of
vitamin C results in increased secretion of apoB VLDL, ex-
plaining in part the hypertriglyceridemia observed in guinea
pigs fed marginal concentrations of ascorbic acid (Montano et
al. 1998). Bobek et al. (1980) reported that borderline vitamin
C deficiency in guinea pigs in wk 14 –16 resulted in reduced
fractional plasma TAG turnover.
In addition, supplementation with ascorbic acid has been
reported to decrease endogenous oxidative damage in guinea
pig liver (Cadenas et al. 1994), decrease the susceptibility of
LDL to oxidize in the presence of dietary PUFA (Fernandez et
al. 1997b) and reduce lipid peroxide concentrations in kidney,
heart and brain (Kaplan 1995). These studies suggest a possi-
ble role for this antioxidant in reducing the formation of
oxidized LDL and influencing the uptake of this lipoprotein by
the arterial wall.
17
Atherosclerosis
Oxidized LDL may enhance the progression of atheroscle-
rosis via the following processes: enhancement of monocyte
adhesion and macrophage foam cell generation, stimulation of
platelet adhesion and aggregation, triggering of thrombosis
and impairment of vasodilation (Parthsarathy et al. 1992).
The oxidation of LDL probably takes place in the arterial wall,
where LDL particles are sequestered from circulating antioxi-
dants (Witztum and Steinberg 1991). Vazquez et al. (1998)
measured the oxidation behavior of rat and guinea pig LDL
and concluded that guinea pig LDL composition bears a closer
resemblance to that of human LDL. In a clinical study of
patients with familial hyperlipidemia, these authors observed
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that human LDL oxidation parameters were more similar to
those of guinea pigs than to those of rats (Vazquez et al. 1997).
Studies were conducted to assess whether vitamin E affects
the proteoglycan distribution and vascular permeability in the
aortas of cholesterol-fed guinea pigs. Vitamin E preserved the
morphological and functional integrity of the vascular wall
and contributed to the inhibition of atherosclerosis (Qiao et
al. 1993). This protective effect of vitamin E against in vitro
lipid peroxidation was observed in guinea pigs even in the
presence of an optimal intake of vitamin C (Barja et al. 1996).
Similar to reports in humans (Esterbauer et al. 1991), the
protective concentrations of vitamin E against lipid peroxida-
tion were found to be higher than the concentrations needed
to avoid deficiency syndromes. Liu et al. (1997) showed a
protective effect of vitamin C against LDL oxidation in cases
of impaired vitamin E retention. Similarly, reduced concen-
trations of vitamin E as a result of ethanol intake were raised
when dietary vitamin C was provided (Suresh et al. 1999),
demonstrating the protective role of ascorbic acid in sparing
vitamin E and influencing the oxidative process in plasma.
Other studies in guinea pigs have evaluated the role of ascor-
bic acid– deficient diets in atherosclerosis development. Ginter
(1978) reported edema of the vessel wall and vacuolization of
endothelial cells in guinea pigs fed a vitamin C–deficient diet.
Satinder et al. (1987) found white patchy plaques in the arch and
proximal aorta in two thirds of guinea pigs fed a vitamin C–
deficient diet for 8 wk. Vitamin C deficiency with cholesterol
feeding has also been studied in guinea pigs (Sharma et al. 1988).
After 3 mo, there were significant increases in the severity of
aortic lesions and an additive effect on atherosclerosis was ob-
served with cholesterol feeding. These studies indicate that, sim-
ilar to humans, guinea pigs develop atherosclerosis due to oxida-
tive damages induced by ascorbic acid deficiency or by the lack of
dietary vitamin E.
The development of early atherosclerosis has been demon-
strated in male, female and ovariectomized guinea pigs fed a
hypercholesterolemic diet for 12 wk (Cos et al. 2000). Partial
substitution of insoluble by soluble fiber resulted in less lesion
development (Table 5). Guinea pigs fed the control diet
exhibited LDL particles that were larger and had higher con-
centrations of CE. A significant correlation between LDL
diameter and fatty streak area (r ⫽ 0.56, P ⬍ 0.01) was found,
suggesting that in guinea pigs, similar to African green mon-
keys, the larger LDL particles induced by hypercholesterolemic
diets are correlated with lesion development (Carr et al. 1992,
Rudel et al. 1986). In the study by Cos et al. (2000), there was
a clear gender effect because, independent of the diet, female
guinea pigs exhibited less lesion development than did male or
ovariectomized animals (Table 5). These results are of great
interest because they suggest a protective effect of estrogen
against atherosclerotic lesions.
18 FERNANDEZ
TABLE 5
Aortic fatty streaks of male, female and ovariectomized guinea
pigs fed a control (12.5% cellulose, 60% casein, 40%
soybean protein) or test (5% pectin, 5% psyllium, 2.5%
cellulose, 100% soybean protein) diet
Fatty streak
n ␮m2/mm2
Control
Male 7 25,871 ⫾ 4292a
Female 6 21,486 ⫾ 1950b
Ovariectomized 10 22,503 ⫾ 4730ab
Test
Male 6 20,705 ⫾ 4752b
Female 6 14,771 ⫾ 2999c
Ovariectomized 5 16,576 ⫾ 2094bc
Two-way ANOVA P
Diet effect ⬍0.0001
Gender effect ⬍0.01
Interaction ⱖ0.05
1 Values are expressed as means ⫾ SD for the number of guinea
pigs indicated in parentheses.
2 Values in a column with different superscript letters are signifi-
cantly different as determined by Fisher’s LSD post hoc test, P ⬍ 0.05.
Conclusions
It is clear from this review that, in addition to carrying the
majority of their plasma cholesterol in LDL, guinea pigs
present other striking similarities to humans in terms of he-
patic cholesterol and lipoprotein metabolism. Guinea pig re-
sponses to dietary factors, drug treatment, ascorbic acid defi-
ciency, oxidative stress, exercise, gender and hormonal status
undoubtedly mimic the human situation. In addition, many of
the mechanisms by which guinea pigs regulate cholesterol and
lipoprotein metabolism as a response to diet or drug treatment
are analogous to those reported in clinical experiments. These
studies clearly document the suitability and appropriateness of
the guinea pig model and reinforce the importance of the use
of alternatives to the more-established and more widely used
animal models.
LITERATURE CITED
Abdel-Fattah, G., Fernandez, M .L. & McNamara, D. J. (1995) Regulation of
guinea pig very low density lipoprotein secretion rates by dietary fat satura-
tion. J. Lipid Res. 36: 1188 –1198.
Abdel-Fattah, G., Fernandez, M. L. & McNamara, D. J. (1998) Regulation of
very low density lipoprotein apo B metabolism by dietary fat saturation and
chain length in the guinea pig. Lipids 33: 23–31.
Andersson, Y., Lookene, A., Shen, Y. Nilsson, S., Thelander, L. & Olivecrona, G.
(1997) Guinea pig apolipoprotein C-II: Expression in E. coli, functional
studies of recombinant wild-type and mutated variants, and distribution on
plasma lipoproteins. J. Lipid Res. 38: 2112124.
Andersson, Y., Thelander, L. & Bengtsson-Olivecrona, G. (1991) Demonstra-
tion of apolipoprotein CII in guinea pigs: Functional characteristics, cDNA
sequence and tissue expression. J. Biol. Chem. 266: 4074 – 4080.
Angelin, B., Olivecrona, H., Reihner, H., Rudling, E., Stahlberg, D., Eriksson, M.,
Ewerth, S., Henricksson, P. & Einarsson, K. (1992) Hepatic cholesterol
metabolism in estrogen-treated men. Gastroenterology 103: 1657–1663.
Auslinkas, T. H., Van der Westhuyzen, D. R. & Coetzee, G. A. (1983) Ascorbate
increases the number of low density lipoprotein receptors in cultured arterial
smooth muscle cells. Atherosclerosis 47: 159 –171.
Barja, G., Cadenas, S., Rojas, C., Perez-Campo, R., Lopez-Torres, M., Prat, J. &
Pamplona, R. (1996) Effect of vitamin E levels on fatty acid profiles and
nonenzymatic lipid peroxidation in the guinea pig liver. Lipids. 31: 963–970.
Barter, P., Faegeman, O. &. Havel, R. J. (1977) Metabolism of cholesteryl
esters of very low density lipoproteins in the guinea pig. Metabolism. 26:
615– 622.
Berglund, L.,. Sharkey, M. E., Elam, R. L. &. Witztum, J. L. (1989) Effects of
lovastatin therapy on guinea pig low density lipoprotein composition and
metabolism. J. Lipid Res. 30: 1591–1600.
Berglund, L., Witxtum, J. L., Galeano, N. F., Khuow, A. S., Ginsberg, H. N. &
Ramakrishnan, R. (1998) Three-fold effect of lovastatin treatment on low
density lipoprotein metabolism in subjects with hyperlipidemia: Increase in
receptor activity, decrease in apo B production and decrease in particle
affinity for the receptor: Results from a novel triple-tracer approach. J. Lipid
Res. 39: 913–924.
Bobeck, P., Ginter, E., Ozdin, L. &. Mikus, L. (1980) The effect of chronic
marginal vitamin C deficiency on the rate of secretion and removal of plasma
triglycerides in guinea pigs. Physiol. Bohemoslov. 29: 337–343.
Bohmer, T. & Havel, J. R. (1975) Genesis of fatty liver and hyperlipemia in the
fetal guinea pig. J. Lipid Res. 16: 454 – 460.
Bohmer, T., Havel, R. J. & Long, J. A. (1972) Physiological fatty liver and
hyperlipemia in the fetal guinea pig: Chemical and ultrastructural character-
ization. J. Lipid Res. 13: 371–382.
Bonithon-Kopp, C., Sacarabin, P. Y., Darne, B. Malmejac, A. & Guize, L. (1990)
Menopause-related changes in lipoproteins and some other cardiovascular
risk factors. Int. J. Epidemiol. 19: 42– 48.
Downloaded from https://academic.oup.com/jn/article-abstract/131/1/10/4686623 by guest on 13 July 2019
Brown, M. S. & Goldstein, J. L. (1986) A receptor mediated pathway for
cholesterol homeostasis. Science 232: 34 – 48.
Cadenas, S., Rojas, C., Perez-Campo, R., Lopez-Torres, M. & Barja, G. (1994)
Effect of dietary vitamin C and catalase inhibition on antioxidants and molec-
ular markers of oxidative damage in guinea pigs. Free Radic. Res. 21: 109 –
118.
Carr, T. P., Parks, J. S. & Rudel, L. L. (1992) Hepatic ACAT activity in African
green monkeys is highly correlated to plasma LDL cholesteryl ester enrich-
ment and coronary artery atherosclerosis. Arterioscler. Thromb. 12: 1274 –
1283.
Castelli, W. P. (1988) Cholesterol and lipids in the risk of coronary heart
disease: The Framingham Heart Study. Can. J. Cardiol. 4: 5A–10A.
Cerna, O. & Ginter, E. (1978) Blood lipids and vitamin C status. Lancet 121:
1055–1056.
Chapman, J. M., Mills, G. C. & Taylaur, C. E. (1972) Lipoprotein particles from
the Golgi apparatus of guinea pig liver. 128:779 –787.
Clifton, P. M., Abbey, M., Noakes, M., Beltrame, S., Rumbelow, N. & Nestel, P. J.
(1995) Body fat distribution is a determinant of the high-density lipoprotein
response to dietary fat and cholesterol in women. Aterioscler. Thromb. Vasc.
Biol. 15: 1070 –1078.
Cobb, M., Greenspan, J., Timmons, M. & Teitelbaum, H. (1993) Gender
differences in lipoprotein responses to diet. Ann. Nutr. Metab. 37: 225–236.
Coleman, R. A., Hayes, E. B. & Coats, C. D. (1987) Ontogeny of microsomal
activities of triacylglycerol synthesis in the guinea pig liver. J. Lipid Res. 28:
320 –325.
Conde, K., Pineda, G., Newton, R. & Fernandez, M. L. (1999a) Hypocholes-
terolemic effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) re-
ductase inhibitors in the guinea pig: Atorvastatin versus simvastatin. Bio-
chem. Pharmacol. 58: 1209 –1219.
Conde, K., Roy, S., Freake, H. C., Newton, R. & Fernandez, M. L. (1999b)
Atorvastatin and simvastatin have distinct effects on hydroxy methylglutaryl-
CoA reductase activity and mRNA abundance in the guinea pig. Lipids 34:
1327–1332.
Conde, K., Vergara-Jimenez, M., Krause, B. R., Newton, R. & Fernandez, M. L.
(1996) The hypocholesterolemic effects of atorvastatin are related to alter-
ations in hepatic cholesterol metabolism and lipoprotein composition in
guinea pigs. J. Lipid Res. 37: 2372–2382.
Corsini, A., Mazzotti, M., Villa, A., Maggi, F. M., Bernini, F., Romano, L., Romano,
C., Fumagalli, R. & Catapano, A. L. (1992) Ability of the LDL receptor from
several animal species to recognize the human apo B binding domain: Stud-
ies with LDL from familial defective apo B-100. Atherosclerosis 93: 95–103.
Cortese, C., Levy, Y., Janus, E. D., Turner, P. R., Rao, S. N., Miller ,N. E. & Lewis,
B. (1983) Modes of action of lipid lowering diets in man: Studies of
apolipoprotein B kinetics in relation to fat consumption and dietary fatty acid
composition. Eur. J. Clin. Invest. 13: 79 – 85.
Cos, E. B., Roy, S., Yoganathan, S., Nicolosi, R. J. & Fernandez, M. L. (2000)
Dietary soluble fiber and soybean protein reduce fatty streak accumulation in
male, female and ovariectomized guinea pigs. FASEB J. 14: A353.7.
Cryer, A., Kirtland, J., Jones, H. M. & Gurr, M. I. (1978) Lipoprotein lipase
activity in the tissues of guinea pigs exposed to different dietary fats from
conception to three months of age. Biochem. J. 170:160 –172.
Douglas, G. & Pownell, J. J. (1991) Comparative specificity of plasma lecithin-
cholesterol acyltransferase from ten animal species. Lipids 26: 416 – 420.
Dustin, J. L. & Haskel, W. L. (1994) Effects of exercise training on plasma lipids
and lipoproteins. Exer. Sport Sci. Rev. 22: 477–521.
Esterbauer, H., Dieber-Rotheneder, M., Striegl, G. & Waeg, G. (1991) Role of
vitamin E in preventing the oxidation of low-density lipoprotein. Am. J. Clin.
Nutr. 53: 314S–321S.
Everson, G. T., Daggy, B. P., McKinley, C. &. Story, J. A. (1992) Effects of
psyllium hydrophilic mucilloid on LDL cholesterol and bile acid synthesis in
hypercholesterolemic men. J. Lipid. Res. 33: 1183–1192.
Fernandez, M. L. (1995) Distinct mechanisms of plasma LDL lowering by
dietary soluble fiber: Specific effects of pectin, guar gum and psyllium. J. Lipid
Res. 36: 2394 –2404.
Fernandez, M. L., Abdel-Fattah, G. & McNamara, D. J. (1993) Dietary fat
saturation modifies the metabolism of LDL subfractions in guinea pigs. Arte-
rioscler. Thromb. 14: 1418 –1428.
 GUINEA PIGS AND LIPOPROTEIN METABOLISM
Fernandez, M. L., Abdel-Fattah, G. & McNamara, D. J. (1995c) Differential
effects of simple vs complex carbohydrates on VLDL secretion rates and HDL
metabolism in the guinea pig. Biochim. Biophys. Acta 1256: 31–38.
Fernandez, M. L., Avalos, C. & Vergara-Jimenez, M. (1998) Differences in
response between 18 carbon fatty acids and 12/14 carbon saturated fatty
acids on plasma cholesterol in guinea pigs. Nutr. Res. 18: 1261–1272.
Fernandez, M. L., Conde, K., Vergara-Jimenez, M. & Abdel-Fattah, G. (1997a)
Regulation of VLDL-LDL apo B metabolism in guinea pigs by dietary soluble
fiber. Am. J. Clin. Nutr. 65: 814 – 822.
Fernandez, M. L., Lin, E.C.K. & McNamara, D. J. (1992a) Regulation of guinea
pig plasma low density lipoprotein kinetics by dietary fat saturation. J. Lipid
Res. 33: 97–109.
Fernandez, M. L., Lin, E.C.K. & McNamara, D. J. (1992b) Differential effects of
saturated fatty acids on low density lipoprotein metabolism in the guinea pig.
J. Lipid Res. 33: 1833–1842.
Fernandez, M. L., Lin, E.C.K. & McNamara, D. J. (1994b) Dietary saturated fat
composition modifies high density lipoprotein binding to guinea pig hepatic
membranes. Nutr. Res. 14: 753–764.
Fernandez, M. L., Lin, E.C.K., Trejo, A. & McNamara, D. J. (1992c) Prickly pear
(Opuntia sp) reverses low density lipoprotein (LDL) receptor suppression
induced by a hypercholesterolemic diet in guinea pigs. J. Nutr. 122: 2330 –
2340.
Fernandez, M. L., Lin, E.C.K., Trejo, A. & McNamara, D. J. (1994c) Prickly pear
(Opuntia sp) pectin alters hepatic cholesterol homeostasis without affecting
cholesterol absorption in guinea pigs fed a hypercholesterolemic diet. J. Nutr.
124: 817– 824.
Fernandez, M. L. & McNamara, D. J. (1989) Dietary fat mediated changes in
hepatic apo B/E receptors in the guinea pig. Metabolism 38: 1094 –1102.
Fernandez, M. L. & McNamara, D. J. (1990) High density lipoprotein binding to
guinea pig hepatic membranes: Comparison of guinea pig and human li-
gands. Biochim. Biophys. Acta 1042: 142–145.
Fernandez, M. L. & McNamara, D. J. (1991) Characterization of high-density
lipoprotein binding to guinea pig hepatic membranes: Effects of dietary fat
quality and cholesterol. Metabolism 40: 127–134.
Fernandez, M. L. & McNamara, D. J. (1992) Regulation of cholesterol and
lipoprotein metabolism in guinea pigs mediated by dietary fat quality and
quantity. J. Nutr. 121: 934 –943.
Fernandez, M. L. & McNamara, D. J. (1994) Dietary fat saturation and chain
length modulate guinea pig hepatic cholesterol metabolism. J. Nutr. 124:
331–339.
Fernandez, M. L., Roy, S. & Vergara-Jimenez, M. (2000) Resistant starch and
cholestyramine have distinct effects on hepatic cholesterol metabolism in
guinea pigs fed a hypercholesterolemic diet. Nutr. Res. 20: 837– 850.
Fernandez, M. L., Ruiz, L. R., Conde, A. K., Sun, C.-M., Erickson, S. & McNamara,
D. J. (1995a) Psyllium reduces plasma LDL in guinea pigs by altering
hepatic cholesterol metabolism. J. Lipid Res. 36: 1128 –1138.
Fernandez, M. L., Soscia, A. E., Sun, G.-S., Tosca, M. & McNamara, D. J.
(1996b) Olive oil and rapeseed oil differ in their effect on plasma low-density
lipoprotein metabolism in the guinea-pig. Br. J. Nutr. 76: 869 – 880.
Fernandez, M. L., Sun, D.-M., Montano, C. & McNamara, D. J. (1995d) Car-
bohydrate-fat exchange and regulation of hepatic cholesterol and plasma
lipoprotein metabolism in the guinea pig. Metabolism 44: 855– 864.
Fernandez, M. L., Sun, D.-M., Tosca, M. &. McNamara, D. J. (1994a) Citrus
pectin and cholesterol interact to regulate hepatic cholesterol homeostasis
and lipoprotein metabolism: A dose response study in the guinea pig. Am. J.
Clin. Nutr. 59: 869 – 878.
Fernandez, M. L., Sun, D.-M., Tosca, M. & McNamara, D. J. (1995e) Differen-
tial effects of guar gum on LDL and hepatic cholesterol metabolism in guinea
pigs fed low and high cholesterol diets: A dose response study. Am. J. Clin.
Nutr. 61: 127–134.
Fernandez, M. L., Trejo, A. & McNamara, D. J. (1990b) Pectin isolated from
prickly pear (Opuntia sp) modifies low density lipoprotein (LDL) in cholesterol-
fed guinea pigs. J. Nutr. 120: 1283–1290.
Fernandez, M. L., Vega, S., Ayala, M. T., Shen, H., Conde, K., Vergara-Jimenez,
M. & Robbins, A. (1997b) The interactive effects of vitamin C deficiency
and dietary fat saturation on hepatic cholesterol and plasma lipoprotein
metabolism in the guinea pig. J. Nutr. Biochem. 8: 414 – 424.
Fernandez, M. L., Vergara, M., Romero, A. L., Erickson, S. & McNamara, D. J.
(1995b) Gender differences in plasma and hepatic hypocholesterolemia
induced by soluble fiber: Effects of pectin, guar gum and psyllium. J. Lipid
Res. 36: 2191–2202.
Fernandez, M. L., Vergara-Jimenez, M., Conde, K. & Abdel-Fattah, G. (1996a)
Dietary carbohydrate type and fat amount alter VLDL and LDL metabolism in
guinea pigs. J. Nutr. 126: 2494 –2504.
Fernandez, M. L., Wilson, T. A., Conde, K., Vergara-Jimenez, M. & Nicolosi, R. J.
(1999) Hamsters and guinea pigs differ in their plasma lipoprotein choles-
terol distribution when fed diets varying in animal protein, soluble fiber or
cholesterol content. J. Nutr. 129: 1323–1332.
Fernandez, M. L., Yount, N. Y. & McNamara, D. J. (1990a) Whole body
cholesterol synthesis in the guinea pig: Effects of dietary fat quality. Biochim.
Biophys. Acta 1044: 340 –348.
Gey, K. F., Moser, U. K., Jordan, P., Stahelin, H. B. & Ludin, E. (1993) In-
creased risk of cardiovascular disease at suboptimal plasma concentrations
of essential antioxidants: An epidemiological update with special attention to
carotene and vitamin C. Am. J. Clin. Nutr. 57: 787S–797S.
Greene, Y. J., Harwood, H. J. & Stacpoole, P.W. (1985) Ascorbic acid regu-
19
lation of 3-hydroxt-3-methylglutaryl coenzyme A reductase activity and cho-
lesterol synthesis in guinea pig liver. Biochim. Biophys Acta 834: 134 –138.
Greeve, J., Altkemper, I., Dietrich, J.-H., Greten, H. & Windler, E. (1993) Apo-
lipoprotein mRNA editing in 12 different mammanlian species: Hepatic ex-
pression is reflected in low concentrations of apoB-containing plasma li-
poproteins. J. Lipid Res. 34: 1367–1383.
Ginter, E. (1978) Marginal vitamin C deficiency, lipid metabolism and athero-
genesis. Adv. Lipid Res. 16: 167–215.
Ginter, E. & Jurcovicova, M. (1977) Chronic vitamin C deficiency lowers
fractional catabolic rate of low-density lipoproteins in guinea pigs. Ann. N. Y.
Acad. Sci. 260: 473– 475.
Grundy, S. M. (1986) Comparison of monounsaturated fatty acids and carbo-
hydrates for lowering plasma cholesterol. N. Engl. J. Med. 314: 745–748.
Guo, L.S.S., Hamilton, R. L., Kane, P. J., Fielding, C. J. & Chen, G. C. (1982)
Characterization and quantitation of apolipoproteins A-I and E of normal and
cholesterol-fed guinea pigs. J. Lipid Res. 23: 531–542.
Guo, L.S.S., Meng, M., Hamilton, R. L. & Ostwald, R. (1977) Changes in the
plasma lipoprotein-apoproteins of guinea pigs in response to dietary choles-
Downloaded from https://academic.oup.com/jn/article-abstract/131/1/10/4686623 by guest on 13 July 2019
terol. Biochemistry 16: 5807–5812.
Ha, Y. C. & Barter, P. A. (1982) Differences in plasma cholesteryl ester transfer
protein activity in sixteen vertebrate species. Comp. Biochem. Physiol. 71:
265–269.
Hassan, A. S., Yunker, R. L., Sprinker, J. & Subbiah, M. T. (1983) Chronic
suppression of cholesterol 7-alpha-hydroxylase by dietary chenodeoxycholic
acid in neonatal guinea pigs: Its effect on subsequent bile acid metabolism in
the adult. J. Nutr. 113986 –995.
Hassan, A. S., Yunker, R. L. & Subbiah, M.T.R. (1981) Decreased bile acid pool
in neonates of guinea pigs fed cholesterol during pregnancy. J. Nutr. 111:
2030 –2033.
He, L. & Fernandez, M. L. (1998a) Saturated fat and simple carbohydrates
elevate plasma LDL cholesterol concentrations by specific alterations on
hepatic cholesterol metabolism. Nutr. Res. 18: 1003–1015.
He, L. & Fernandez, M. L. (1998b) Dietary carbohydrate type and fat saturation
independently regulate hepatic cholesterol and LDL metabolism in guinea
pigs. J. Nutr. Biochem. 9: 37– 46.
Heller, F. R. (1983) Adipose tissue and skeletal muscle lipoprotein lipase and
hepatic lipase activities in cholesterol-fed guinea pigs. Biochim. Biophys.
Acta 752: 357–360.
Hide, W. A., Chan, L. & Li, W.-H. (1992) Structure and evolution of the lipase
superfamily. J. Lipid Res. 33: 167–178.
Hikada, K., Takada, Y., Matsunaga, A., Sasaki, J. &. Arawaka, K. (1992) Effects
of probucol and low-density lipoprotein catabolism in guinea pigs. Artery 19:
162–176.
Holloway, D. E., Peterson, F. J., Prigge, W. F. &. Gebbard, R. L. (1981) Influ-
ence of dietary ascorbic acid upon enzymes of sterol biosynthesis in the
guinea pig. Biochem. Biophys. Res. Commun. 102: 1283–1289.
Horton, J. D., Cuthbert, J. A. & Spady, D. K. (1994) Regulation of hepatic
7␣-hydroxylase expression by dietary psyllium in the hamster. J. Clin. Invest.
93: 2084 –92.
Horton, J. D., Cuthbert, J. A. & Spady, D. K. (1995) Regulation of hepatic
7-alpha hydoxylase expression and response to dietary cholesterol in the rat
and hamster. J. Biol. Chem. 270: 5381–5387.
Hulse, J. D., Ellis, S. R. & Hendersson, L. M. (1978) Carnitine biosynthesis. J.
Biol. Chem. 253: 1654 –1661.
Ibrahim, J. & McNamara, D. J. (1988) Cholesterol homeostasis in guinea pigs
fed saturated and polyunsaturated fat diets. Biochim. Biophys. Acta 963:
109 –118.
Jackson, R. L., Baker, H. N., Gillian, E. B. & Gotto, A. M. (1977) Primary
structure of very low density apolipoprotein C-II of human plasma. Proc. Natl.
Acad. Sci. USA 74: 1942–1945.
Kaplan, B. (1995) Correlations between lipid peroxide and glutathione levels in
vitamin C supplemented fasting guinea pigs. Horm. Metab. Res. 27: 419 – 420.
Krause, B. R., Black, A., Bousley, R., Essenburg, A., Cornicelli, J.A.H., Reynold,
K., Kieft, C., Sekerke, M.K., Shaw-Hes, R., Stanfield, B., et al. (1993) Divergent
pharmacological activities of PD 132301–2 and CL 277,082, urea inhibitors of
acyl-CoA:cholesterol acyltransferase. J. Pharmacol. Exp. Ther. 267: 734 –743.
Krause, B. R., Bousley, R., Kieft, K., Robertson, D., Stanfield, R., Urda, E. &
Newton, R. S. (1994) Comparison of lifibrol to other lipid-regulating agents
in experimental animals. Pharmacol. Res. 29: 345–357.
Krause, B. R. & Newton, R. S. (1991) Animal models for the evaluation of
inhibitors of HMG-CoA reductase. Adv. Lipid Res. 1: 57–72.
Kris-Etherton, P. M. & Yu-Poth, S. (1997) Individual fatty acid effects on
plasma lipids and lipoproteins: Human studies. Am. J. Clin. Nutr. 65(suppl):
1628S–1644S.
Li, J. R., Dinh, D. M., Ellefson, R. D. & Subbiah, M.R.T. (1979) Sterol and bile
acid metabolism during development. 3. Occurrence of neonatal hypercho-
lesterolemia in guinea pig and its possible relation to bile acid pool. Metab-
olism 28: 151–156.
Lin, E.C.K., Fernandez, M. L. & McNamara, D. J. (1992) Dietary fat type and
cholesterol quantity interact to affect cholesterol metabolism in guinea pigs. J.
Nutr. 122: 2019 –2029.
Lin, E.C.K., Fernandez, M. L. & McNamara, D. J. (1994) Dietary fat and
cholesterol regulation of hepatic LDL in the guinea pig. J. Lipid Res. 35:
446 – 457.
Lin, E.C.K., Fernandez, M. L. & McNamara, D. J. (1995) Dietary fat and
20 FERNANDEZ
cholesterol regulation of HDL metabolism: Hepatic HDL binding and in vivo
apolipoprotein A-I catabolism in guinea pigs. Atherosclerosis 112: 161–175.
Liu, J.-F. & Le, Y.-W. (1997) Vitamin C supplementation restores the impaired
vitamin E status of guinea pigs fed oxidized frying oil. J. Nutr. 128: 116 –122.
Martignetti, J. A. & Brosius, J. (1993) Neural BCI RNA as an evolutionary
marker: Guinea pig remains a rodent. Proc. Natl. Acad. Sci. USA 90: 9698 –
9702.
Matsunaga, A., Sasaki, J., Hidaka, K., Takada, Y., Araki, K., Moriyama, K. &
Arakawa, K. (1994) Pravastatin-induced changes in receptor-mediated
metabolism of low density lipoprotein in guinea pigs. Artery 21: 94 –113.
Matsunaga, A., Sasaki, J., Takada, Y., Hidaka, K., Kazuko, K. & Arakawa, K.
(1991) Effect of simvastatin on receptor mediated metabolism of low density
lipoprotein in guinea pigs. Atherosclerosis 90: 31–37.
McNamara, D. J. (1984) Cholesterol homeostasis in the guinea pig. The
importance of quantitating net tissue accumulation of cholesterol in sterol
balance studies. Biochim. Biophys. Acta 796: 51–54.
McNamara, D. J., Ensign, W., Montano, C., Sun, D.-M. & Soscia, A. (1993)
Exercise and plasma lipoproteins in the guinea pig. FASEB J. 7: A869. (abs.)
McNamara, D. J., Kolb, R., Parker, T. S. & Batwin, H. (1987) Heterogeneity of
cholesterol homeostasis in man: Response to changes in dietary fat quality
and cholesterol quantity. J. Clin. Invest. 79: 1729 –1739.
Meng, M., Guo, L. & Ostwald, R. (1979) Isolation and partial characterization
of a guinea pig serum apolipoprotein comigrating with apo E on sodium
dodecyl sulphate-polyacrylamide electropherograms. Biochim. Biophys. Acta
576:134 –140.
Montano, C. E., Fernandez, M. L. & McNamara, D. J. (1998) Regulation of
apolipoprotein B-containing lipoproteins by vitamin C level and dietary fat
saturation in guinea pigs. Metabolism 47: 883– 891.
Naseem, S., Khan, M. A., Heald, F. P. & Nair, P. P. (1980) The influence of
cholesterol and fat in maternal diet of rats on the development of hepatic
cholesterol metabolism in the offspring. Atherosclerosis 36: 1– 8.
Nawrocki, J. W., Weiss, S. R., Davidson, M. H., Sprecher, D. L., Swartz, S. L.,
Lupien, P. J., Jones, P. H., Haber, H. E. & Balck, D. M. (1995) Reduction
of LDL cholesterol by 25% to 60% in patients with primary hypercholester-
olemia by atorvastatin, a new HMG-CoA reductase inhibitor. Arterioscler.
Thromb. Vas. Biol. 17: 1527–1531.
Nguyen, L. B., Guorong, X., Shefer, S., Tint, G. S., Batta, A. & Salen, G. (1999)
Comparative regulation of hepatic sterol 27-hydroxylase and cholesterol
␣-hydroxylase activities in the rat, guinea pig and rabbit: Effects of cholesterol
and bile acids. Metabolism 48: 1542–1548.
Nicolosi, R. J. (1997) Dietary fat saturation effects on low-density-lipoprotein
concentrations and metabolism in various animal models. Am. J. Clin. Nutr.
65(suppl):1617S–1627S.
Noguchi, T., Fujiwara, S., Hayashi, S. & Sakuraba, H. (1994) Is the guinea-pig
(Cavia porcellus) a rodent? Comp. Biochem. Physiol. 107: 179 –182.
Olivecrona, T. & Bengsston-Olivecrona, G. (1993) Lipoprotein lipase and he-
patic lipase. Curr. Opin. Lipidiol. 4: 187–196.
Oscai, L. B., Essig, D. A., &. Palmer, W. K. (1990) Lipase regulation of muscle
triglyceride hydrolysis. J. Appl. Physiol. 69: 1571–1577.
Ostwald, R. & Shannon, A. (1964) Composition of tissue lipids and anaemia of
guinea pigs in response to dietary cholesterol. Biochem. J. 91: 146 –154.
Parthsarathy, S., Steinberg, D. & Witztum, J. L. (1992) The role of oxidized low
density lipoproteins in the pathogenesis of atherosclerosis. Annu. Rev. Med.
43: 219 –225.
Puppione, D. L., Sardet, C., Yamanaka, W., Ostwald, R. & Nichols, A. V. (1971)
Plasma lipoproteins of cholesterol-fed guinea pigs. Biochim. Biophys. Acta
231: 295–301.
Qiao, Y., Yokoyama, M., Kameyama, K. & Asano, G. (1993) Effect of vitamin E
on vascular integrity in cholesterol-fed guinea pigs. Arterioscler. Thromb. 13:
1885–1892.
Ramjiganesh, T., Roy, A., Young, T. L., Nicolosi, R., McIntyre, J. &. Fernandez,
M. L. (2000) Corn fiber oil lowers plasma LDL cholesterol concentrations
by decreasing cholesterol absorption and altering bile acid metabolism. J.
Nutr. Biochem. 11: 358 –366.
Reihner, E., Angelin, B., Bjorkhem, I. & Einarsson, K. (1991) Hepatic choles-
terol metabolism in cholesterol gallstone disease. J. Lipid Res. 32: 469 – 475.
Reihner, E., Angelin, B., Rudling, M., Ewerth, S., Bjorkhem, I. & Einarsson, K.
(1990) Regulation of hepatic cholesterol metabolism in humans: Stimulatory
effects of cholestyramine on HMG-CoA reductase activity and low density
lipoprotein receptor expression in gallstone patients. J. Lipid Res. 31: 2219 –
2226.
Romero, A. L. & Fernandez, M. L. (1996) Dietary fat amount and carbohydrate
type regulate hepatic acyl CoA:cholesterol acyltransferase (ACAT) activity:
Possible links between hepatic ACAT activity and plasma cholesterol levels.
Nutr. Res. 16: 937–948.
Roy, S., Vega-Lopez, S. & Fernandez, M. L. (2000) Gender and hormonal
status affect the hypolipidemic mechanisms of dietary soluble fiber in guinea
pigs. J. Nutr. 130: 600 – 607.
Rudel, L. L.,. Parks, J. S., Johnson, F. L. & Babiack, J. (1986) Low density
lipoproteins in atherosclerosis. J. Lipid Res. 27: 465– 474.
Sack, M. N., Rader, D. J. & Cannon, R. O., II (1994) Oestrogen and inhibition
of oxidation of low-density lipoproteins in postmenopausal women. Lancet
343: 269 –270.
Sardet, C., Hansma, H. & Ostwald, R. (1972) Characterization of guinea pig
plasma lipoproteins: The appearance of new lipoproteins in response to
dietary cholesterol. J. Lipid Res. 13: 624 – 639.
Satinder, S., Sarkar, A. K., Majumdar, S. & Chakravari, R. N. (1987) Effects of
ascorbic acid on the development of experimental atherosclerosis. Indian
J. Med. Res. 86: 351–360.
Sauberlich, H. E. (1978) Pharmacology of vitamin C. Annu. Rev. Nutr. 14:
371–391.
Savard, R. & Bouchard, C. (1990) Genetic effects in the response to adipose
tissue lipoprotein lipase activity to prolonged exercise: A twin study. Int. J.
Obes. 14: 771–777.
Schlierf, G., Schuler, G., Hambrecht, R., Niebauer, J., Hauer, H., Vogel, G. &
Kubler, W. (1995) Treatment of coronary heart disease by diet and exer-
cise. J. Cardiovasc. Pharmacol. 25: S32–S34.
Semb, H. & Olivecrona, T. (1986) Nutritional regulation of lipoprotein lipase in
guinea pig tissues. Biochim. Biophys. Acta 876: 249 –255.
Sharma, P.,. Pramod, J., Sharma, P. K., Chaturvedi, S. K. & Kothari, L. K. (1988)
Effect of vitamin C administration on serum and aortic lipid profile of guinea
pigs. Indian. J. Med. Res. 87: 283–287.
Shen, H., He, L., Price, R. L. & Fernandez, M. L. (1998) Dietary soluble fiber
Downloaded from https://academic.oup.com/jn/article-abstract/131/1/10/4686623 by guest on 13 July 2019
lowers plasma LDL cholesterol concentrations by altering lipoprotein metab-
olism in female guinea pigs. J. Nutr. 128: 1434 –1441.
Shirai, K., Fitzharris, T. J., Shinomiya, M., Muntz, H. G., Harmony, J.A.H., Jack-
son, R. L. & Quinn, D. M. (1983) Lipoprotein lipase-catalyzed hydrolysis of
phosphatidylcholine of guinea pig very low density lipoproteins and discoidal
complexes of phospholipid and apolipoprotein: Effect of apolipoprotein C-II
on the catalytic mechanism. J. Lipid Res. 24: 721–730.
Sun, D., Fernandez, M. L., Lin, E.C.K. & McNamara, D. J. (1999) Regulation of
guinea pig hepatic acyl-CoA:cholesterol acyltransferase activity by dietary fat
saturation and cholesterol. J. Nutr. Biochem. 10: 172–180.
Suresh, M. V., Kumar, C.V.S., Lal, J. J. & Indira, M. (1999) Impact of massive
ascorbic acid supplementation on alcohol induced oxidative stress in guinea
pigs. Toxicol. Lett. 104: 221–229.
Swann, A., Wiley, M. H. & Sipperstein, M. D. (1975) Tissue distribution of
cholesterol feedback control in the guinea pig. J. Lipid Res. 16: 360 –366.
Swinkels, D. W., Demacker, P.N.M., Hak-Lemmers, H.L.M., Mol, J.T.M., Yap,
S. H. & Vol, A. (1988). Some metabolic characteristics of low-density lipopro-
tein subfractions, LDL-1 and LDL-2 in vivo studies. Biochim. Biophys. Acta
960: 1–9.
Turley, O., West, C. E. &. Horton, B. J. (1976) The role of ascorbic acid in the
regulation of cholesterol metabolism and in the pathogenesis of atheroscle-
rosis. Atherosclerosis. 24: 1–18.
Turner, J., Lee, N.-A. & Brown, W. V. (1981) Effects of changing dietary fat
saturation on low-density lipoprotein metabolism in man. Am. J. Physiol. 241:
E37–E65.
Vazquez, M., Merlos, M., Adzet, T. & Laguna, J. C. (1998) Influence of lipid
profile and fatty acid composition on the oxidation behavior of rat and guinea
pig low density lipoprotein. Comp. Biochem. Physiol. 119B: 311–316.
Vazquez, M., Zambon, D., Hernandez, Y., Azdet, T., Merlos, M. & Laguna, J. C.
(1997) Lipoprotein composition and oxidative modification during therapy
with gemfibrozil and lovastatin in patients with combined hyperlipidemia.
Br. J. Clin. Pharmacol. 45: 263–269.
Vergara-Jimenez, M., Conde, K., Erickson, S. K. & Fernandez, M. L. (1998)
Hypolipidemic mechanisms of pectin and psyllium in guinea pigs fed high
fat-sucrose diets: Alterations on hepatic cholesterol metabolism. J. Lipid Res.
39: 1455–1465.
Vergara-Jimenez, M., Furr, H. C. &. Fernandez, M. L. (1999) Pectin and
psyllium decrease the susceptibility of LDL to oxidation in guinea pigs. J. Nutr.
Biochem. 10: 118 –124.
Vidal-Quintanar, R. L., Hernandez, L., Conde, K., Vergara-Jimenez, M. &. Fernan-
dez, M. L. (1997) Fiber isolated from corn husks reduces plasma LDL
cholesterol in guinea pigs by altering lipoprotein metabolism. J. Nutr. Bio-
chem. 8: 479 – 486.
Wallinder, L., Bengtsson, G. & Olivecrona, T. (1979) Guinea pig very low
density lipoproteins are a good substrate for lipoprotein lipase. Biochim.
Biophys Acta 575: 458 – 462.
Wallinder, L., Bentsson, G. & Olivecrona, T. (1981) Demonstration of hepatic
heparin-releasable lipase in the guinea-pig. Biochim. Biophys. Acta 663:
356 –358.
Witztum, J. L. & Steinberg, D. (1991) Role of oxidized low density lipoprotein
in atherogenesis. J. Clin. Invest. 88: 1785–1792.
Witztum, J. L., Young, S. G., Elam, R. L., Carew, T. E. & Fisher, M. (1985)
Cholestyramine-induced changes in low density lipoprotein composition and
metabolism. I. Studies in the guinea pig. J. Lipid Res. 26: 92–103.
Yamada, N.,. Murase, T., Akanuma, A., Itakura, H. & Kosaka, K. (1979) A
selective deficiency of hepatic triacylglycerol lipase in guinea pigs. Biochim.
Biophys. Acta 575: 128 –134.
Yin, Y. & Olivecrona, G. (1999) Apolipoprotein CIII from guinea pig (Cavia
porcellus) is shorter and less homologous than apolipoprotein CIII from other
mammals. Comp. Biochem. Physiol. B. Biochem. Mol. Biol. 124: 157–161.
Yokota, F., Igarashi, Y. & Suzue, R. (1981) Hyperlipidemia in guinea pigs
induced by ascorbic acid deficiency. Atherosclerosis 38: 249 –254.
Yount, N. Y. & McNamara, D. J. (1991) Dietary regulation of maternal and fetal
cholesterol metabolism in the guinea pig. Biochim. Biophys. Acta 1085:
82–90.