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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
KEY WORDS: ● Guinea pigs ● lipoprotein metabolism ● hepatic cholesterol metabolism ● soluble fiber
● atherosclerosis.
The goal of this review is to provide insight into the 3. They have plasma cholesteryl ester transfer protein
benefits and advantages of using guinea pigs to explain how (CETP)2 (Ha et al. 1982), lecithin-cholesterol acyl-
hepatic cholesterol and lipoprotein metabolisms are affected transferase (LCAT) (Douglas and Pownell 1991) and
by dietary factors, drug treatment, marginal intake of Vitamin lipoprotein lipase (LPL) (Olivecrona and Bengsston-
C, exercise, gender, development and menopause. Olivecrona 1993) activities for intravascular processing
There is some controversy as to whether guinea pigs (Cavia of plasma lipoproteins.
porcellus) should be classified as rodents (Martignetti et al. 4. They exhibit comparable moderate rates of hepatic
1993, Noguchi et al. 1994). Although this issue is not relevant cholesterol synthesis (Reihner et al. 1990) and catab-
to the present discussion, there is one aspect of guinea pigs olism (Reihner et al. 1991).
that makes them stand out from other rodents: the fact that 5. Similar to humans, the binding domain for the LDL
they carry the majority of their cholesterol in LDL (Fernandez receptor differentiates between normal and familial
and McNamara 1989). This outstanding difference raises the binding defective apolipoprotein (apo)B-100 (Corsini
question as to whether guinea pigs have other similarities to et al. 1992).
humans in cholesterol and lipoprotein metabolism. Research- 6. Apo B mRNA editing in the liver is negligible (⬍1%)
ers at our laboratory and other investigators have found that compared with 18 –70% in other species (Greeve et al.
guinea pig cholesterol metabolism does indeed have some 1993).
analogies to human cholesterol metabolism that merit discus- 7. They require dietary vitamin C (Sauberlich 1978).
sion. 8. Females have higher HDL concentrations than males
Some of these similarities include the following: (Roy et al. 2000).
1. Guinea pigs have high LDL-to-HDL ratios (Fernandez 9. Ovariectomized guinea pigs have a plasma lipid profile
et al. 1990a). similar to that of postmenopausal women (Roy et al.
2. They have higher concentrations of free than of ester- 2000).
ified cholesterol in the liver (Angelin et al. 1992). 10. During exercise in guinea pigs, plasma triacylglycerol
(TAG) decreases and plasma HDL cholesterol
(HDL-C) increases (McNamara et al. 1993).
1
To whom correspondence should be addressed. 11. Guinea pigs respond to dietary interventions (Fernan-
E-mail: maria-luz.fernandez@uconn.edu dez and McNamara 1992b, 1992a and 1995a, He and
2
Abbreviations used: ACAT, acyl coenzyme A cholesteryl acyltransferase; Fernandez 1998a) and drug treatment (Berglund et
apo, apolipoprotein; Bmax, maximal binding; CETP, cholesterol ester transfer
protein; CE, cholesteryl ester; CO, corn oil; Cyp7, cholesterol 7␣-hydroxylase; FC, al.1989, Hikada et al. 1992) by lowering plasma LDL
free cholesterol; FCR, fractional catabolic rate; GG, guar gum; HC, high concen- cholesterol (LDL-C)
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; Hepatic cholesterol metabolism
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- In contrast to rats (Swann et al. 1975), guinea pigs have
erol; VLDL-C, VLDL cholesterol. moderate rates of hepatic cholesterol synthesis (Fernandez et
10
GUINEA PIGS AND LIPOPROTEIN METABOLISM 11
pig apoC-III was cloned and sequenced (Yin and Olivecrona vitamin C (Montano et al. 1998) have also been shown to
1999). The two most conserved areas of guinea pig apoC-III increase plasma HDL-C concentrations in guinea pigs.
were found in residues 16 –33 and 50 – 69, which have been
predicted to form amphipathic helices assumed to play impor- Effects of dietary factors on cholesterol and lipoprotein
tant roles in the inhibition of LPL. metabolism
LPL activity is modulated in guinea pigs by food depriva-
tion (Sem and Olivecrona 1986) and by dietary fat being Dietary fat. Effects of fatty acids varying in chain length
higher in the dietary regimens that result in lower concentra- and degree of saturation on cholesterol and lipoprotein me-
tions of plasma LDL-C. For example, a diet rich in PUFA tabolism have been studied in guinea pigs. Diets high in PUFA
resulted in higher LPL activity compared with a diet rich in [corn oil (CO)] lower plasma LDL-C concentrations compared
SAT (Cryer et al. 1978). Similarly, rapeseed oil intake resulted with highly SAT palm kernel oil (PK), which is rich in
in lower plasma LDL-C concentrations compared with intake short-chain fatty acids, or SAT lard, which is rich in long-
of either olive oil or palm oil, and lower LDL-C also correlated chain fatty acids (Abdel-Fattah et al. 1995, Fernandez et al.
with higher LPL activity (Fernandez et al. 1996b). 1992a and 1993). Numerous aspects of lipoprotein metabolism
LDL. Various animal models have been used to determine modulated by dietary fatty acids accounted for the observed
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
specific effects of these fatty acids on hepatic cholesterol LDL with hepatic membranes, and the number of receptors
homeostasis, VLDL secretion, alterations in the intravascular was decreased as the amount of dietary cholesterol increased
compartment and LDL catabolic rates. In addition, the cho- (Lin et al. 1994).
lesterolemic response of guinea pigs to dietary fatty acids is In addition, guinea pigs can be hyporesponders or hyperre-
similar to reports from clinical studies (Nicolosi 1997), and is sponders to dietary cholesterol (Fernandez et al. 1990b), dem-
in agreement with proposed mechanisms reported in studies in onstrating that the responses to dietary cholesterol are highly
humans (Cortese et al. 1983, Turner et al. 1981). individualized, in agreement with clinical studies (McNamara
Dietary cholesterol. Earlier reports of the deleterious ef- et al. 1987). Our laboratory has also demonstrated that guinea
fects of dietary cholesterol on guinea pigs, including hemolytic pigs present early atherosclerotic development and fatty streak
anemia characterized by accelerated destruction of the eryth- accumulation after 12 wk when challenged with amounts of
rocytes (Puppione et al. 1971) and death before considerable dietary cholesterol in the range of 2000 mg/d consumption by
plaques developed, precluded the use of guinea pigs as models humans (Cos et al. 2000).
of cholesterol and lipoprotein metabolism. In addition, these Dietary soluble fiber. The effectiveness of several types of
reports focused on the appearance of abnormal lipoproteins soluble fiber in reducing plasma LDL-C concentrations and
and changes in lipid metabolism, which were postulated to be their specific effects on hepatic cholesterol and lipoprotein
species specific (Guo et al. 1982, Meng et al. 1979, Ostwald metabolisms have been studied in guinea pigs. Prickly pear
and Shannon 1964, Sarted et al. 1972). These carefully con- (Opuntia sp.), a plant commonly grown in Mexico, has been
trolled studies failed to stress that the amount of cholesterol traditionally used for diabetes treatment and as a hypocholes-
provided to guinea pigs was 1–2%, which, based on our careful terolemic agent. Studies were carried out with pectin isolated
calculations, is equivalent to 7500 –15,000 mg cholesterol/d in from this plant (PPP) to test its potential properties in lower-
humans. Thus, remarks concerning these earlier studies have ing plasma cholesterol (Fernandez et al. 1990b, 1992b and
to be taken with caution and interpretation of the results must 1994d). Guinea pigs were fed hypercholesterolemic diets con-
be made with the consideration that these experiments cannot taining 0, 1 or 2.5% PPP, and plasma lipids and some meta-
possibly have any clinical relevance. bolic parameters were compared. Plasma LDL-C was 33%
The effects of dietary cholesterol on plasma lipids, lipopro- lower in guinea pigs fed the PPP diet compared with the
tein composition, hepatic LDL receptors and HDL metabolism control group. The hepatic apoB/E receptor was 60% higher in
have been evaluated in guinea pigs fed 0.08, 0.17 or 0.33% guinea pigs fed the PPP diets, which was in agreement with the
dietary cholesterol, which is equivalent to 600-2500 mg cho- twofold faster receptor-mediated LDL FCR observed in guinea
lesterol/d in humans (Lin et al. 1992, 1994 and 1995). These pigs fed this type of fiber. Although a 46% reduction in hepatic
concentrations of dietary cholesterol correspond to an amount free cholesterol was observed, HMG-CoA reductase and
of absorbed cholesterol equal to half, one time and two times ACAT activities were not altered by PPP (Fernandez et al.
the endogenous cholesterol synthesis in guinea pigs (Lin et al. 1994d).
1992). Increasing the concentration of dietary cholesterol In another study, guinea pigs were fed increasing concen-
resulted in a dose-dependent increase in plasma cholesterol trations of pectin (PE) (0, 2.5, 5, 7.5, 10 and 12.5%) with low
associated with the LDL fraction, which was independent of (LC, 0.04%) or high (HC, 0.25%) concentrations of dietary
the dietary fat level. HMG-CoA reductase activity was signif- cholesterol (Fernandez et al. 1994a). Guinea pigs fed LC had
icantly down-regulated with an absorbed amount equivalent to lower concentrations of plasma LDL-C at 10 and 12.5% PE
half the endogenous cholesterol synthesis (0.08% dietary cho- compared with controls. In contrast, guinea pigs fed HC ex-
lesterol) as a first compensatory mechanism. The amount of hibited a PE dose–related decrease in plasma LDL-C and a PE
cholesterol in the liver was also increased in a dose-dependent dose– dependent increase in hepatic LDL receptors. HMG-
manner as the concentration of dietary cholesterol increased CoA reductase activity was suppressed by high dietary choles-
(Lin et al. 1992) (Table 1). The hepatic LDL receptor number terol and only intake of 12.5% PE reversed this suppression.
was measured by incubating increasing concentrations of 125I- Guinea pigs fed 12.5% PE with HC diets had a complete
GUINEA PIGS AND LIPOPROTEIN METABOLISM 15
inhibitors (Krause et al. 1993), HMG-CoA reductase inhibi- important differences in the gender response to dietary treat-
tors such as pravastatin (Matsunaga et al. 1994), simvastatin ments. In addition, we have observed that female guinea pigs
(Conde et al. 1999a and 1999b), lovastatin (Berglund et al. have higher HDL-C concentrations than do males (Roy et al.
1989, Krause et al. 1994, Krause and Newton 1991) and 2000).
atorvastatin (Conde et al. 1996, 1999a and 1999b). In a recent study using male, female and ovariectomized
Cholestyramine has a potent hypocholesterolemic effect in guinea pigs, several important findings emerged that reinforce
guinea pigs, reducing plasma LDL-C concentrations by 55– the suitability of ovariectomized guinea pigs to mimic human
75% (Fernandez et al. 2000). Witztum et al. (1985) measured menopause. Ovariectomized guinea pigs had higher concen-
cholestyramine effects on LDL size and composition and how trations of plasma TAG than did either males or females,
these affected LDL FCR. Their findings suggest that LDL from higher concentrations of LDL-C and a more detrimental li-
cholestyramine-treated guinea pigs, which were smaller in size, poprotein profile overall (Roy et al. 2000). In addition, ovari-
had a slower turnover in plasma than did LDL derived from ectomized guinea pigs exhibited a higher susceptibility of LDL
controls. The plasma LDL-C lowering by cholestyramine was to oxidize compared with intact females. It has been shown
due to increases in the LDL receptor in treated guinea pigs, that estrogen exerts a protective effect against free radical
suggesting that compositional changes in LDL have profound
Guinea pigs are the most appropriate model in which to Oxidized LDL may enhance the progression of atheroscle-
study the role of vitamin C in hepatic lipid metabolism, rosis via the following processes: enhancement of monocyte
plasma lipids and progression of atherosclerosis because they adhesion and macrophage foam cell generation, stimulation of
are one of the few species that has a dietary requirement for platelet adhesion and aggregation, triggering of thrombosis
ascorbic acid (Turley et al. 1976). Epidemiological studies and impairment of vasodilation (Parthsarathy et al. 1992).
have shown a negative correlation between intake of vitamin The oxidation of LDL probably takes place in the arterial wall,
C and plasma cholesterol concentrations (Cerna and Ginter where LDL particles are sequestered from circulating antioxi-
1978). In addition, the Basel protective study documented dants (Witztum and Steinberg 1991). Vazquez et al. (1998)
that low plasma carotene and ascorbate concentrations corre- measured the oxidation behavior of rat and guinea pig LDL
lated with a higher risk for coronary heart disease (Gey et al. and concluded that guinea pig LDL composition bears a closer
1993). Studies in guinea pigs have shown that inadequate resemblance to that of human LDL. In a clinical study of
intake of vitamin C leads to hypercholesterolemia (Montano patients with familial hyperlipidemia, these authors observed
TABLE 5 lovastatin therapy on guinea pig low density lipoprotein composition and
metabolism. J. Lipid Res. 30: 1591–1600.
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