Research note

Assessment of four experimental models

of hyperlipidemia
Yisel González Madariaga, MS, María Boffill Cárdenas, PhD, Maibia Tamayo Irsula, MS,
Orestes Castillo Alfonso, Bennia Alfonso Cáceres & Emoe Betancourt Morgado, MS

Various animal models of hyperlipidemia are used in research. Four rodent

hyperlipidemia experimental models are examined in this study: three chronic
hyperlipidemia models based on dietary supplementation with lipid or sucrose for
3 months and one acute hyperlipidemia model based on administration of the nonionic
surfactant poloxamer. Neither lipid supplementation nor sucrose supplementation in
Wistar rats was effective for establishing hyperlipidemia. Combining both lipid and
sucrose supplementation in BALB/c mice induced hypercholesterolemia, as reflected
in a considerable increase in blood cholesterol concentration, but did not produce an
increase in blood triglyceride concentration. Poloxamer administration in C57BL/J6
mice produced increases in blood cholesterol and triglyceride concentrations. The
authors conclude that supplementation of both lipid and sucrose in BALB/c mice was
the most effective method for developing chronic hypercholesterolemia.

In recent years, the incidence of diseases such as some researchers have shown that diet can be used to
obesity, insulin resistance, dyslipidemia and type 2 promote metabolic disturbances in rodents10,11. In rats,
diabetes has increased, owing to both genetic and hypercholesterolemia can be induced by diets high in
environmental factors1,2. Changes in the nutritional cholesterol or saturated fat alone or in combination
composition of diets, such as increases in refined sugar with proteins such as casein12,13. Drinks sweetened with
and saturated fats, as well as lifestyle changes, such as sucrose or fructose and diets rich in carbohydrates pro-
increased sedentary behavior, seem to have a role in the voke an increase in body weight and hyperlipidemia14,15.
development of these pathologies3,4. On the other hand, Changes in body weight and metabolic parameters such
maintaining blood triglyceride and cholesterol levels as triglyceride, cholesterol, glucose, very-low-density
within normal ranges is associated with the prevention lipoprotein, fibrinogen and total protein have been
of diseases such as arteriosclerosis, obesity, cardiovas- assessed in such animal models16–18, but plasma lipid
cular disease and diabetes. profiles in animal models fed carbohydrate–rich diets
Different nutritional experimental models with vary among studies. Moreover, several studies have
metabolic and biochemical characteristics similar to shown that a high-fat, high-sucrose diet can result in
those described in dyslipidemia have been developed. metabolic imbalances19–21. Hyperlipidemia can also
Although the application of these nutritional experi- be caused by injections of non-ionic surfactants like
mental models to humans may be limited, they are poloxamer, which provoke a considerable increase in
extremely useful for research purposes5,6. Rabbits fed plasma lipids within 24 h. These substances block the
a high-cholesterol diet have been used to study hyper- lipoprotein lipase and prevent cholesterol from entering
lipidemia and atherosclerosis7. Similarly, turkeys that the cell, resulting in an increase in plasma lipoprotein
consume high-cholesterol foods develop hypercholes- levels and hyperlipidemia22–24. They are relatively non-
terolemia in rather short periods of time8. Rodents are toxic to animals, with LD50 values reported at 5–34.6 g
more resistant to high blood cholesterol levels9, but per kg body weight (ref. 25).

Department of Experimental Research, Toxicology Center, Medical College of Villa Clara, Villa Clara, Cuba. Correspondence should be
addressed to Y.G.M. ([email protected]).

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© 2015 Macmillan Publishers Limited. All rights reserved
Research note

600
20 g chow per animal daily, and mice were fed 10 g
L
chow per animal daily. Rodents had free access to tap
500
C
water. Food and water were provided early in the morn-
Body weight (g)
400
ing each day.

300 Experiment 1: lipid supplementation in Wistar rats

Twelve Wistar rats were randomly assigned to one of
200 two groups that received different diets for a period of
3 months. The control group (n  =  6) was fed the stand-
100 ard diet of laboratory rodent chow, whereas the experi-
mental group (n  =  6) received a modified version of the
0
0 1 2 3 4 5 6 7 8 9 10 11 12 standard diet in which 10% of the diet (by weight) was
Time (weeks) substituted with chicken fat (20% saturated fat, 60%
FIGURE 1 | Effects of lipid supplementation on body weight in unsaturated fat; Meats’s Company, Villa Clara, Cuba).
Wistar rats. Body weight was greater in rats that received lipid This diet modification was similar to one previously
supplementation (L) than in control rats (C) after 12 weeks of described in which 20% of the diet was substituted
supplementation. with fat26. To produce the modified diet, we homog-
enized 90 g of chow and 10 g of chicken fat in distilled
We carried out experiments to evaluate four different water at 50 °C in an automatic mixer (Tecnopast,
approaches for inducing hyperlipidemia in rodents. Charlotte, NC) and then dried it into pellets. The pel-
lets were prepared weekly and stored at 4 °C. Rats in
METHODS the experimental group ate all but 1 g or less of the food
Animals they were given during the week of the experiment and
The experimental protocol was approved by the Animal ate all of the food they were given during the remaining
Ethics Committee of the Toxicology Center of Medical 11 weeks of the experiment.
College of Villa Clara, Cuba. All rodents were purchased
at the National Center of Laboratory Animal Production Experiment 2: sucrose supplementation in Wistar rats
(Havana, Cuba). In total, we used 24 six-week-old male Twelve Wistar rats were randomly assigned to one of
Wistar rats weighing 180–200 g, 30 six-week-old male two groups that received different drinking water for
BALB/c mice weighing 20–25 g and 16 six-week-old a period of 3 months. The control group (n  =  6) had
male C57BL/J6 mice weighing 20–25 g for our studies. free access to regular tap water, whereas each rat in the
experimental group (n  =  6) received 15 ml of drinking
Housing water containing 9.75 mg sucrose per day. After the rats
Wistar rats were housed six rats per cage in polycar- in the experimental group had consumed the sucrose-
bonate cages (Tecniplast, Buguggiate, Italy) with mesh containing water, they were given free access to regular
bottoms with spacing of 11 mm × 11 mm and a floor tap water for the remainder of the day.
area of 1,800 cm2. We housed the mice in polycarbonate
cages (Tecniplast, Buguggiate, Italy) with mesh bot- Experiment 3: lipid and sucrose supplementation
toms with spacing of 7 mm × 7 mm and a floor area in BALB/c mice
of 820 cm2. BALB/c mice were housed ten mice per Thirty BALB/c mice were randomly assigned to one of
cage. C57BL/6 mice were housed eight mice per cage. three groups that received different diets and different
Rodents were acclimatized to their
environments for 7 d before the begin-
ning of the experiment. Animals were TABLE 1 | Mean ± s.d. blood cholesterol and triglyceride
kept in specific pathogen–free condi- concentrations (mmol/l) in Wistar rats that received lipid
tions. Room temperature was 22 ± 2 °C supplementation or standard chow (control) for 3 months
on a 12-h:12-h light:dark cycle. Baseline 1 month 2 months 3 months
Cholesterol
Standard diet and drinking water
Lipid 1.63 ± 0.38 2.10 ± 0.21* 1.56 ± 0.16 1.39 ± 0.16
Animals were fed a standard diet of lab-
oratory chow for rodents manufactured Control 1.63 ± 0.20 1.83 ± 0.16 1.39 ± 0.19 1.42 ± 0.13
at the National Center of Laboratory Triglyceride
Animal Production (Havana, Cuba). Lipid 0.43 ± 0.13 1.34 ± 0.68* 0.42 ± 0.10 0.56 ± 0.16
The content of this diet was 16% pro-
tein, 2% fat, 5% fiber, 0.39% calcium Control 0.50 ± 0.13 0.39 ± 0.11 0.60 ± 0.15 0.68 ± 0.22
and 0.49% phosphorus. Rats were fed *P  <  0.05.

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 Research note

500 retro-orbital sinus. For experiments 1–3, blood was

450 S collected at the beginning of the experiment and once
400 C per month during the experiment, and the animals
Body weight (g) had been fasting for 18 h before blood collection. For
350
experiment 4, blood was collected at 0 h, 24 h and 48 h
300 after injections were administered. Heparin-treated
250 blood samples were stored at 4 °C and processed
200
within 7 d after extraction for biochemistry analyses.
Concentrations of total cholesterol, triglyceride and,
150
for experiments 2 and 3 only, glucose in blood samples
100 were assayed using Helfa diagnostic kits (EPB
0 1 2 3 4 5 6 7 8 9 10 11 12
Time (weeks) Carlos J. Filany, Havana, Cuba) and a spectrophotometer
(Hitachi 902 Automated machine; Roche Diagnostic,
FIGURE 2 | Effects of sucrose supplementation on body
weight in Wistar rats. Body weight was greater in rats that
Tokyo, Japan). Data are presented as mean ± s.d. Body
received sucrose supplementation (S) than in control rats (C) weights were compared by Student’s t-test. Cholesterol
beginning after 2 weeks of supplementation and continuing for and triglyceride concentrations in experiments 1 and 4
the remainder of the experiment. were compared by Student’s t-test. Cholesterol, triglyc-
eride and glucose concentrations in experiments 2 and 3
drinking water for a period of 3 months. One group were compared by analysis of variance. We used SPSS
(n  =  10) was fed the standard diet of laboratory rodent software version 18 (SPSS Inc., Chicago, IL).
chow and received 15 ml of drinking water containing
4.5 mg sucrose per day. A second group (n  =  10) received RESULTS
a modified version of the standard diet in which 20% of Experiment 1: lipid supplementation in Wistar rats
the diet (by weight) was substituted with lard (46% sat- Mean body weight was greater in rats that received lipid
urated fat, 44% unsaturated fat; Meats’s Company, Villa supplementation than in rats that were fed a stand-
Clara, Cuba) and had free access to regular tap water. ard diet after 12 weeks of supplementation (P  <  0.05;
The third group (n  =  10) received the lard-substituted Fig. 1). Mean cholesterol and triglyceride concentra-
diet and the sucrose-containing drinking water. To pro- tions in rats after 1 month of lipid supplementation
duce the modified diet, we homogenized 80 g of chow were significantly greater than baseline concentrations
and 20 g of lard in distilled water at 50 °C in an auto- (P  <  0.05) and significantly greater than those in con-
matic mixer (Tecnopast, Charlotte, NC) and then dried trol rats at the same time point (P  <  0.05; Table 1).
it into pellets. The pellets were prepared weekly and Mean triglyceride concentration after 1 month of lipid
stored at 4 °C. After the mice in the groups that received supplementation was three times higher than mean
sucrose-containing water had consumed all the sucrose- baseline concentration (Table 1). After 2 months of
containing water, they were given free access to regular lipid supplementation, however, mean cholesterol
tap water for the remainder of the day. and triglyceride concentrations returned to roughly

Experiment 4: poloxamer injections in

C57BL/J6 mice TABLE 2 | Mean ± s.d. blood cholesterol, triglyceride and
Sixteen C57BL/J6 mice were randomly glucose concentrations (mmol/l) in Wistar rats that received
assigned to one of two groups. Mice in both sucrose supplementation or normal drinking water (control)
groups were fed a diet of standard chow and for 3 months
had free access to regular tap water. Mice in Baseline 1 month 2 months 3 months
the experimental group (n  =  8) were given Cholesterol
a single intraperitoneal (i.p.) injection of
Sucrose 1.63 ± 0.20 2.59 ± 0.59 2.80 ± 0.19 3.89 ± 0.37*
0.6 g per kg body weight poloxamer 338
(P-338; Sigma-Aldrich, Lyon, France)25. Mice Control 2.26 ± 0.09 1.56 ± 0.16 3.40 ± 0.26
in the control group (n  =  8) were given a Triglyceride
single i.p. injection of saline (pH of 7.4).
Sucrose 0.96 ± 0.20 1.66 ± 0.45 1.25 ± 0.59 1.80 ± 0.60

Body weight measurement and Control 1.71 ± 0.42 0.86 ± 0.63 1.63 ± 0.24
blood sampling Glucose
For experiments 1–3, rodents were weighed Sucrose 3.37 ± 1.29 9.70 ± 1.58* 9.45 ± 2.07* 8.08 ± 1.77*
weekly using a Sartorius BP160P balance
(Sartorius, Gottingen, Germany). For all Control 6.46 ± 2.88 7.57 ± 1.04 5.94 ± 1.12
experiments, blood was collected from the *P  <  0.05.

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Research note

30 supplementation alone or mice that received both lipid

29 and sucrose supplementation.
28
S
Mean cholesterol concentration increased signifi-
27 cantly in mice that received lipid supplementation
LS alone and in mice that received both lipid and sucrose
Body weight (g)

26
supplementation after 1 month, 2 months and 3 months
25
L of supplementation compared with baseline (P  <  0.05;
24
Table 3). Mean cholesterol concentration at the end of
23 the experiment was greatest in mice that received lipid
22 supplementation alone. Mean cholesterol concentra-
21 tion did not change significantly in mice that received
20 sucrose supplementation alone during the experiment
0 1 2 3 4 5 6 7 8 9 10 11 12 (Table 3). Mean triglyceride concentration did not
Time (weeks)
change significantly in any of the three groups during
FIGURE 3 | Effects of lipid and sucrose supplementation the experiment (Table 3). Mean glucose concentration
on body weight in BALB/c mice. Mice that received sucrose was significantly higher in mice that received lipid sup-
supplementation alone (S) gained more weight during
plementation alone after 2 months of supplementation
the 12-week experiment than did mice that received lipid
supplementation alone (L) or mice that received both lipid and than after 1 month of supplementation (P  <  0.05), but
sucrose supplementation (LS). none of the mice had significantly elevated glucose lev-
els at the end of the study (Table 3).
baseline levels and remained relatively stable for the
rest of the experiment (Table 1). Experiment 4: poloxamer injections in C57BL/J6 mice
Mean concentrations of cholesterol and triglycer-
Experiment 2: sucrose supplementation in Wistar rats ide were significantly greater in mice that received
Mean body weight was greater in rats that received poloxamer injections than in control mice at 24 h and
sucrose supplementation than in control rats begin- 48 h after injection (P  <  0.001; Table 4).
ning after 2 weeks of supplementation and continuing
for the remainder of the experiment (P  <  0.001; Fig. 2). DISCUSSION
Mean cholesterol concentration was significantly We evaluated four different rodent models of hyperli-
greater in rats that received sucrose supplementation pidemia. In the first experiment, lipid supplementation
after 3 months of supplementation than at baseline for 3 months did not induce hypercholesterolemia in
(P  =  0.002; Table 2). Mean triglyceride concentration Wistar rats. We used chicken fat as lipid supplemen-
was similar in rats that received sucrose supplementa- tation in this experiment, which, like any animal fat,
tion and in control rats at all time points
throughout the experiment (Table 2).
TABLE 3 | Mean ± s.d. blood cholesterol, triglyceride and glucose
Mean blood glucose level was signifi­
concentrations (mmol/l) in BALB/c mice that received lipid
cantly greater in rats that received supplementation alone, sucrose supplementation alone or both
sucrose supplementation than in con- lipid and sucrose supplementation for 3 months
trol rats after 1 month, 2 months and Baseline 1 month 2 months 3 months
3 months of sucrose supplementation Cholesterol
(P  =  0.05; Table 2).
Lipid alone 2.33 ± 0.31 2.98 ± 0.39* 3.67 ± 0.52* 4.27 ± 0.82*
Experiment 3: lipid and sucrose Sucrose alone 2.35 ± 0.30 2.36 ± 0.86 2.78 ± 0.52
supplementation in BALB/c mice Lipid and sucrose 3.72 ± 0.62* 3.44 ± 0.31* 3.71 ± 0.61*
Mean body weight increased signifi-
Triglyceride
cantly in mice that received lipid sup-
plementation alone (after 2 weeks of Lipid alone 1.30 ± 0.41 0.98 ± 0.21 1.22 ± 0.42 1.19 ± 0.33
supplementation, P  =  0.045), sucrose Sucrose alone 1.05 ± 0.18 1.28 ± 0.61 1.15 ± 0.23
supplementation alone (after 3 weeks
Lipid and sucrose 1.05 ± 0.21 1.24 ± 0.22 1.01 ± 0.18
of supplementation, P  =  0.029) and
both lipid and sucrose supplementation Glucose
(after 5 weeks of supplementation, Lipid alone 4.59 ± 0.51 3.20 ± 0.48 5.22 ± 0.76* 4.21 ± 1.14
P  =  0.004; Fig. 3). Mice that received Sucrose alone 2.73 ± 0.71 2.50 ± 0.73 4.29 ± 0.88
sucrose supplementation alone gained
more weight during the 12-week experi­ Lipid and sucrose 3.66 ± 1.09 3.32 ± 1.15 3.53 ± 1.15
ment than did mice that received lipid *P  <  0.05.

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 Research note

3 months resulted in increases in blood cholesterol

TABLE 4 | Mean ± s.d. blood cholesterol and
level, but not triglyceride level, in BALB/c mice.
triglyceride concentrations (mmol/l) in C57BL/J6
mice that received injections of poloxamer or of Endogenous cholesterol production should be favored
saline (control) in these models by an increase in insulinemia38,39.
Baseline 24 h 48 h
Increases in glucose input and lipid absorption
combine to raise insulin levels, which in turn lead
Cholesterol
to higher levels of acetyl coenzyme A, increasing
Poloxamer 1.94 ± 0.34   5.14 ± 2.83* 6.33 ± 1.44* endogenous cholesterol production40.
Control 1.80 ± 0.15   1.88 ± 0.37 3.74 ± 0.87 In our fourth experiment, injection of the nonionic
Triglyceride
surfactant poloxamer resulted in increases in blood
concentrations of cholesterol and triglyceride, result-
Poloxamer 0.81 ± 0.17 11.87 ± 3.25* 8.76 ± 2.50* ing in acute hyperlipidemia. Poloxamer blocks lipase,
Control 0.70 ± 0.13   0.71 ± 0.17 3.33 ± 2.41 reducing cholesterol input to peripheral tissues such as
*P  <  0.001. the liver and favoring endogenous cholesterol synthesis,
which is regulated by negative feedback mechanisms,
is a mixture of saturated and unsaturated fatty acids. resulting in a net increase in the circulation of triglyc-
Similar to our results, other authors reported no signifi- erides and cholesterol23,41.
cant increases in cholesterol concentrations induced by The combination of lipid and sucrose supple­
feeding animals a mixture of saturated and unsaturated mentation seems to be the most effective of the
fatty acids27,28. Chicken fat has more unsaturated fatty four methods we tested for inducing hyperlipidemia
acids or saturated short chain ones than saturated fatty resulting from biochemical metabolic imbalance. Our
acids, which could explain its lack of hyperlipidemic results suggest that lipid and sucrose supplementation
properties in this model. It is also possible that lipid in BALB/c mice can induce chronic hyperlipidemia
supplementation with chicken fat for longer periods of as well as obesity.
time could produce hypercholesterolemia. In a previ-
ous study, rats fed an oil palm diet plus 0.1% cholesterol Acknowledgments
showed no changes in cholesterol levels after 2 months We thank Yuliet González Madariaga, Head of Foreign Language
Department of Central University Marta Abreu of Las Villas, for her
but did develop hypercholesterolemia after 6 months29. help with the English translation of this paper.
Triglyceride concentration did increase after 1 month
of lipid supplementation with chicken fat, probably COMPETING FINANCIAL INTERESTS
owing to an increase in lipid absorption rate30. The authors declare no competing financial interests.
Previous research suggested that high-carbohydrate
diets can lead to hypertriglyceridemia in animals31,32. Received 10 April 2014; accepted 18 August 2014
Hyperinsulinemia and hyperlactinemia resulting Published online at http://www.labanimal.com/
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