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Diet-induced metabolic hamster model of nonalcoholic fatty liver disease

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Obesity, hypercholesterolemia, elevated triglycerides, and type 2 diabetes are major risk factors for metabolic syndrome. Hamsters, unlike rats or mice, respond well to diet-induced obesity, increase body mass and adiposity on group housing, and increase food intake due to social confrontation-induced stress. They have a cardiovascular and hepatic system similar to that of humans, and can thus be a useful model for human pathophysiology. Experiments were planned to develop a diet-induced Bio F(1)B Golden Syrian hamster model of dyslipidemia and associated nonalcoholic fatty liver disease in the metabolic syndrome. Hamsters were fed a normal control diet, a high-fat/high-cholesterol diet, a high-fat/high-cholesterol/methionine-deficient/choline-devoid diet, and a high-fat/high-cholesterol/choline-deficient diet. Serum total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, atherogenic index, and body weight were quantified biweekly. Fat deposition in the liver was observed and assessed following lipid staining with hematoxylin and eosin and with oil red O. In this study, we established a diet-induced Bio F(1)B Golden Syrian hamster model for studying dyslipidemia and associated nonalcoholic fatty liver disease in the metabolic syndrome. Hyperlipidemia and elevated serum glucose concentrations were induced using this diet. Atherogenic index was elevated, increasing the risk for a cardiovascular event. Histological analysis of liver specimens at the end of four weeks showed increased fat deposition in the liver of animals fed with a high-fat/high cholesterol diet, as compared to animals fed with the control diet. Our study established that hamsters fed with a high-fat/high-cholesterol diet developed fatty liver and mild diabetes. Bio F(1)B hamsters fed with a high-fat/high-cholesterol diet may thus be a good animal model for research on the treatment of diet-induced metabolic syndrome complicated by nonalcoholic fatty liver disease.
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ORIGINAL RESEARCH
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Open Access Full Text Article
DOI: 10.2147/DMSO.S18435
Diet-induced metabolic hamster model
of nonalcoholic fatty liver disease
Jasmine Bhathena
Arun Kulamarva
Christopher Martoni
Aleksandra Malgorzata
Urbanska
Meenakshi Malhotra
Arghya Paul
Satya Prakash
Biomedical Technology and Cell
Therapy Research Laboratory,
Department of Biomedical
Engineering, Artificial Cells and
Organs Research Centre, Faculty
of Medicine, McGill University,
Montreal, Québec, Canada
Correspondence: Satya Prakash
3775 University Street, Montreal,
Québec H3A 2B4, Canada
Tel +1 514 398 3676
Fax +1 514 398 7461
Email satya.prakash@mcgill.ca
Background: Obesity, hypercholesterolemia, elevated triglycerides, and type 2 diabetes are
major risk factors for metabolic syndrome. Hamsters, unlike rats or mice, respond well to diet-
induced obesity, increase body mass and adiposity on group housing, and increase food intake
due to social confrontation-induced stress. They have a cardiovascular and hepatic system similar
to that of humans, and can thus be a useful model for human pathophysiology.
Methods: Experiments were planned to develop a diet-induced Bio F
1
B Golden Syrian
hamster model of dyslipidemia and associated nonalcoholic fatty liver disease in the metabolic
syndrome. Hamsters were fed a normal control diet, a high-fat/high-cholesterol diet, a high-
fat/high-cholesterol/methionine-deficient/choline-devoid diet, and a high-fat/high-cholesterol/
choline-deficient diet. Serum total cholesterol, high-density lipoprotein cholesterol, low-density
lipoprotein cholesterol, triglycerides, glucose, atherogenic index, and body weight were quanti-
fied biweekly. Fat deposition in the liver was observed and assessed following lipid staining
with hematoxylin and eosin and with oil red O.
Results: In this study, we established a diet-induced Bio F
1
B Golden Syrian hamster model
for studying dyslipidemia and associated nonalcoholic fatty liver disease in the metabolic syn-
drome. Hyperlipidemia and elevated serum glucose concentrations were induced using this diet.
Atherogenic index was elevated, increasing the risk for a cardiovascular event. Histological analysis
of liver specimens at the end of four weeks showed increased fat deposition in the liver of animals
fed with a high-fat/high cholesterol diet, as compared to animals fed with the control diet.
Conclusion: Our study established that hamsters fed with a high-fat/high-cholesterol diet
developed fatty liver and mild diabetes. Bio F
1
B hamsters fed with a high-fat/high-cholesterol
diet may thus be a good animal model for research on the treatment of diet-induced metabolic
syndrome complicated by nonalcoholic fatty liver disease.
Keywords: fatty liver disease, in vivo model, diet, atherogenic index, obesity
Introduction
Obesity is exponentially increasing, and its pervasiveness is at epidemic levels in the
world. Obesity may be the cause of or a precursor to other diseases, such as insulin
resistance and dyslipidemia (hypertriglyceridemia and reduced high-density lipopro-
tein [HDL] cholesterol). The term “metabolic syndrome” was coined to describe the
concurrent occurrence of these diseases. Individuals with metabolic syndrome are at
amplified risk for type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver
disease.
1–3
The liver is a target organ in metabolic syndrome, in which it manifests
itself as nonalcoholic fatty liver disease, spanning the spectrum of hepatosteatosis to
hepatocellular carcinoma through steatohepatitis and cirrhosis. Because metabolic
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syndrome and nonalcoholic fatty liver disease affect the
same insulin-resistant patients, it stands to reason that there
would be a similarity between the metabolic syndrome and
nonalcoholic fatty liver disease in terms of prevalence,
pathogenesis, clinical features, and outcome.
4
The costs of
treating metabolic syndrome and its associated disorders
are growing, and the research community is seeking animal
models that mimic the human phenotype so that potential
therapies can be tested.
Data from various animal models have provided the con-
ceptual framework for much of the clinical investigations,
and permit study of the pathophysiology and fundamental
biological mechanisms of disease. Continued studies in
animals provide further clarification of the pathogenesis
of metabolic disorders and may therefore be very useful to
improve diagnosis and treatment of metabolic syndrome.
5–7
However, the study of the pathophysiologic process of meta-
bolic syndrome and nonalcoholic fatty liver disease is limited
by the lack of appropriate animal models that can depict
the combined features of nonalcoholic fatty liver disease
and the cluster of metabolic abnormalities associated with
metabolic syndrome.
Obesity is strongly associated with hepatosteatosis
in humans.
8
Nonetheless, it remains unclear whether the
intake of excessive amounts of food by itself causes fatty
liver. Because of the pivotal role that diet plays in causing
metabolic syndrome in humans, most metabolic disease
animal models use diet as a way to precipitate this syndrome.
Uncertainty abounds as to whether or not diets that are
augmented with certain types of food are more likely to
cause obesity and/or fatty liver than other types of diets.
It is difficult to control for all of the complex genetic and
environmental factors that control energy homeostasis in
humans. Therefore, studies that manipulate dietary composi-
tion of food and its consumption in animal models may well
provide vital insights into the role of diet in the pathogenesis
of obesity-related hepatic steatosis.
In order to gain a greater understanding of human obe-
sity, rodents are the commonly used models. Generally,
high-fat diets, high sucrose/fructose diets, diets high in
saturated fats and restricted in certain essential nutrients,
like choline and methionine, have been shown to cause
obesity and fatty livers in a number of different strains and
species of rodents.
9
High-fat/high-cholesterol Western diets
induce extreme hypercholesterolemia and also lead to con-
comitant features of the metabolic syndrome, such as weight
gain, decreased HDL levels, obesity, hypertriglyceridemia,
hyperinsulinemia, and insulin resistance.
10–12
In addition,
these diets generate pathologies independent of atheroscle-
rosis, such as changes in fur and skin integrity, changes in
plasma lipids, and hepatic steatosis.
13
This suggests that
“overnutrition” might play a role in the genesis of obesity-
related fatty liver disease and other risk factors associated
with metabolic syndrome.
14
Unfortunately, it is relatively
difficult to induce obesity in normal rats and mice.
15
Not
all high-fat diets are the same, because both the level and
source of fat may differ between diets. Most rodents tend
to become obese on high-fat diets, but there can be vari-
able responses in insulin resistance, triglycerides, and other
parameters, depending on the strain and gender, and source
of dietary fat.
14
Normal mice and rats are not ideal models
in which to raise the levels of circulating total cholesterol
and low-density lipoprotein [LDL] cholesterol, thereby
increasing the risk of cardiovascular disease. These mod-
els typically have very low levels of total cholesterol and
LDL cholesterol, but high levels of HDL cholesterol.
14–16
This is in contrast to humans, in whom the reverse is true.
Moreover, like human populations, rodent populations dif-
fer in their susceptibility to diet-induced obesity and fatty
liver, suggesting that subtle strain, age, or gender-related
variations in genetic factors that regulate intermediary
metabolism probably influence the response to various
diets. For example, elevated triglycerides are associated
with an increase in oxidative stress, and special diets are
needed to mimic lipid profiles similar to those of humans.
Therefore, it is clear that there is a necessity to develop an
animal model of metabolic syndrome expressing fatty liver
and other cardiovascular risk factors. To achieve this goal,
we used Golden Syrian hamsters, because they have been
observed to respond consistently to dietary modulation of
cholesterol, and have shown a close similarity to the human
lipoprotein profile in comparison with other animals of
similar size, eg, rats and mice.
17
Materials and methods
Animals
Male Bio F
1
B Golden Syrian hamsters (Mesocricetus
auratus, 8 weeks old, approximately 90 g) were obtained from
Biobreeders Inc (Watertown, MA) and housed two per cage in a
room with controlled temperature (22–24°C), humidity and an
inverse alternating light and dark cycle (12:12-hour light:dark
cycle, lights on at 7 pm). All experimental protocols complied
with the Animal Care Committee of McGill University and
Canadian Council on Animal Care guidelines.
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Diet-induced hamster model for fatty liver
Experimental protocol and diets
After arrival, animals were allowed free access to a basal
diet of commercial rodent ration (LabDiet
®
rodent labora-
tory chow 5001, Purina Laboratories, St Louis, MO) and
water for two weeks to allow adaptation to the environment.
Baseline values of serum total cholesterol were measured
at the end of two weeks in hamsters that were deprived of
food overnight. Further, these basal serum total cholesterol
values were used to assign animals into four groups using
a randomized block design. The control group continued
to be fed the reference diet 5001. Each of the other groups
(n = 8) was from then onwards fed a grain-based, hyper-
cholesterolemic chow diet (Modified LabDiet laboratory
rodent diets with added cholesterol and 6% coconut oil
as saturated fat, Purina Laboratories, see Table 1), with
free access to water for five weeks. Diet consumption and
body weight were measured every 10 days. Food efficiency
ratio was computed as g body weight gain/g feed intake.
Blood samples were collected once every 14 days from
food-deprived hamsters (14 hours) that has been mildly
sedated using 3 µL of 5 mg/mL acepromazine. Briefly, after
immobilizing the hamster, approximately 150 µL of blood
was collected from the lateral saphenous vein which runs
dorsally and then laterally over the tarsal joint with a sterile
23 gauge/25 mm needle, into Microtainer
®
serum separator
tubes from Becton Dickinson (Franklin Lakes, NJ). At the
end of the experimental period (five weeks), the hamsters
were euthanized by carbon dioxide asphyxiation and blood
was withdrawn by cardiac puncture using a 22 gauge/25 mm
needle and a 5 mL syringe. Cardiac blood was transferred
into serum separator tubes and allowed to clot prior to
placement on ice.
Serum cholesterol and triglyceride
measurements
Blood from hamsters that had been food deprived for 14 hours
was collected under mild sedation into serum separator
tubes. The blood was allowed to clot at 23°C for 30 minutes
and subsequently placed at 4°C until centrifugation. Serum
was separated by low-speed centrifugation at 2000 g for
20 minutes at 4°C temperature. Serum was frozen at 85°C
until analysis for serum total cholesterol, HDL cholesterol,
LDL cholesterol, triglycerides, and glucose. Serum total
lipids and glucose were assayed by conventional enzymatic
methods on a Hitachi 911 automated analyzer from Roche
Diagnostics (Laval, QC, Canada). Total cholesterol, HDL
cholesterol, triglycerides, and glucose were measured on the
Hitachi 911 automated analyzer using reagent kits supplied
by Roche Diagnostics. The precision performance of these
assays was within the manufacturer’s specifications. LDL
Table 1 Prole of the normal and hypercholesterolemic test diets
LabDiet
®
reference
rodent laboratory chow
Modied LabDiet laboratory rodent test diet
Nutritional prole 5001 5A4C 5D4F 5D4E
Protein, % 23.9 25 15.1 22.5
Fat (ether extract), % 5 10.3 10 10.2
Total saturated fatty acids, % 1.56 6 6 5.89
Total monounsaturated fatty acids, % 1.6 2.10 1.24 2.10
Polyunsaturated fatty acids, % 1.42 1.15 2.19 0.87
Cholesterol, ppm 200 500 500 500
Linoleic acid, % 1.22 1.57 2.16 1.60
Omega-3 fatty acid, % 0.19 0.19 0.03 0.14
Choline chloride, ppm 2250 2299 0.00 1200
Methionine, % 0.67 0.43 0.13 0.4
Fiber, % 5.1 5.1 0.0 4.6
Nitrogen-free extract, % 48.7 42.5 46.4
Starch, % 31.9 28.37 36.89
Sucrose, % 3.70 2.21 1.34
Total digestible nutrients, % 76 81 80.9
Calories provided by:
Protein, % 28.5 27.5 14.4 24.5
Fat, % 13.5 25.6 21.3 25
Carbohydrates, % 57.9 46.9 64.3 50.6
Abbreviations: 5A4C, diet adequate in methionine and choline levels; 5D4F, diet decient in methionine and devoid of choline; 5D4E, diet decient in choline but with
adequate levels of methionine.
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cholesterol was calculated by the Friedewald equation.
18
The atherogenic index was determined as (total cholesterol-
HDL cholesterol)/HDL cholesterol.
19
Collection of the liver
The whole liver was excised from each animal, immersed in
chilled phosphate-buffered saline and blotted dry. A 4 mm
section of the liver was placed into a histological cassette.
The cassette containing the liver section of each animal was
individually immersed in a 10% (v/v) buffered formalin
phosphate solution for fixing and subsequent staining.
Histology
Liver sections soaked in 10% buffered formalin phosphate
solution were processed for normal histological section.
The formalin-fixed, paraffin-embedded tissue samples were
ultrasectioned (4–5 µm thickness), stained with hema-
toxylin and eosin and Oil red O, and examined under a light
microscope.
Statistical analysis
Results were expressed as mean ± standard deviation. The
significance of the difference between the means of test and
control studies was established by repeated-measures analy-
sis of variance. An alpha level of 0.05 was set to determine
statistical significance (P , 0.05).
Results
Following a two-week acclimatization to the basal control
diet, the animals were sorted into control and diet groups
based on basal serum total cholesterol concentrations to start
the experimental period. During the four-week experimental
acute feeding period, the animals were divided into four
groups, including control animals that received a normal
diet. Three different hypercholesterolemic-hyperlipidemic
diets were tested during the study, ie, a diet with adequate
methionine and choline levels (5A4C), a diet deficient in
choline but with adequate levels of methionine (5D4E) and,
lastly, a diet which was deficient in methionine and devoid
of choline (5D4F).
Body weight and general health
The body weights of all animals were monitored at 10-day
intervals and are presented in Figure 1. Animals in all treat-
ment groups showed an increase in body weight over the
duration of study, which could be attributed to the normal
growth phase and the hyperlipidemic diets. The animals fed
on the 5D4E diet showed the highest increase in body weight
(21.3%), with each hamster putting on 7.25 g per week. The
5A4C diet induced a 16% increase in body weight over the
four-week period, with each animal gaining an average of
5.25 g per week. The normal diet leads to an 8.6% increase
in body weight, corresponding to a weight gain of 2.75 g per
animal per week. In contrast, hamsters fed on the 5D4F diet
did not show any significant weight gain during the experi-
mental period. Diets deficient in methionine and choline have
been proven to lead to weight loss in rodent models studied
earlier.
20
However, the hamsters fed on this choline-devoid
diet showed marked differences in their physical appearance.
These animals showed crusting of the upper lip, loss of fur
texture with the hair appearing wet or greasy, and were gener-
ally very sluggish. The animals fed on the other diets were all
very active and appeared to be in good health. Food intake
was significantly lower in hamsters on diets which were either
0
120
125
130
135
140
145
150
155
160
165
0.5 1 1.5
Normal diet 5A4C 5D4F 5D4E
2 2.5
Time (weeks)
Body weight (g)
3 3.5 4 4.5
Figure 1 Average animal weight on food intake and food efciency ratio. A) normal diet, B) 5A4C, C) 5D4F, and D) 5D4E.
Abbreviations: 5A4C, diet adequate in methionine and choline; 5D4F, diet decient in methionine and choline; 5D4E, diet adequate in methionine and decient in
choline.
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Diet-induced hamster model for fatty liver
deficient or devoid of choline (Figure 1) compared with the
other two diets. Methionine-deficient and choline-deficient
diets have been associated with lower food intakes in prior
studies on rodents.
21,22
The 5D4E diet showed the best food
efficiency ratio among the diets evaluated.
Serum total cholesterol levels
Compared with the baseline control level, serum total choles-
terol levels were elevated in all groups of animals on the test
diets (Figure 2A). As other short-term studies have shown,
this elevation of serum total cholesterol concentration likely
resulted from the dietary cholesterol ingested.
23,24
Hamsters
fed the 5D4E diet showed a dramatic increase (232%) in
serum total cholesterol levels (P , 0.0001). The 5A4C diet
led to a 25% increase in total cholesterol levels over the four-
week study (P = 0.084). Total cholesterol levels in hamsters
on the 5D4F diet increased during the first two weeks, but
reduced during the next two weeks, showing a 16% reduction
in serum total cholesterol levels (P = 0.038).
Serum HDL and LDL cholesterol
and triglycerides
HDL cholesterol decreased over the study period in all the
experimental diet groups compared with the group on the
normal diet (Figure 2B). The 5D4F diet showed the highest
decrease in serum HDL cholesterol levels (P , 0.0001),
followed by the 5D4E (P = 0.0006) and 5A4C (P = 0.0014)
diets. In contrast, hamsters fed with the 5D4E diet showed
a dramatic increase in LDL cholesterol levels (P , 0.0001)
during the study, compared with those on a normal diet, the
values for which remained stable (Figure 2C). The 5A4C diet
had a similar effect on LDL cholesterol levels (P = 0.0049)
although not to the same extent as did the 5D4E diet. Serum
LDL cholesterol values for animals fed with the 5D4F diet
showed a decreasing trend (P = 0.82). Hamsters fed with
the 5D4E diet (P = 0.0007), 5D4F diet (P = 0.27), and the
normal diet showed an increase in serum triglycerides, while
the triglyceride values decreased for those with the 5A4C
diet (P = 0.086, Figure 2D).
0
0.0
2.0
6.0
4.0
8.0
10.0
12.0
14.0
1
Normal diet 5A4C 5D4F
5D4E
2
Time (weeks)
*
*
*
*
Serum total cholesterol (mmol/L)
345
A
0
0.0
2.0
6.0
4.0
8.0
10.0
12.0
1
Normal diet 5A4C 5D4F
5D4E
2
Time (weeks)
Serum triglycerides (mmol/L)
345
D
0
0.0
5.0
4.0
3.0
2.0
1.0
6.0
7.0
8.0
9.0
1
Normal diet 5A4C 5D4F
5D4E
2
Time (weeks)
Serum LDL-cholesterol (mmol/L)
34 5
C
0
1.0
2.5
2.0
1.5
3.0
3.5
4.0
1
Normal diet 5A4C 5D4F
5D4E
2
Time (weeks)
Serum HDL-cholesterol (mmol/L)
345
B
Figure 2 Changes with time in serum A) total cholesterol, B) HDL cholesterol, C) LDL cholesterol, and D) triglycerides of hamsters (n = 8 per group) fed with a normal
diet, 5A4C, 5D4F, or 5D4E. Animals were sacriced after having been fed the respective diets ad libitum for four weeks. Liver triglycerides and serum lipoproteins were
determined biweekly. Each point represents the mean ± standard deviation.
Notes: *P , 0.0001 for total cholesterol; *P = 0.0006 for HDL cholesterol; *P , 0.0001 for LDL cholesterol; and *P = 0.0007 for triglycerides.
Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein; 5A4C, diet adequate in methionine and choline; 5D4F, diet decient in methionine and choline;
5D4E, diet adequate in methionine and decient in choline.
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Bhathena et al
Glucose and atherogenic index
Glucose levels were elevated in all animals to varying
extents. These doubled in the hamsters fed on the 5D4E
diet (P , 0.0001), while those on the 5A4C diet showed an
increase of 85% compared with baseline values (P = 0.011).
In comparison, serum glucose levels showed a 48% and 25%
increase in hamsters fed with the 5D4F diet (P = 0.0046) and
normal diets, respectively (Figure 3A). The atherogenic index,
which is correlated with cardiovascular disease, increased
over five-fold in animals on the 5D4E diet (P , 0.0001),
and by 50% in animals on the 5A4C diet (P = 0.0008). It
remained stable in animals on the normal and 5D4F diets
(P = 0.0020, Figure 3B).
Histopathology
Histopathological analysis of hamster liver samples through
H&E and Oil red O staining show marked differences
between the diets studied. Hematoxylin and eosin staining
demonstrated elevated amounts of fat deposits in liver tissue
from animals fed on the test diets (Figures 4B, 4C, and 4D)
compared with the normal diet (Figure 4A). Macrovesicular
deposition of fat and hepatocellular ballooning was observed
in hamsters fed on the 5D4F (Figure 4B) while microve-
sicular fat deposits and ballooning to a lesser extent were
found in hamsters on diets of 5A4C (Figure 4C) and 5D4E
(Figure 4D). Oil red O staining of the liver tissue samples
substantiate these results (Figure 5). A very high amount
0
0.0
1.0
2.0
3.0
4.0
5.0
6.0
1
Normal diet 5A4C 5D4F 5D4E
2
Time (weeks)
*
*
Atherogenic index
345
0
2.0
4.0
3.0
7.0
6.0
5.0
9.0
8.0
10.0
11.0
12.0
1
Normal diet 5A4C 5D4F 5D4E
2
Time (weeks)
Serum glucose (mmol/L)
345
A
B
Figure 3 Effect on A) atherogenic index and B) serum glucose on Bio F
1
B hamsters (n = 8 per group) on administering a normal diet, 5A4C, 5D4F, or 5D4E. Each point
represents the mean ± standard deviation.
Notes: *P , 0.0001 for serum glucose and atherogenic index.
Abbreviations: 5A4C, diet adequate in methionine and choline; 5D4F, diet decient in methionine and choline; 5D4E, diet adequate in methionine and decient in
choline.
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Diet-induced hamster model for fatty liver
of fat deposition was found in hamsters fed on diet 5D4F
(Figure 5C), followed by 5D4E (Figure 5D). Histological
analysis confirm the development of fatty liver in animal
models fed with the three test diets, compared with those on
a normal diet. However, there were no signs of fibrosis.
Discussion
Animal models offer a convenient medium to investigate
and understand the pathophysiology of disease and facilitate
development of means to prevent or treat the studied disease.
Studies on such models greatly contribute towards enhancing
knowledge in the field. Animal models that express clinical
manifestations of metabolic syndrome, such as insulin resis-
tance, fatty liver, and dyslipidemia, will be of immense value
in understanding metabolic syndrome. We have investigated
induction of metabolic syndrome in male Bio F
1
B Golden
Syrian hamsters through nutritional intervention. The use of
only male hamsters was encouraged to avoid gender-related
response due to female hormones on a fatty acid diet.
25
Serological and histopathological changes in hamsters fed
on hyperlipidemic diets varying in methionine and choline
levels in comparison with a normal diet were evaluated dur-
ing this study. Our results suggest that BioF1B Golden Syrian
hamsters are a potential model for diet-induced metabolic
syndrome with associated non-alcoholic fatty liver disease.
Among the three test diets, the choline-deficient 5D4E
diet provided optimal induction of metabolic syndrome,
while the methionine-deficient/choline-devoid 5D4F lead
to some undesirable effects on the normal well being of the
animals. The hamsters displayed several manifestations of
the human metabolic syndrome. The hyperlipidemic effects
of the diets were visibly demonstrated in the increased
body weight and lipid profile of serological samples from
hamsters fed on the test diets. The animals showed hyper-
glycemia and an elevated atherogenic index, which are
commonly associated with metabolic syndrome. In addition,
histopathological analysis revealed extensive diet-induced
hepatocellular fat deposition and ballooning in the liver
samples from the hamsters, while the control hamsters had
normal liver histology. However, the spectrum of conditions
characterized by fatty change in the liver had not progressed
to necrosis, fibrosis, or inflammation. In comparison with the
normal diet, the hyperlipidemic diets were also associated
with elevated serum total cholesterol levels, decreased HDL
cholesterol, and hyperglycemia and hypertriglyceridemia,
thereby confirming the induction of metabolic syndrome and
nonalcoholic fatty liver in the hamsters.
It is evident that special diets are needed to develop and
study an animal model of metabolic syndrome. However, no
phenotype of any animal model is guaranteed, and cautious
choosing of the species and strain as well as satisfactory
control over environmental factors is important. In this paper,
we have shown that BioF1B Golden Syrian hamsters can be
used as a model that develops clinical and histopathological
manifestations of the human metabolic syndrome through
dietary intervention. It is known that the dietary factors
may promote multiple phenotypes,
26,27
for example, the use
AB
CD
Figure 4 Hematoxylin and eosin staining of liver tissue from hamsters fed with
hyperlipidemic diets. Magnication 400×. A) Normal diet, B) diet adequate in
methionine and choline (5A4C), C) diet decient in methionine and choline (5D4F),
and D) diet adequate in methionine and decient in choline (5D4E). Hepatocytes
are lled with microvascular and macrovesicular fat deposits, leaving the nuclei in a
central position, and the hepatocytes have assumed a very foamy appearance.
AB
CD
Figure 5 Oil red O staining of liver tissue from hamsters fed on hyperlipidemic
diets. Magnication 400×. A) Normal diet, B) diet adequate in methionine and
choline (5A4C), C) diet decient in methionine and choline (5D4F), and D) diet
adequate in methionine and decient in choline (5D4E). Hamster hepatocytes are
lled with microvesicular and/or macrovesicular fat deposits; they are depicted as
reddish-orange deposits, as shown with Oil red O staining.
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Bhathena et al
of high-fat diets induces obesity, insulin resistance, and
hyperglycemia and the use of high-fructose diets promote
insulin resistance, hypertriglyceridemia, and hypertension.
However, we did not monitor for reversion of the phenotypic
characteristics of the animal model by replacing their diet
from hyperglycemic to normal diet. In addition, it should be
noted that the hamster diet, although adequate for the pro-
posed work, does not represent an actual human diet that can
potentially stimulate nonalcoholic fatty liver disease. Thus,
this study opens up new approaches to investigate further the
long-term effects of choline deprivation on the animal model.
This concurrent advance of diseases is not unexpected, given
the multifaceted interactions and relationships between these
diseases. At present, diet-induced animal models of metabolic
syndrome are still being developed, and there may not be one
single model that will satisfy all metabolic disease research
needs. Ongoing research using different species/strains along
with existing and new purified ingredient diet formulations
should lead to the development of more and more useful
metabolic syndrome phenotypes.
Conclusion
In conclusion, we have developed a successful model of
metabolic syndrome in BioF1B Golden Syrian hamsters. This
metabolic syndrome model with hyperlipidemia and insulin
resistance was established (along with nonalcoholic fatty
liver) in hamsters fed a high-fat, high-cholesterol, inadequate
methionine- and choline-containing diet. This model may be
useful for the evaluation of preventive medicine, including
food factors, for obesity-induced metabolic syndrome. The
increasing prevalence of obesity, diabetes and insulin resis-
tance, and nonalcoholic fatty liver disease within Western
society makes research in this field vital. In addition, using
this model, it may be possible to elucidate the mechanisms
involved in the development of metabolic syndrome, espe-
cially the association between lipid accumulation-induced
dysfunction of hepatocytes and the induction of insulin
resistance. It is only through better understanding of patho-
genic mechanisms that novel therapies targeting the cluster
of diseases in metabolic syndrome may be discovered.
Acknowledgment
The authors acknowledge the support of a Canadian Institutes
of Health Research (CIHR; MOP-94308) Micropharma
research contract grant (to SP). A doctoral research award
from the Canadian Institutes of Health Research to JB,
a Canada graduate scholarship from NSERC to CM, an
Alexander Graham Bell Canada graduate scholarship from
NSERC to AK, a McGill University majors scholarship to
MM, and a postgraduate scholarship from NSERC to AMU.
AP is grateful for the nancial support from a NSERC
Alexander Graham Bell Canada graduate scholarship. We
would also like to acknowledge the technical support of
Melina Narlis.
Disclosure
SP and JP have a conflict of interest with Micropharma Ltd,
given that the technology mentioned in this research is optioned
to Micropharma Ltd. None of the other authors have any per-
sonal or financial conflicts of interest to report in this work.
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