Prednisone Increases Low Density Lipoprotein in Cynomolgus Monkeys Fed Saturated Fat and Cholesterol
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Prednisone Increases Low Density Lipoprotein in
Cynomolgus Monkeys Fed Saturated
Fat and Cholesterol
Walter H. Ettinger, Robert C. Dysko, and Thomas B. Clarkson
Cynomolgus monkeys were given prednlsone to determine its effects on lipopro-
tein metabolism and other risk factors for atherosclerotic cardiovascular disease.
After 1 month of oral prednlsone, the mean total plasma cholesterol (TPC) concen-
tration increased from 240±36 to 476±78 mg/dl (pPREDNISONE EFFECTS ON UPOPROTEINS Ettinger etal. 849
Table 1. Composition of Diets Fed to Cynomolgus Monkeys
Ingredient Grams/100 g Protein (g) Fat (g) Carbohydrate (g)
Diet A
Purina monkey chow-25 75.70 19.3 3.86 39.06
Dry egg yolk 8.20 1.8 5.41 0.21
Brewer's yeast 4.00 1.48 0.06 1.50
Raw wheat germ 2.00 0.50 0.20 0.99
Lard 10.00 — 10.00 —
DietB
Casein, USP 8.0 8.0 — —
Lactalbumin 8.0 8.0 — —
Wheat flour 35.5 3.72 0.36 30.2
Dextrin 6.0 — — 6.0
Sucrose 5.0 — — 5.0
Applesauce 4.5 0.02 Trace 1.08
Lard 9.5 — 9.5 —
Butter 3.0 0.01 2.43 0.01
Beef tallow 7.0 — 7.0 —
Dry egg yolk 3.5 0.77 2.24 0.09
Safflower oil 0.5 — 0.5 —
DietC
Purina monkey chow-25 100.0 19.3 3.86 39.06
Diet A kg/day divided into two feedings) to provide 43% of
The first part of the study was a prospective trial of calories as fat (P/M/S, 1.0 : 3.3 : 2.8), 39% of calories as
orally administered prednisone to determine the effects of carbohydrate, 18% as protein, and 0.25 mg/kcal of cho-
chronically administered corticosteroids on CAD risk fac- lesterol (Diet B in Table 1). Plasma lipids were measured
tors. Seven animals were used in this part of the study, and low density lipoprotein (LDL) apolipoprotein (apo) B
which was 11 months long. These animals were selected turnover studies were carried out before and after the
to represent both hypo- and hyperresponders to dietary 6-week prednisone treatment (0.011 mg/kcal/day). For
cholesterol.18 The animals consumed a diet which pro- these studies, the animals were housed in individual
vided 36% of calories as fat [polyunsaturated/monounsat- cages. One week before the start of a metabolic study, the
urated/saturated (P/M/S), 1.0:3.9 = 4.1], 34% of calories as animals were habituated to wearing a monkey jacket with
carbohydrate, 19% calories as protein, and 0.39 mg/kcal
a 3-foot tether line that attached to the back of the cage
of cholesterol (Diet A in Table 1). The animals were fed
(Alice King Chatam, Incorporated, Los Angeles, CA). At
150 kcal/kg/day in two feedings at 8:00 A.M. and 2:00 P.M.
During the first 2 months, the animals were not given 4 days before the study, each animal was anesthetized, a
prednisone, and measurements were made of plasma sterile Tygon cannula (0.03 inches inside diameter) was
lipoproteins, serum glucose, blood pressure, and anthro- inserted into a femoral artery and vein, and the cannula
pometric variables. During the next 6.5 months, the ani- was threaded through the tether line and out the back of
mals were given prednisone twice daily mixed in the diet. the cage. The lines were kept patent by a constant saline
The initial dose of prednisone was 0.022 mg/kcal/day, infusion.21 The animals were fasted overnight before the
which was given for 3 months. The amount was chosen to turnover studies and were then fed their usual diets
represent the equivalent of 40 mg of prednisone per day in beginning with the 2:00 P.M. feeding on Day 1. Radiola-
a 50 kg human woman and was based on the relative beled LDL was injected through the venous catheter, and
caloric requirements of humans and monkeys.20 The daily 2 ml blood samples were obtained from the arterial
prednisone dose was then reduced to 0.011 mg/kcal/day catheter for radioiodine counts at 3, 30, and 90 minutes
for 2 months, and finally to 0.0055 mg/kcal/day for and 3, 6, 9, 24, 48, 72, and 96 hours after injection.
1.5 months. The third phase of the study was a drug-free
period of 2.5 months. Plasma lipoprotein concentrations, DietC
blood pressure, and weight were measured monthly.
The third part of the study was a prospective trial of five
Serum glucose was measured every 3 months, and
animals who consumed a standard monkey chow diet,
skinfold thickness and a ponderosity index were mea-
150 kcal/kg/day in two divided feedings (Diet C in Table 1).
sured once during each phase of the study.
These experiments were undertaken to determine if
changes in lipoprotein concentration occurred in animals
Diet B fed a diet low in fat and free of cholesterol. Plasma
The second part of the study was a prospective trial of lipoproteins were measured before and at 6 weeks after
five animals who were fed a synthetic diet (150 kcal/ treatment with prednisone (0.011 mg/kcal/day).
Downloaded from http://atvb.ahajournals.org/ by guest on November 7, 2015850 ARTERIOSCLEROSIS VOL 9, No 6, NOVEMBER/DECEMBER 1989
Table 2. Blood Pressure, Fasting Serum Glucose, and Anthropometric Variables In Seven
Monkeys Fed Diet A
Variables Month 1 Month 8 Month 11
Systollc/diastollc blood pressure (115±9)/(59±5) (109±7)/(67±7) (112±4)/(52±4)
(mm Hg)
Ponderosity index 95.4±6.2 101.1 ±9.4 97.7±3.4
(g/cm)
Subscaputar/triceps skinfold 2.2±0.8 2.0±0.6 2.3±0.3
ratio
Fasting serum glucose 81 ± 5 75±6 70±3
(mg/dl)
Values are means±SE.
too f _- o - - TOW ChokOKOl
Laboratory Measurements — HDLChol-Wrt
y' s
T
Measurements of weight and blood pressure and blood
collection were made after animals were anesthetized
900
~\ [
I
Intramuscularly with 15 mg of ketamine. Weights were
obtained with a spring scale, and blood pressure was
«0
/1 1 N
measured in a lower limb with a Dynamap blood pressure xo Pradnbcna(mgAal)
022
monitor. The anthropometric profile included a ponderosity HflBBBHHfc
index [weight (g)Arunk length (cm)] and measures of the zn : ^
s^ I
subscapular and triceps skinfold.22 Fasting serum glucose
was measured using a Beckman glucose analyzer. 100 •
•
Blood for lipoprotein measurements was collected after
an overnight fast into tubes containing 0.1% ethylenedi-
aminetetraacetic acid (EDTA), 0.02% NaN3, and 0.05%
Figure 1 . Plasma concentrations (mg/dl) of total cholesterol (O)
5',5'-dithiobis-(2 nitrobenzoic acid). The plasma was sep- and high density lipoprotein (HDL) cholesterol (•) during the
arated from the cells by using low-speed centrifugation 11 months of the study of animals fed Diet A. Each point
and was refrigerated at 4°C until analyzed. Very low represents the mean±SE of seven animals.
density lipoprotein (VLDL), intermediate density lipopro-
tein (IDL), and LDL were isolated by sequential ultra-
were isolated by puncturing the bottom of the tube and
centrrfugation.23 HDL was isolated by precipitation of apo
pumping Florinet into the tubes. The LDL peak was
B containing lipoproteins with dextran sulfate-magnesium
identified from the absorbance profile at 280 nm and the
chloride.24 Cholesterol (C) and triglyceride (TG) were
measured by enzymatic methods. Apo E was measured radioactivity in the fractions; the fractions then were
by an enzyme-linked immunosorbent assay (EUSA), and pooled for further analyses. Radioactivity in LDL apo B
apo B and apo A-l, by radial immunodrffusion.13-25 was isolated by isopropanol precipitation.29
Lipoprotein subtraction heterogeneity was measured Statistical Analyses
by nondenaturing gradient gel electrophoresis.26'27 The
Statistical comparison of multiple means was done with
dPREDNISONE EFFECTS ON LIPOPROTEINS Ettinger et al. 851
TG LDL-C
100
80
60
" / /
40
20
: £>
110 - HDL-C ApoE
90 - r
70 - N\
SO • - \ \
30
10
Figure 2. Plasma concentrations of lipids and apoproteins at 1 month before administration and after
6 months of dally prednisone in animals fed Diet A (6-month time point in Rgure 1). The concentrations
are given as mg/dl. Solid dots represent individual animals, and horizontal lines, the means of seven
animals. TG = total triglyceride, TC = total cholesterol, VLDL-C = very tow density lipoprotein
cholesterol, LDL-C = low density lipoprotein cholesterol, HDL-C = high density lipoprotein cholesterol,
Apo A1 = apolipoprotein A-l, Apo B «= apolipoprotein B, Apo E = apolipoprotein E.
(311 ± 4 6 mg/dl) within 6 weeks after prednisone was
discontinued. DIET R
The increase in total plasma cholesterol concentration
was due to an increase in the concentrations of the
a p o B-100-containing lipoproteins (Figure 2). After
6 months of treatment, the mean concentration of LDL-C
had increased from 1 5 9 ± 3 1 to 341 ± 3 8 mg/dl, p < 0 . 0 5 ,
and that of VLDL-C from 1 0 ± 6 to 3 8 ± 1 6 mg/dl, p < 0 . 0 5 .
In parallel, the concentrations of apo B ( 1 4 7 ± 4 6 vs.
2 4 8 ± 1 5 mg/dl, p < 0 . 0 1 ) and apo E ( 7 . 2 ± 3 vs. 1 2 . 4 ± 2
mg/dl, p < 0 . 0 1 ) increased significantly. Plasma triglycer- DIET C
ide concentrations increased moderately during cortjcc- dl852 ARTERIOSCLEROSIS VOL 9, No 6, NOVEMBER/DECEMBER 1989
electrophoresis of HDL showed that the decline in HDL
during steroid treatment was due to a reduction in the
amount of the larger (>5.0 mm radius) HDL subparticles
(Figure 6). However, HDL-C concentrations returned to
pretreatment levels after prednisone was stopped. Similar
effects of prednisone on HDL-C concentration were noted
in animals fed Diet B; however, in the animals who
consumed monkey chow, there was no significant differ-
ence in HDL-C after treatment (60±6 mg/dl vs. 54±5).
Discussion
CO One of the principle aims of this study was to determine
the effect of chronically administered corticosteroids on
risk factors for CHD in the cynomolgus monkey. The
results show that corticosteroids have a marked effect on
o lipoprotein metabolism. Plasma cholesterol, LDL-C, and
B. LDL molecular weight increased, while HDL levels
O decreased, during prednisone treatment in cynomolgus
monkeys fed a diet containing saturated fat and choles-
terol. Such changes in lipoproteins increase the risk of
developing atherosclerosis in the nonhuman primate.17 In
contrast, there was no demonstrable effect on other CAD
risk factors: body weight, body fat distribution, fasting
serum glucose, and blood pressure. While more sensitive
measures may be needed to detect changes in these risk
factors (such as a glucose tolerance test), these data
Migration Distance from Origin suggest that the dyslipoproteinemia is potentially the more
important risk factor for CAD caused by corticosteroids. It
Figure 4. Densttometric scan of low density llpoprotein (LDL) is likely that there would be progression in the extent of
nondenaturing gradient gel electrophoresis from Animal #4, fed coronary artery atherosclerosis in these animals if these
Diet A, before (—) and after (—) 6 months of prednisone. This
migration of the major peaks (arrows) was used to calculate the lipoprotein abnormalities persisted over a 24- to 36-month
molecular weights of LDL from an LDL of known molecular weight period. 1718 While anatomic studies are necessary to
and protein standards. confirm this hypothesis, this study suggests that the
cynomolgus monkey may be a model for examining the
100 effects of corticosteroids on the development of athero-
sclerosis and its risk factors in an immunosuppressed
host.
The increased concentrations of LDL-C, apo B, and
apo E in these otherwise healthy animals are analogous
to what has been reported in a diverse group of humans
taking long-term corticosteroids. 611 - 143132 The slight
increase in TG concentration is also consistent with what
occurs in humans, because most human beings treated
with corticosteroids have only moderate increases in TG
concentration. 891112 Marked hypertriglyceridemia is usu-
ally seen in patients with underlying diabetes or renal
insufficiency.833 Nonetheless, the absolute plasma levels
of VLDL are considerably lower, and the composition of
VLDL is different, in the cynomolgus monkey fed satu-
20 40 60 80 100 rated fat and cholesterol than in humans. The plasma
Time (Hrs.) VLDL in these monkeys is relatively enriched in choles-
terol ester and depleted of TG, and when plasma choles-
Figure 5. Decay curves of low density lipoproteln apolipopro-
tein (apo) B specific counts before prednisone (A) and after terol levels exceed 500 mg/dl, a /3-migrating VLDL is
6 weeks of prednisone (•) in one animal fed Diet B. The vertical present.1834Therefore, caution is indicated when drawing
axis shows the percent of injected apo B counts, and the a parallel between the two species.
horizontal axis shows the hours after injection.
The effect of the type and quantity of dietary fat and
cholesterol on the dyslipoproteinemia caused by cortico-
low HDL concentrations persisted throughout the treat- steroids is an important question. This study suggests that
ment period, and plasma levels of apo A-l paralleled the while the quantity and quality of dietary fat and cholesterol
changes in HDL-C (Figure 2). Nondenaturing gradient gel may modify the magnitude of change in LDL levels,
Downloaded from http://atvb.ahajournals.org/ by guest on November 7, 2015PREDNISONE EFFECTS ON LIPOPROTEINS Ettinger et al. 853
Table 3. Low Density Upoprotein Kinetic Data before and during Prednlsone Treatment In Monkeys Fed Diet B
Control Prednisone
TPC ApoB FCR ACR TPC ApoB FCR ACR
Animal (mg/dl) (mg/kg) (mg/kg/h) (mg/dl) (mg/kg) (h-1) (mg/kg/hr)
1 286 46.5 0.025 1.2 400 111 0.017 1.9
2 135 23.6 0.063 1.5 257 68.6 0.042 1.6
3 282 42.3 0.031 1.3 487 100 0.022 2.2
4 167 28.7 0.053 1.5 180 37.1 0.064 2.4
5 144 30.5 0.048 1.5 431 107 0.019 2.0
Mean 203 34.3 0.044 1.4 351* 85.7* 0.033* 2.0*
±SD ±67 ±8.6 ±0.014 ±0.13 ±114 ±28 ±0.018 ±0.27
TPC = total plasma cholesterol, Apo B = apolipoprotein B, FCR = fractional calabolic rate, ACR = absolute catabolic rate.
*p854 ARTERIOSCLEROSIS V O L 9, No 6, NOVEMBER/DECEMBER 1989
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Index Terms: corticosteroids • lipoproteins • non-human primate
Downloaded from http://atvb.ahajournals.org/ by guest on November 7, 2015Prednisone increases low density lipoprotein in cynomolgus monkeys fed saturated fat and
cholesterol.
W H Ettinger, R C Dysko and T B Clarkson
Arterioscler Thromb Vasc Biol. 1989;9:848-855
doi: 10.1161/01.ATV.9.6.848
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