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The relation of types of dietary fat to hepatic liposis and myocardial damage in mice.

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The Relation of Types of Dietary Fat to Hepatic Liposis
and Myocardial D a m a g e in Mice'
W. LANE WILLIAMS AND ROBERT I. OLIVERZ
Departments of Anatomy, University of Mississippi School of Medicine,
Jackson, Mississippi and University of Minnesota,
Minneapolis, Minnesota..
Low protein, high fat, choline-deficient
diets in which the lipid component is a
natural fat, such as lard or butter, produce
rapid and extensive hepatic liposis in mice
(Buckley and Hartroft, '55; Meader and
Williams, '57; Williams, '60). During the
one month duration of a preliminary study,
the substitution of three saturated triglycerides for lard as the dietary fat component greatly diminished the rate and
amount of hepatic liposis (Williams,
Cardle and Meader, '59).
The experiments reported here included
the feeding of this choline-deficient, triglyceride diet for as long as 7 months. The
data thus obtained show that the responses
of the livers and the hearts of these mice
were very different from those in mice fed
the same basic diet containing lard as the
lipid component.
The vitamin powder contains:
Thiamine hydrochloride
Riboflavin
Pyridoxine hydrochloride
Calcium pantothenate
Nicotinic acid
Powdered sugar
0.500
0.250
0.200
1.000
1.000
997.050
Fat was supplied in one diet as Iard. In
the other the fat component (40% of total
diet) consisted of the following saturated
triglycerides: frihexanoin (50% ), trimyristin ( 2 5 % ) and tripalmitin (25%).
Both diets have been used in previous studies (Meader and Williams, '57; Williams,
Cardle and Mlsader, '59; Williams, '60).
Within the mouse cages the food was kept
in metal containers constructed with partitions and wire-mesh covers to restrict contact with the diet to the mouth and snout.
A wire-mesh floor was placed above the
permanent floctr of the cage to limit coprophagia. Mice were weighed daily during
the first month of feeding the experimental
MATERIALS AND METHODS
diets and weekly thereafter.
Histological technics. The methods
Animals. Mice of the C (Bagg albino)
stock with an initial body weight of 20- have been described in detail previously
22 gm were restricted to the choline-de- (Williams, '60). Abdominal and thoracic
organs were fixed in 10% formaldehyde or
ficient diets when 8 to 10 weeks of age.
Diets. From weaning (30 days of age) in Lavdowsky's solution or in both. Hearts
until 8 to 10 weeks of age these mice were were cut into two relatively equal frontal
fed a standard laboratory ration that was sections for fixation in 10% formaldehyde
adequate in choline, vitamins and min- and Lavdowsky's solution. Thigh muscle
erals; and was composed of approximately from about one-half of the mice, and dia25% protein, 6% fat, and 47% carbohy- phragm from essentially all were fixed in
drate. The composition of the basic cho- Lavdowsky's solution. Routine paraffin
line-deficient diet used here is as follows: sections (10 v ) of all of these organs and
gm
tissues were si:ained with hematoxylin and
Vitamin free casein
80.0
eosin.
Sucrose
Fat
Salt mixture (no. 2, U.S.P. XIII)
L-Cystine
Cod liver oil (Navitol)
Vitamin powder
480.5
400.0
40.0
5.0
4.5
10.0
1 Supported by grants A-2693 and H-4052 from
the National Institutes of Health, U.S.P.H.S. and
from the Mississippi Heart Association.
2 N.I.H. (2G-:!87) Predoctoral Trainee in the
Anatomical Sciences.
97
98
W. LANE WILLIAMS
Fat was demonstrated by staining frozen
sections of formalin fixed material with
oil red 0 in the same manner as with other
Sudan dyes. It was essential to use gelatin
embedding to make adequate frozen sections of the hearts. As the result of poor
technic only one-third of these specimens
were stained satisfactorily for fat.
The PAS (periodic acid-Schiff's reagent)
technic was used to show glycogen, ceroid
pigment, and sites of recent myocardial injury (Kent and Diseker, '55). Ceroid pigment was demonstrated more specifically
by staining dehydrated and defatted (i.e.,
embedded in paraffin) specimens with oil
red 0 or Sudan black. The Masson (with
aniline blue), the PAS and the Laidlaw
reticulum methods were used to show fibrosis, and the von Kossa and the alizarin
technics to demonstrate minerals.
Selection of mice for study. At the intervals shown in table 2, mice were killed
by digital compression of the cervical
spinal column. The usual procedure was
to select those showing weakness, decreased activity, and respiratory difficulties; and also extreme weight loss, provided
the other signs of ill health just mentioned
were evident. During the first 8 weeks of
the experiment, such evidence of ill health
was relatively infrequent and mice were
killed on a schedule that produced a chronologic survey of changes in the livers and
hearts of the members of the two dietary
groups. Approximately 80% of the mice
killed after 8 weeks of feeding were females. Of those killed earlier, one-half
were males. The males were difficult to
use because of their activity in upsetting
and burrowing into the food containers
and in becoming entrapped during such
activities.
Study of the material
Livers. One large lobe was fixed in
Lavdowsky's solution (for subsequent paraffin-embedding) and another in 10%
formaldehyde. Six to 8 sections of the latter (across the entire lobe) were stained to
show fat. Complete sections of the paraffin embedded specimens were processed as
follows: 6 to 8 sections, H. and E.; 4 to 6 ,
PAS; and when so indica.ted by the results
of staining with H. and E. or PAS, 4 to 6
AND ROBERT I. OLIVER
additional sections were stained by the
Laidlaw reticulum method. Ceroid pigment is recognizable in H. and E. and in
PAS preparations and also in frozen sections stained with Sudan dyes. When the
pigment was so observed more sections
(paraffin) were cut and then stained with
Sudan dyes (Meader and Williams, '57;
Williams, '60).
Hearts. One-half of each heart (complete frontal or sagittal section) was embedded in paraffin and the other was kept
in formalin (10% ) for frozen sections and
also as reserve material. At least 80% of
every heart and all of a majority were
completely consumed in making the following preparations, all of which had some
value in identifying myocardial lesions:
H. and E., Masson, PAS, Laidlaw reticulum (in a variety of combinations with
PAS and H. and E.), von Kossa or alizarin,
and frozen sections stained with oil red 0.
Subsequent to frozen sectioning the remaining portion of the formalin fixed half
of the heart was dehydrated and embedded in para& and prepared for study
by the staining procedures mentioned
above. These sections permitted study of
structures located at or near the cardiac
base, including aorta, vena cava, pulmonary vessels, thymus, lymph nodes, nerves,
autonomic ganglia, uniloculax and multilocular fat, esophagus, bronchi and a large
number and variety of small blood vessels
within or near these several structures.
Other organs and tissues. Adrenals
and kidneys as a single 'block" were cut
into two equal portions in the usual fashion for fixation in Lavdowsky and in 10%
formaldehyde. Two to 4 sections were
stained with H. and E. and a similar number with PAS. Skeletal muscle (diaphragm, thigh and esophagus) and gonads
and spleen were studied in two to 4 sections stained with H. and E. In most instances two to 4 sections of adrenals (embedded in paraffin and included in same
section as kidney) and gonads were stained
with Sudan black to demonstrate ceroid
pigment. The simple statistical analysis
(means and standard deviations) of the
data on body weights (tables 1, 2 and 4 )
was based on the methods and tables presented by Croxton ( ' 5 3 ) .
99
HEPATIC FAT AND CARDIAC DAMAGE
TABLE 1
Weight changes in mice fed choline-deficient, low protein-high fat diets
Lard as dietary fat
Months
fed
Total
notof
mce
1
84
Mean
weight
change
Saturated triglycerides as dietary fat
Per cent of mice :
$%$
Total
no. of
mice
weight
Lost
Mean
weight
change
%
2
41
(6.1)2
2 2.9
29
(10)
zt 7.3
45
(9.5)
26
52
(9.8)
rt 7.2
44
(8.3)
r+ 5.2
33.3
(7.7)
rfr 2.4
8.5
(3.2)
-4.2
f 9.8
3
- 1.0
56
f11.1
4
-3.9
48
2 14.8
5
-4.3
40
2 11.9
6
- 5.0
24
2 9.4
7
- 10.4
21
-t 7.9
8
15
9
8
10
6
z;kt
%
- 1.2'
2 6.53
69
Per cent of mice:
$2:
-11.7
-C 13.1
-20.0
8.4
- 24.2
e4.1
*
- 1.3
0
47
(7.7)
f4.6
60
(12)
f7.8
55
(10.2)
r+ 7.5
48
(18.7)
2 10.3
56
(14.4)
f10.8
66.6
(11.5)
29.1
83
(13)
f8.3
100
72
f6.1
40
(6.8)
25
22
(7.4)
-4.7
22
(6.7)
25.6
14
(4.1)
16
- 9.8
2 5.1
6
(5)
16
.- 16.0
0
0
100
No survivors
0
100
N o survivors
2 8.1
- 8.4
59
tt 10.0
41
-8.0
2 8.2
29
-- 12.1
51
(7.9)
f6.1
73
(13.8)
-9.0
73
(13)
28.6
86
(14.1)
f7.7
94
(11)
5
100
I- 7.9
14
.- 18.0
7.2
-+: 8.5
(5.0)
92.8
(20.0)
f9.9
No survivors
-
Weights are those of all mice living at the stated intervals.
*Numbers in parentheses are means of weight changes ( % ) in animals ( % of total in group)
listed directly above.
3Standard deviations are those of changes in body weight (i.e., the mean listed directly above)
and were not determined for groups smaller than 5 mice.
TABLE 2
Changes in hearts and livers of mice fed choline-deficient diets conttaining 40% fat as lard (L) M
as saturated triglycerides (TG)
Per cent of mice showing
Weeks
fed
diet
No. of
mice
killed
Ll
1 4
5-8
9-15
16-21
22-27
28-33
34-39
40
64
17
7
8
21
8
7
6
TG*
41
14
28
16
14
NS3
NS
NS
Changes in livers
Myocardial
lesions
Complete
lobular
liposis
L
TG
L
TG
0
0
0
37
24
13
29
33
0
43
32
56
71
1004
100
100
100
100
100
100
100
0
57
29
37
71
NS
NS
NS
NS
NS
NS
Fatty
cysts
L
0
100
100
100
100
100
100
100
Reticulinosis
and
nodular
parenchytqal
hyperplasia
TG
L
TG
L
TG
0
29
15
31
14
0
0
14
100
100
100
100
100
0
0
0
19
14
0
0
0
0
33
100
100
100
0
0
0
0
0
NS
NS
NS
NS
NS
NS
'L, diet containing lard as fat.
* TG,
Ceroid
pigment
diet containing three triglycerides as fat.
3NS, no survivors.
4Complete lobular liposis within three days in all mice fed lard.
NS
NS
NS
W.
100
LANE WILLIAMS AND ROBERT I. OLIVER
OBSERVATIONS
dial fibrosis in which there was no eviAt autopsy the significant findings in dence of inflammation, active necrosis, or
mice killed after more than 8 weeks of of deposition of ceroid pigment or of calcirestriction to the diet were depletion of the fication. The total incidence was approxiusual fat depots, pneumonia, and obvi- mately 10% and no lesions were observed
ously fatty livers in the mice fed lard. prior to 17 weeks of feeding the lard diet.
Other tissues and organs, including the Maximal fibrosis was less than that shown
alimentary tract, appeared normal.
in figure 13.
Livers. The results are summarized in
As early as 10 weeks (tables 2 and 4)
table 2. In chronologic order the livers of of feeding triglycerides myocardial lesions
mice fed the lard-containing diet showed : were present (figs. 6-13). The total inci(1) complete lobular liposis within 72
hours; ( 2 ) formation of fatty cysts within dence was 30% and the most common le5 weeks; ( 3 ) ceroid pigment within 9 sion contained necrotic myocardial fibers,
weeks; and ( 4 ) within 22 weeks a nodular collagenous fibers and large amounts of
hyperplasia of the parenchyma and an ap- calcium and of ceroid pigment (figs. 6-9).
parent increase of reticular fibers between One-half of the damaged hearts contained
these nodules. Some of these changes are such lesions (table 3 ) . Other lesions were
shown in figures 1-5, and all have been of two types (table 3 ) : necrosis and fidescribed in detail previously (Meader and brosis without calcium and ceroid (figs.
10-13), and small areas of myocarditis.
Williams, '57; Williams, '60).
Hepatic liposis and development of In some instances the necrosis seemed very
ceroid pigment were retarded and limited recent in that there was little or no leucoin livers of mice fed triglycerides as fat cytic, histiocytic or fibroblastic response;
(table 2, figs. 1-5). The level of maximal and the damaged fibers were strongly PASliposis was approximately one-half of that positive (fig. 12) subsequent to diastaseseen in the mice fed lard. Ceroid pigment hydrolysis to remove glycogen (Kent and
was present in only trace amounts (figs. 4 Diseker, '55). As well as could be deterand 5). The number of triglycerides-fed mined from the small number of sections
mice surviving until the period in which stained to show fat and from the numerous
reticulinosis and nodular parenchymal hy- sections stained by other methods there
perplasia usually develop in mice receiving was no myocardial liposis in either dietary
lard (Meader and Williams, '57) was so group. The blood vessels of the hearts and
small (table 2) that the data are not sig- of the other organs showed no significant
nificant. In the triglyceride group liposis changes from normal. There were no lewas insufficient to produce extensive dis- sions of epicardium, valves or endocartortion of parenchyma or stroma, (figs. 1, dium. When mice of the stock used here
are fed a completely adequate commercial
2, 5).
Hearts. In table 2, 3 and 4 the types diet, the incidence of myocardial lesions is
and incidence of myocardial damage are approximately 1% in animals more than
presented. The lesions in the lard diet 6 months older than those used here. Such
group consisted of small areas of myocar- lesions consist of small areas of fibrosis
TABLE 3
Types o f myocardial lesions i n mice f e d choline-deficient, low protein-high f a t diets
138 Mice
fed lard as fat
(13 lesions)
113 Mice fed fat as three saturated triglycerides (34 lesions)
Restricted
myocardial
fibrosis
Extensiye
necrosis
and
fibrosis
Calcivm,
ceroid
pigment
and
fibrosis
Diffuse
myocarditis
100% of lesions
(185 days)'
4 1% of lesions
(101 days)'
50% of lesions
(133 days)'
9% of lesions
(79 days)'
Mean.
101
HEPATIC FAT AND CARDIAC DAMAGE:
TABLE 4
Myocardial lesions
~Lard as fat
Weeks
fed
&et
No: of
mice
killed
Per cent
with
lesions
Triglycerides as fat
Weight loss
With
lesions
Without
lesions
No. of
mice
killed
Per cent
with
lesions
Weight loss
l
~
~Without
lesions
~
~
~-
~
%
1-4
5-8
9-15
16-21
64
17
7
8
0
0
0
30
-
35
k 4.1
22-27
28-33
21
8
24
12.5
16
* 8.1
18
2
34-39
7
28.6
22
2
40
6
33
26
2
%
1.21
f6.5
4.9
f4.3
33
C 5.7
34
f7.9
19
f9.1
16
f8.1
20
f7.7
23
C 4.8
%
41
0
-
%
1.3'
f8.1
14
43
33
f8.3
28
16
14
32
56
71
23
17
27.3
2 11.7
19.7
f8.9
35
* 10
10
f10.3
24
f5.2
17
2 4.8
No survivors
No survi~vors
No surv..vors
__
1Av. wt. changes in all mice surviving at 4 weeks.
2 N o standard deviation determined for groups smaller than 4 m ~ c e .
with minimal evidence of active necrosis figs. 1-5). These hepatic changes were
(Williams and Aronsohn, ' 5 6 ) .
retarded and restricted in the triglycerideOther organs and tissues. The kidney fed mice (table 2; figs. 1-5). This dewere normal. Pneumonia was common in creased liposis was apparent in the triglycall mice fed either diet (lard or triglyceride) eride group prior to any significant loss in
for more than three months. The skeletal body weight (ta.bles 1 and 2). The greatest
muscles of the triglyceride group usually incidence of complete lobular liposis was
contained calcium and ceroid when such in the mice that survived longest (table 2).
materials were present in myocardium. No
Here it is not possible to present the
significant changes were observed in other complete history of weight changes of inorgans. Ceroid pigment was not increased dividual mice. There was no instance of
in adrenals or gonads.
rapid weight loss followed by significant
gain of weight. Frequently there was rapid
Relation of general health and of weight loss of weight during the two weeks imloss to changes in livers and hearts
mediately preceding the time at which the
After 4 weeks weight loss was sign& animal was killed.
A great majority of the heart lesions
cantly greater in mice fed the triglyceride
diet (table 1). At all intervals the range were in mice with extreme decreases in
in weight loss was broad in both dietary body weight. However, only at 9-15 weeks
groups (tables 1 and 4). After the first 8 were the weight losses of animals killed
weeks, all mice killed for study represented within a specific chronologic interval sigthe less healthy members of the dietary nificantly greater in those with cardiac legroups and the majority had lost consider- sions (table 4). Despite this, the situation
able amounts of weight (tables 1 and 4). responsible for the early and rapid weight
The changes in the livers showed no rela- loss of the triglyceride group must be contion to amount of loss in body weight. sidered as contributory to the production of
Very fatty livers were present in all of the myocardial lesions (Williams, '60). The
lard-fed mice and the other hepatic mani- constant finding of pneumonia in mice
festations of the deficiency ensued in the killed after 8 weeks on the diets was menexpected relation to its duration (table 2; tioned earlier. Several experimental proce-
102
W. LANE WILLIAMS AND ROBERT I. OLIVER
dures seem to precipitate this disease in
mice (Williams and Davis, '59; Williams,
'60). It seems highly probable that pneumonia contributed significantly to the poor
health including the weight loss observed
in all animals, those fed lard and those fed
triglycerides.
DISCUSSION
Hepatic liposis. In choline deficiency
maximal liposis occurs in livers of rats or
mice fed diets containing natural fats
(lard or butter) composed of a broad
range (as to chain length and degree of
saturation) of lipids including unsaturated
compounds (Williams, Cardle and Meader,
'59). In the triglyceride diet used here the
40% level of fat consisted of 50% of a Cs
compound (trihexanoin), 25% of a CM
compound (trimyristin) and 25% of a CI6
compound (tripalmitin). This diet lacked
many of the saturated compounds and all
of the unsaturated ones present in lard and
butter (Bailey, '51). In choline deficiency
the quantity of the hepatic liposis is controlled to some extent by the chemical
composition of the dietary lipids (Stetten
and Salcedo, '45; Hartroft, '55; Williams,
Cardle and Meader, '59).
Ceroid pigment. In mice fed the triglycerides the rarity of ceroid in livers and
its frequency in myocardium seem to present a contradiction as to the specific relation of diet to the production of this pigment. The small amount of hepatic ceroid
is explained by the absence of unsaturated
fat in the diet (Endicott, '44; Dam, '49;
Hartroft, '51; Alpert, '53). In the absence
of unsaturated dietary fats the presence of
small amounts of ceroid in these livers is
probably the result of local synthesis of
unsaturated compounds (Stetten and Salcedo, '45; Gurin, '53) which would be available for atypical oxidation or polymerization that may produce the pigment (see
Alpert, '53). In livers the usual oxidative
processes related to fatty acids may be absent or severely restricted or altered in
choline deficiency (Artom, '53, '58, '60).
The small amount of unsaturated fat available from the cod liver oil mixture used as
the source of vitamins A and D may have
been used in ceroidogenesis in mice fed
the triglyceride diet. However, the low incidence and delayed appearance of this
pigment would not seem to substantiate
such a conclusion. In this same group of
mice (those fed triglycerides) material
staining as does ceroid was common in
areas of myocardial necrosis. This ceroid
is probably part of a local response to tissue injury and necrosis (see Alpert, '53;
and Hartroft, '53b) and in no way related
to a high intake of fat (Williams and
Aronsohn, '56).
Calcium-ceroid in myocardial lesions.
The occurrence of the mineral or the pigment, or both, has a broad background as
to contributory nutritional deficiencies. Included are low protein, vitamin E deficiency, and cystine supplementation (Mason and Emmel, '45; Moore, '49; Highman
and Daft, '51; Alpert, '53; Williams and
Aronsohn, '56); fatty acid deficiencies
(Hill, Warmanen, Hayes and Holman,
'57); and non-specific relations to feeding
of highly purified diets (Constant, Phillips
and Angevine, '52; Constant and Phillips,
'54). In some species deficiencies in essential fatty acids seem to have a direct relationship to calcification in the cardiovascular system (Hill, Warmanen, Hayes
and Holman, '57).
The lesions containing ceroid and calcium occurred in both types of striated
muscle, skeletal and cardiac. Deposition of
ceroid in skeletal muscle has been associated with deficiencies of protein and of
vitamin E (Mason and Emmel, '45; Williams and Aronsohn, '56). Neither ceroid
nor calcium, nor the combination, was observed in striated (including cardiac) muscle of mice fed diets low in protein, not
supplemented with vitamin E, but high in
content of saturated and unsaturated fats
(Williams, '60). The livers of these mice
contained large amounts of ceroid when
the diets, as above, were deficient in choline.
Other types of myocardial lesions. The
low incidence of myocarditis (table 3)
does not seem significant. Necrosis and
fibrosis (without calcium and ceroid) represented 41% of the lesions (table 3 ) .
Such lesions were similar if not identical
with those previously observed in mice fed
choline-supplemented diets that were high
in fat (lard) and low in protein (Williams,
'60). The incidence and relatively prolonged latent period of all cardiac lesions
HEPATIC FAT AND CARDIAC DAMAGE
observed here do not suggest the type
of myocardial injury produced in young
rats fed a choline deficient-diet containing
ethyl laurate as the lipid component (Kesten, Salcedo and Stetten, '45). Myocardial
necrosis, fibrosis and liposis, with and
without arterial lesions, have been described in young rats fed high fat diets
(Hartroft, '53a; Wilgram and Hartroft, '55;
Thomas and Hartroft, '59).
It should be emphasized that in mice,
the heart, rather than the liver seems to be
the more common target for necrotizing
actions of several diets which have one
feature in common-low protein, but vary
considerably as to content of fat and of
choline (Highman and Daft, '51; Williams and Aronsohn, '56; Meader and Williams, '57; Williams, '60). In mice fed low
protein diets the incidence of extensive myocardial necrosis is significant in the absence of a high fat intake (Highman and
Daft, '51; Williams and Aronsohn, '56).
When the dietary level of fat is very high,
an adequate supplementation with choline
increases the amount of cardiovascular injury over that observed in choline deficiency (Wissler, Eilert, Schroeder and
Cohen, '54; Williams, '60).
The composition of the lipid component
of the triglyceride diet used here was so
atypical (i.e,, completely lacking in unsaturated fat) that on a nutritional basis
it could be considered as deficient in fat
(Hill, Warmanen, Hayes and Holman, '57).
This may explain the similarity of the my+
cardial lesions to those previously described in mice fed diets low in protein,
but not high in fat (Highman and Daft,
'51; Williams and Aronsohn, '56).
SUMMARY
1. In mice fed choline-deficient diets for
as long as 7 months hepatic liposis was
extremely limited when dietary fat consisted of three saturated triglycerides. In
these mice significant production or deposition of ceroid pigment did not occur in
livers. In livers of mice fed lard the liposis
was rapid, massive, and progressive; and
the expected pattern of abundant ceroide
genesis, parenchymal hyperplasia and reticulinosis ensued.
2. In the mice fed triglycerides 30%
showed extensive myocardial lesions that
103
included necrosis, calcinosis and deposition of ceroid pigment. In lard-fed mice
cardiac damage consisted of a very limited
amount of myocardial fibrosis and the total
incidence of such lesions was 10%.
3. It is Concluded that a broad range
(with reference to saturation and chain
length) of dietary lipids is essential for
production of the massive hepatic liposis
and of ceroid pigment characteristic of
choline deficiency. The absence of unsaturated compounds from the diet seems to
afford considerable protection (from liposis) to the liver, but renders the myocardium susceptible to extensive damage.
LITEIRATURE CITED
Alpert, M. 1953 Hormonal induction of deposition of ceroid pigment in the mouse. Anat.
Rec., 116: 469-494.
Artom, C. 1953 Role of choline in the oxidation of fatty acids by the liver. J. Biol. Chem.,
205: 101-111.
1958 Rolle of choline in the hepatic
oxidation of fat. Am. J. Clin. Nutrition, 6:
22 1-234.
1960 Mechanism of action of choline.
Ibid., 8: 303-3051.
Bailey, A. E., (editor) 1951 Industrial Oil and
Fat Products. Interscience Publishers, New
York, chap. 11, pp. 39-73.
Buckley, G. F., and W. S. Hartroft 1955 Pathology of choline deficiency in the mouse. Arch.
Path., 59: 185-197.
Constant, M. A., and P. H. Phillips 1954 The
occurrence of a calcinosis syndrome in cotton
rats. IV. The effect of diet and the age of the
animals on the development of the disease and
on the urinary excretion of various metabolites.
J. Nutrition, 5 2 . 165-186.
Constant, M. A., P. H. Phillips and D. M. Angevine
1952 The occurrence of a calcinosis syndrome
in the cotton iat. 11. Pathology. Ibid., 47:
327-339.
Croxton, F. E. 1933 Elementary Statistics with
Application in Medicine and the Biological Sciences. Dover Publications, New York.
Dam, H. 1949 Relationship of vitamin E deficiency to tissue peroxides. Ann. N. Y. Acad.
Sci., 52: 195-19!3.
Endicott, K. M. 1944 Similarity of the acid
fast pigment ceroid and oxidized unsaturated
fat. Arch. Path., 37: 49-53.
Gurin, S. 1953 The liver and fat metabolism.
Transactions of the Twelfth Conference on
Liver Injury. Josiah Macy, Jr. Foundation, pp.
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1953a Cardiovascular lesions in choline-deficient rats. Transactions of the Twelfth
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104
W . LANE WILLIAMS AND ROBERT I . OLIVER
Conference on Liver Injury. Josiash Macy, Jr.
Foundation, pp. 98-100.
1953b Pathogenesis and significance of
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PLATE 1
EXPLANATION OF FIGURES
All figures show livers ( X 100) of mice fed the lard or triglyceride diet for 16 weeks (figs.
I, 2, 3) or 27 weeks (figs. 4 and 5).
1
Maximal liposis produced by triglyceride diet. Frozen section, oil red 0 stain.
2
Minimal liposis produced by triglyceride diet. Frozen section, oil red 0.
3 Usual amount of liposis seen in mice fed the lard diet. Frozen section, oil red 0.
4 Usual amount of ceroid pigment in mice fed lard diet. Paraffin section, Sudan black.
5
Maximal amount of ceroid pigment seen in mice fed triglyceride diet. Paraffin section,
Sudan black.
HEPATIC FAT AND CARDIAC DAMAGE
W. Lane Williams and Robert I. Oliver
PLATE 1
105
HEPATIC FAT AND CARDIAC DAMAGE
PLATE 2
Mi". Lane Williams and Robert I. Oliver
All figures show hearts of mice fed triglyceride diet for 16 weeks.
Positive reaction for calcium. Alizarin stain. X 68.
7 Several areas showing myocardial necrosis and deposition of calcium and ceroid pigment. H. and E. X 100.
8 Positive reaction for ceroid pigment. Paraffin section decalcified with nitric acid and
stained with oil red 0. X 500.
9 Lesions similar to those i n figure 7. PAS with hematoxylin counterstain. X 100.
6
106
HEPATIC FAT AND CARDIAC DAMAGE
W. Lane Williams and Robert I. Oliver
PLATE 3
All figures show hearts of mice fed triglyceride diet for 12 1.0 26 weeks as stated.
10 Extensive myocardial fibrosis at 12 weeks. H. and E. X 80.
11 Small area within same section as shown in figure 10. The fibers shown in cross section
are shrunken. X 475.
12 Intense PAS positivity (following diastase-hydrolysis ) indiczding very early necrosis of
myocardial fibers at 16 weeks. Hematoxylin counterstain. > 200.
13 Minimal necrosis and fibrosis as seen in a triglyceride-fed (2.6-week) mouse. Masson
stain, x 200.
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