Cholesterol Production in Obesity
By TATU A. MIETTINEN, M.D.
SUMIMARY
Sterol-balance studies were performed in 10 control subjects, 10 normolipidemic
ol)ese patieints, and 10 hypertriglyceridemic (type IV, mostly obese) patients on a
low-cholesterol solid-food diet. Fecal elimination of cholesterol was markedly elevated
in the overweight patients and tended to be high in the hypertriglyceridemic subjects
also. A signiificant correlation wx as found between body weight and fecal excretion of
neutral, acidic, and total steroids, inidicating that the greater the body wveight the
higher was the rate of cholesterol synthesis. Sterol-balance data in obese subjects
showed that excess daily cholesterol production roughly amounted to 20 mg/kg of
adipose tissue. The control subjects produced only 12 mg/kg of body weight daily.
Thus, obesity is associated with an increased rate of cholesterol synthesis in man. However, the correlationi between serum cholesterol concentration and cholesterol production
was low, suggesting that the overall rate of cholesterol synthesis was not the only
factor determining the serum cholesterol level. That enhanced cholesterol production
is not an irreversible phenomenon in obese subjects was indicated by the normalization
of sterol-balance values in three overweight patients after their weights had been
reduced by total fast folloved by a low-calorie diet.
Additional Indexing Words:
Hypercholesterolemia
Hypertriglycerider
Sterol balance
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YPERCHOLESTEROLEMIA is frequently found in patients with obesity,
so that the average serum cholesterol level is
significantly higher in overweight subjects
than in lean ones, and usually a significant
correlation exists between serum cholesterol
and obesity.1 2 It should be borne in mind,
however, that a great many obese patients
have normal serum lipid concentrations.3
Hypercholesterolemia4 5 and obesity6 are
known to be associated with the development
of ischemic heart disease, although the association is relatively weak in the case of
obesity, according to recent studies.7 It
therefore seemed worthwhile to study the
Fecal steroids
Bile acids
cholesterol metabolism of obese patients in
greater detail, the sterol-balance technique
being used for determination of cholesterol
synthesis. Kinetic analysis of serum cholesterol
after administration of radioactive cholesterol
has disclosed a positive correlation between
cholesterol production and excess body
weight.8 Results of the preliminary studies9' 10
and those reported here clearly demonstrate
that obesity enhances cholesterol synthesis
very potently and that reduction of weight
effectively normalizes cholesterol production.
Material and Methods
Sterol balance was measured in three groups of
patients, for whom clinical data are presented in
table 1. The control group consisted partly of
volunteers from among the laboratory personnel
and partly of hospital patients with no detectable
metabolic or other active disease. The obese
group consisted of 10 markedly overweight
patients, most of whom were hospitalized for
reduction of weight. Although at the time of
admission to the hospital some of the patients had
From the Third Department of Medicine, University of Helsinki, Finland.
This study has been carried out under contract with
the Association of Finnish Life Assurance Companies.
Address for reprints: Tatu A. Miettinen, M.D.,
Third Department of Medicine, University of Helsinki, Helsinki 29, Finland.
Received November 18, 1970; revision accepted for
publication July 19, 1971.
842
Circulation, Volume XLIV, November 1971
CHOLESTEROL PRODUCTION IN OBESITY
843
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Circulation, Volume XLIV, November 1971
MIETTINEN
(844
Downloaded from http://ahajournals.org by on December 10, 2023
slightly elevated serum clholesterol and/or triglycerides, the serum lipid values were within normal
liimiits during the period of fecal collections. In
this group excess body weight (calculated as the
difference between the actual and ideal'1
weights) ranged from 15 to 80 kg and relative
weight (absolute weight/ideal weight) from 1.21
to 2.42. Diabetes (controlled by diet) or diabetic
glucose tolerance was found in six of the patients,
twvo of whom had gallstones and two had clinical
and electrocardiographic signs of coronary beart
disease; one patient (no. 19) of the latter group
had heart failure, which required relatively large
doses of digitalis and diuretics for compensation.
The third group contained 10 patients in whom
hvpertriglyceridemia was conspicuous and whose
lipoprotein pattern was consistent with type IV
hyperlipoproteinemia according to the classification of Fredrickson et al.,12 although in some of
them hypercholesterolemia and f3-lipoprotein
bands in lipoprotein electrophoresis were also
relatively marked. The excess body weight in this
group ranged from -1 to 42 kg and the relative
body weight from 0.98 to 1.60. Two of the
patients had cutaneous xanthomatosis, six had
clinical and electrocardiographic signs of ischemic
heart disease but no heart failure, and seven
exhibited diabetic glucose tolerance.
All of the subjects were placed on a lowcholesterol solid-food diet, and chromic oxide
(Cr203) and /3-sitosterol were given so that the
respective corrections for fecal flow and degradation of cholesterol during intestinal transit13 could
be made. From one to three 3-day stool
collections were made for each subject after 5-10
days on the diet, Cr203, and /3-sitosterol. Analysis
of the diet showed that the average cholesterol
content was 120 mg/2400 kcal. In patients 12,
14, and 19 the study was repeated after the
weights had fallen, in response to total fast
followed by a low-calorie diet, by 38, 13, and 68
kg, respectively. In view of the times for which
the new stable weights had been maintained (12,
1, and 6 months after weight reduction had been
achieved), it was assumed that a new metabolic
steady state had already been attained.
Serum cholesterol was measured according to
the method of Pearson and associates14 and
triglycerides by the method of Carlson.15 Dietary
sterols and fecal acidic and neutral steroids were
measured by the thin-layer chromatographic gasliquid chromatographic method.16 17 In one case,
recovery of administered and dietary /8-sitosterol
in the feces was only 70%, and neutral steroid
excretion was therefore corrected for the recovery
of /3-sitosterol. In the others, the values for
recovery ranged from 94 to 108%, suggesting that
no sterol degradation had occurred.13 Therefore,
in these cases the results were expressed in
relation to Cr,O3, which was determined according to Bolin and associates.'8
Sterol balance, which in the steady state is
equal to cholesterol synthesis, was obtained as the
difference between fecal steroids derived from
cholesterol and dietary cholesterol. Because
weight reduction with a low-calorie diet was
found to lead to decreased fecal steroid excretion
in obese subjects,19 the amount of calories was
rigidly adjusted to maintain the body weight
constant. None of the subjects studied actually
showed any significant change in weight during
the experimental period of 14-19 days, at the end
of which the fecal collections were performed.
This indicates that a steady state with respect to
calories had been achieved.
Cholesterol intake varied little during the
study, ranging, according to analyses, from 98 to
136 mg/2400 keal; serum cholesterol was constant during the experimental period; and fecal
steroid analyses of 2-3 consecutive collections in
each subject (for one control and one hypertriglyceridemic patient only a single collection was
available) showed constant excretion. The latter
was indicated by the finding that the difference
between the total fecal steroids of the first and
third (or second) collection did not differ
significantly from zero (- 21 -+ 30 mg/day). The
same was true of acidic and neutral steroids,
indicating that cholesterol elimination from the
body as bile acids and as cholesterol itself was
stable. It is therefore reasonable to infer that the
subjects of the three groups were in a comparable
metabolic steady state.20 On the assumption that
at their ideal body weights the obese and
hypertriglyceridemic patients would synthesize
cholesterol at the rate observed in the controls,
their theoretical, ideal sterol balance was calculated by multiplying the ideal weight by the
average sterol-balance value of the controls,
expressed as milligrams per day per kilogram of
body weight. Excess sterol balance, corresponding
to excess cholesterol synthesis, was the difference
between the actual and ideal values for sterol
balance.
Results
Table 2 shows that in the obese patients
fecal excretion of acidic, neutral, and total
steroids (derived from cholesterol) is markedly higher than in the controls or even in the
hypertriglyceridemic patients. The differences
between the two latter groups were insignificant, although the actual (but not ideal) body
weights were markedly higher in the hypertriglyceridemic group than in the controls. The
sterol-balance values indicate that in the obese
Circulation, Volume XLIV, November 1971
CHOLESTEROL PRODUCTION IN OBESITY
845
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Circulation, Volume XLIV, Novefraber 1971
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MIETTINEN
846
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TOTAL
0.42 2
40
,
60
,
80
100
120
140
kg
BODY WEIGHT
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Figure 1
Relationship of body weight to fecc I1 neutral steroids
(upper panel), bile acids (middle panel), and total
steroids (sum of neutral and acidifc steroids; lower
panel) in control subjects and in patjients with obesity
and hypertriglyceridemia. 9 = feim ile controls; 8 male controls; x hypertriglycerideimic patients; a
obese female patients; o = obese nuaile patients.
cholesterol synthesis was twice as high,
and in the hypertriglyceridemiic subjects 1.3
times as high, as in the cont rols. Since the
average relative weights of th e three groups
were 1.69, 1.27, and 0.96, and s ince their ideal
weights were the same, it can be concluded
that obesity, particularly witlhout hyperlipidemia, effectively stimulates ctolesterol synthesis in man.
Figure 1 shows the positiive correlations
between body weight and the fecal excretion
of neutral, acidic, and total steroids. The
controls exhibited a significant correlation for
all parameters, the lighter females having
lower acidic- and total-steroid XTalues, and lessgroup
negative sterol-balance values than the heavier males. However, the sex difference, which
was not seen in the obese patients because of
the similar weight of the two sexes, disappeared when fecal-steroid values were expressed per kilogram of body weight, although
even then the bile acid output was slightly
lower in the women than in the men (table 2).
The association between fecal steroids and
body weight tended to be less significant in
the hypertriglyceridemic than in the obese
subjects, because, particularly in one markedly
obese and hypertriglyceridemic patient, cholesterol elimination, both as bile acids and as
neutral steroids, happened to be relatively
low. Sterol balance, when expressed per
kilogram of body weight, was no longer
significantly higher in the obese (- 14.9 ± 0.8
mg) than in the hypertriglyceridemic (13.0 + 1.1 mg) or control subjects (-12.4 + 1.0
mg). The positive correlation (r - 0.64) between excess body weight and excess sterol
balance (fig. 2) indicates that cholesterol
synthesis is enhanced over a wide range of
obesity. The average increment of cholesterol
synthesis per kilogram of adipose tissue was
calculated for the obese subjects by dividing
the excess sterol balance by the excess body
weight. It was found to be 20 + 2 mg/kg/day,
which again demonstrates the effectiveness of
adipose tissue in enhancing cholesterol production in man, cholesterol synthesis in the
control subjects being only 12 mg/kg/day.
However, the correlation between serum
cholesterol and sterol balance or excess
balance (fig. 3) did not reach a significant
level in this small series, which indicates that
the serum cholesterol concentration is not
determined solely by the overall rate of
cholesterol synthesis. Neither body weight,
excess weight, nor relative weight of the obese
group was correlated significantly with the
serum cholesterol concentration.
From table 3 it is seen that in three
excessively obese subjects reduction of weight
to near-normal values led to a marked
decrease in the elimination of fecal cholesterol
from the body. This indicates that the
Circulation, Volume XLIV, November 1971
CHOLESTEROL PRODUCTION IN OBESITY
0
.+1.2
0
4
xN.
0
0
L
z
o
4.+0.8
0
0
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~~~~~~r=0.65
0
~~.0~~
0
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U.,
-5 0
+80
+4 0
+6 0
+2 0
EXCESS BODY WEIGHT, kg
Figure 2
Relationship between excess body weight and excess
sterol balance in patients with obesity (o) and hypertriglyceridemia (-).
abnormally high cholesterol synthesis occurring in obese subjects can be normalized by
effective weight reduction.
Discussion
Downloaded from http://ahajournals.org by on December 10, 2023
The results of the present study show that
cholesterol synthesis is normally proportional
to body size, obesity being especially potent in
EXCESS BALANCE g/DAY
E
Body
weight
Collection
period
(days)
119.8
120.3
119.8
0-3
4-6
7-9
Mean
0-3
4-6
7-9
Mean
(kg)
82.1
81.9
82.2
* r=0.60
CD
C)
Table 3
Effect of Weight Reduction on Fecal Steroid
Excretion in Three Obese Subfects
111.7
112.2
0 r= 0.54
300
stimulating this process. Thus, the marked
difference in cholesterol synthesis found between the male and female control subjects
disappeared when the values were expressed
per kilogram of body weight. No sex difference was seen in the obese patients, among
whom the body weight happened to be similar
in males and females (fig. 1). The fact that in
our earlier series21 no difference (expressed in
relation to total body weight) was found
between men and women turned out, on
retrospective study, to be due to the similar
body weights in the two groups.
Only a few sterol-balance studies made with
accurate methods on human subjects have
-1.2
-0.7I
-0.2
847
250
99.4
98.9
99.2
*
O
* 0
E
152.0
152.5
151.9
@000
200p
00
0 0
0
150L
0 00
-2.0
-1.5
BALANCE,g /DAY
Figure 3
Relationship of the serum cholesterol concentration to
sterol balance (o) and excess sterol balance (-) in
obese subjects. Correlation coefficients (r = 0.54 and
0.60) did not reach a statistically significant level.
.0
-1.
Cii.culation, Volume XLIV, November 1971
84.1
84.1
83.9
84.1
Fecal steroids (mg/day)
Acidic
Neutral
Total*
Patient no. 12
395
362
383
380
242
346
267
285
Patient no. 14
0-3
282
4-6
238
Mean
260
0-3
172
4-6
148
7-9
220
Mean
180
Patient no. 19
0-3
1045
4-6
892
931
7-9
Mean
9a6
0-3
452
422
4-6
7-9
429
10-12
497
Mean
475
1420
1.532
1369
1440
825
903
704
810
1815
1894
1752
1820
1067
1249
961
1095
1258
1398
1328
1162
1099
1281
1159
1540
1636
1588
1334
1247
1438
1339
802
918
863
861
578
664
1847
1810
1794
1817
1030
1086
984
1164
1090
555
663
615
*Three determinations of dietary cholesterol on each
body weight showed that the average intake had fallen
significantly between the two studies in cases 12 and
19 (31 and 49 mg/day, respectively) and insignificantly
(14 mg/day) in case 14.
848
Downloaded from http://ahajournals.org by on December 10, 2023
been reported so far. Effects of dietary fats on
fecal steroid excretion were studied by Connor
and associates in six normocholesterolemic
prisoners." The mean sterol-balance values
for two control periods on a cholesterol-free
liquid-formula diet (fat consisted of cocoa
butter), one before and the other after a cornoil diet, were -783 and -682 mg/day (neutral
steroids corrected for losses of ,B-sitosterol),
respectively. Despite marked differences in
the diet, the figures are in good agreement
with the control value of the present study (777 mg/day). The data did not appear to be
correlated with body weight. Grundy and
Ahrens`0 23 reported sterol-balance data on
formula diets varying in cholesterol, plant
sterol, and fat composition, for 15 hypercholesterolemic (type II, types as described
by Fredrickson and associates'2 ), one normocholesterolemic, and four hypertriglyceridemic (three type V and one type IV) subjects. The sterol balance ranged from -374
to -749 mg/day for hypercholesterolemic
subjects and from -726 to -1833 mg/
day for hyperglyceridemic subjects on a formula diet containing saturated fat; the
data appeared to bear some relationship to body weight. In 43 patients with
familial hypercholesterolemia, sterol balance,
fecal neutral steroids, and bile acids were
found to be correlated with body weight.9 As
in the present investigation, some but not all
of the hyperglyceridemic patients exhibited a
high bile acid production in the studies by
Grundy and Ahrens20° 23 and by Kottke .24 In
the latter series bile acid metabolism was
measured isotopically, and a marked interindividual heterogeneity in bile acid production
was observed.
Monkey adipose tissue synthesizes cholesterol in vitro at a rate25 that would account
for the increment revealed by sterol-balance
data in the obese subjects studied here. However, more recent studies have indicated that
human and rat adipocytes are not able to convert labeled glucose or acetate into cholesterol,
and that adipose tissue is only a cholesterolstorage organ that receives its cholesterol from
circulating lipoproteins or chylomicron.26 The
MIETTINEN
liver and intestinal mucosa,27 on the other hand,
have been shown to be the sites where serum
cholesterol is primarily synthesized, which suggests that these organs are responsible for the
augmented production of cholesterol in obesity. Studies with a labeled acetate-mevalonate
mixture also indicated that synthesis was
markedly enhanced in obese patients and that
this stimulation took place between acetate
and mevalonate.10 Furthermore, the rapid
appearance of newly synthesized radioactive
cholesterol in the serum suggested that it
originated from a rapidly equilibrating cholesterol pool ( s), supposedly situated primarily
in the liver and intestinal wall.27 Hypertriglyceridemic (type IV) subjects, who are usually
obese and whose cholesterol synthesis in the
present study was only moderately increased,
have been shown by Salen et al.28 to have a
high rate of intestinal cholesterol synthesis.
The latter was minimal in hypercholesterolemic (type II) patients, but it was markedly
stimulated by interruption of the enterohepatic circulation of bile acids with cholestyramine; clofibrate inhibited synthesis in the
cholestyramine-treated hypercholesterolemic
patients and in a case with hypertriglyceridemia.
The cholesterol ester turnover is also higher
in obese subjects than in lean ones and is
significantly correlated not only with body
weight but also with serum cholesterol and
triglyceride concentrations.29 3 Nestel et
al.,8 using the two-pool model for calculation
of cholesterol metabolism, showed that cholesterol production, which bears no correlation
to serum cholesterol, is increased by 22
mg/day/kg of excess body weight. This is in
good agreement with the value of 20
mg/day/kg obtained in the present study by
drect measurement of the fecal end products
of cholesterol metabolism.
Primarily enhanced elimination of cholesterol from the body, resulting, for instance,
from treatment with cholestyramine or from
an ileal bypass operation,,3Y
is almost
always accompanied by a reduced level of
serum cholesterol. The magnitude of the latter
is not correlated with the increment of fecal
Circulation, Volume XLIV, November 1971
CHOLESTEROL PRODUCTION IN OBESITY
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elimination, owing to a compensatory increase
in the synthesis and possibly in the mobilization of tissue cholesterol.31 32 On the other
hand, primarily enhanced synthesis, such as
obviously occurs in obesity, can be assumed to
increase the serum cholesterol level in almost
every case, although the magnitude of the
increase is not necessarily correlated with the
enhancement of synthesis, because simultaneous stimulation of cholesterol elimination
prevents this augmentation to an extent which
differs from one subject to another. This
compensatory increase of elimination is
enough to keep the serum cholesterol level
low in some obese patients, while in others
elimination may be more or less defective, so
that hypercholesterolemia results. Thus, the
latter may accompany both reduced and
enhanced synthesis; in familial hypercholesterolemia the primary disorder appears to be
defective elimination of cholesterol, this being
secondarily associated with a compensatory
decrease in cholesterol synthesis;9' 10, 21 in
obesity it is synthesis that is primarily
enhanced, but in some cases augmentation of
elimination is not proportionate and hypercholesterolemia results.
The variable response of elimination to
enhanced cholesterol synthesis in obesity may
explain why the serum cholesterol level
usually shows only a weak correlation with
body weight or body fatness.1' 2 However,
since obesity is frequent in modern society, it
may, as a potent factor enhancing cholesterol
synthesis, be a very important etiologic factor
in hypercholesterolemia and hence in ischemic
heart disease, even though, according to the
more-recent epidemiologic studies,7 the association between the latter and obesity is
relatively weak. Weight reduction was accompanied with a marked decrease in cholesterol synthesis in -the limited number of
subjects studied. This therapeutic measure, so
commonly recommended for prevention and
treatment of hypercholesterolemia and ischemic heart disease, seems to be a very
effective procedure as far as reduction of
cholesterol synthesis is concerned. Weight
reduction has actually been reported to
Circulation, Volume XLIV, Novemnber 1971
849
decrease the serum choiesterol level in obese
subjects,34 although in the new steady state
initial values may be resumed.35
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Circulation, Volume XLIV, November 1971