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. How- ever, 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 YPERCHOLESTEROLEMIA is fre- quently 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 asso- ciation is relatively weak in the case of obesity, according to recent studies.7 It therefore seemed worthwhile to study the From the Third Department of Medicine, Univer- sity 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 Helsin- ki, Helsinki 29, Finland. Received November 18, 1970; revision accepted for publication July 19, 1971. 842 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 produc- tion. 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 Circulation, Volume XLIV, November 1971 by guest on June 3, 2018 http://circ.ahajournals.org/ Downloaded from
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Cholesterol Production in ObesityBy TATU A. MIETTINEN, M.D.
SUMIMARYSterol-balance studies were performed in 10 control subjects, 10 normolipidemic
ol)ese patieints, and 10 hypertriglyceridemic (type IV, mostly obese) patients on alow-cholesterol solid-food diet. Fecal elimination of cholesterol was markedly elevatedin the overweight patients and tended to be high in the hypertriglyceridemic subjectsalso. A signiificant correlation wx as found between body weight and fecal excretion ofneutral, acidic, and total steroids, inidicating that the greater the body wveight thehigher was the rate of cholesterol synthesis. Sterol-balance data in obese subjectsshowed that excess daily cholesterol production roughly amounted to 20 mg/kg ofadipose 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. How-ever, the correlationi between serum cholesterol concentration and cholesterol productionwas low, suggesting that the overall rate of cholesterol synthesis was not the onlyfactor determining the serum cholesterol level. That enhanced cholesterol productionis not an irreversible phenomenon in obese subjects was indicated by the normalizationof sterol-balance values in three overweight patients after their weights had beenreduced by total fast folloved by a low-calorie diet.
YPERCHOLESTEROLEMIA is fre-quently found in patients with obesity,
so that the average serum cholesterol level issignificantly higher in overweight subjectsthan in lean ones, and usually a significantcorrelation exists between serum cholesteroland obesity.1 2 It should be borne in mind,however, that a great many obese patientshave normal serum lipid concentrations.3Hypercholesterolemia4 5 and obesity6 areknown to be associated with the developmentof ischemic heart disease, although the asso-ciation is relatively weak in the case ofobesity, according to recent studies.7 Ittherefore seemed worthwhile to study the
From the Third Department of Medicine, Univer-sity of Helsinki, Finland.
This study has been carried out under contract withthe Association of Finnish Life Assurance Companies.
Address for reprints: Tatu A. Miettinen, M.D.,Third Department of Medicine, University of Helsin-ki, Helsinki 29, Finland.
Received November 18, 1970; revision accepted forpublication July 19, 1971.
842
Fecal steroids Bile acids
cholesterol metabolism of obese patients ingreater detail, the sterol-balance techniquebeing used for determination of cholesterolsynthesis. Kinetic analysis of serum cholesterolafter administration of radioactive cholesterolhas disclosed a positive correlation betweencholesterol production and excess bodyweight.8 Results of the preliminary studies9' 10and those reported here clearly demonstratethat obesity enhances cholesterol synthesisvery potently and that reduction of weighteffectively normalizes cholesterol produc-tion.
Material and MethodsSterol balance was measured in three groups of
patients, for whom clinical data are presented intable 1. The control group consisted partly ofvolunteers from among the laboratory personneland partly of hospital patients with no detectablemetabolic or other active disease. The obesegroup consisted of 10 markedly overweightpatients, most of whom were hospitalized forreduction of weight. Although at the time ofadmission to the hospital some of the patients had
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slightly elevated serum clholesterol and/or triglyc-erides, the serum lipid values were within normalliimiits during the period of fecal collections. Inthis group excess body weight (calculated as thedifference between the actual and ideal'1weights) ranged from 15 to 80 kg and relativeweight (absolute weight/ideal weight) from 1.21to 2.42. Diabetes (controlled by diet) or diabeticglucose tolerance was found in six of the patients,twvo of whom had gallstones and two had clinicaland electrocardiographic signs of coronary beartdisease; one patient (no. 19) of the latter grouphad heart failure, which required relatively largedoses of digitalis and diuretics for compensation.The third group contained 10 patients in whomhvpertriglyceridemia was conspicuous and whoselipoprotein pattern was consistent with type IVhyperlipoproteinemia according to the classifica-tion of Fredrickson et al.,12 although in some ofthem hypercholesterolemia and f3-lipoproteinbands in lipoprotein electrophoresis were alsorelatively marked. The excess body weight in thisgroup ranged from -1 to 42 kg and the relativebody weight from 0.98 to 1.60. Two of thepatients had cutaneous xanthomatosis, six hadclinical and electrocardiographic signs of ischemicheart disease but no heart failure, and sevenexhibited diabetic glucose tolerance.
All of the subjects were placed on a low-cholesterol solid-food diet, and chromic oxide(Cr203) and /3-sitosterol were given so that therespective corrections for fecal flow and degrada-tion of cholesterol during intestinal transit13 couldbe made. From one to three 3-day stoolcollections were made for each subject after 5-10days on the diet, Cr203, and /3-sitosterol. Analysisof the diet showed that the average cholesterolcontent was 120 mg/2400 kcal. In patients 12,14, and 19 the study was repeated after theweights had fallen, in response to total fastfollowed by a low-calorie diet, by 38, 13, and 68kg, respectively. In view of the times for whichthe new stable weights had been maintained (12,1, and 6 months after weight reduction had beenachieved), it was assumed that a new metabolicsteady state had already been attained.
Serum cholesterol was measured according tothe method of Pearson and associates14 andtriglycerides by the method of Carlson.15 Dietarysterols and fecal acidic and neutral steroids weremeasured by the thin-layer chromatographic gas-liquid chromatographic method.16 17 In one case,recovery of administered and dietary /8-sitosterolin the feces was only 70%, and neutral steroidexcretion was therefore corrected for the recoveryof /3-sitosterol. In the others, the values forrecovery ranged from 94 to 108%, suggesting thatno sterol degradation had occurred.13 Therefore,in these cases the results were expressed in
relation to Cr,O3, which was determined accord-ing to Bolin and associates.'8
Sterol balance, which in the steady state isequal to cholesterol synthesis, was obtained as thedifference between fecal steroids derived fromcholesterol and dietary cholesterol. Becauseweight reduction with a low-calorie diet wasfound to lead to decreased fecal steroid excretionin obese subjects,19 the amount of calories wasrigidly adjusted to maintain the body weightconstant. None of the subjects studied actuallyshowed any significant change in weight duringthe experimental period of 14-19 days, at the endof which the fecal collections were performed.This indicates that a steady state with respect tocalories had been achieved.
Cholesterol intake varied little during thestudy, ranging, according to analyses, from 98 to136 mg/2400 keal; serum cholesterol was con-stant during the experimental period; and fecalsteroid analyses of 2-3 consecutive collections ineach subject (for one control and one hypertri-glyceridemic patient only a single collection wasavailable) showed constant excretion. The latterwas indicated by the finding that the differencebetween the total fecal steroids of the first andthird (or second) collection did not differsignificantly from zero (- 21 -+ 30 mg/day). Thesame was true of acidic and neutral steroids,indicating that cholesterol elimination from thebody as bile acids and as cholesterol itself wasstable. It is therefore reasonable to infer that thesubjects of the three groups were in a comparablemetabolic steady state.20 On the assumption thatat their ideal body weights the obese andhypertriglyceridemic patients would synthesizecholesterol at the rate observed in the controls,their theoretical, ideal sterol balance was calcu-lated by multiplying the ideal weight by theaverage sterol-balance value of the controls,expressed as milligrams per day per kilogram ofbody weight. Excess sterol balance, correspondingto excess cholesterol synthesis, was the differencebetween the actual and ideal values for sterolbalance.
ResultsTable 2 shows that in the obese patients
fecal excretion of acidic, neutral, and totalsteroids (derived from cholesterol) is marked-ly higher than in the controls or even in thehypertriglyceridemic patients. The differencesbetween the two latter groups were insignifi-cant, although the actual (but not ideal) bodyweights were markedly higher in the hypertri-glyceridemic group than in the controls. Thesterol-balance values indicate that in the obese
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Relationship of body weight to fecc(upper panel), bile acids (middlesteroids (sum of neutral and acidipanel) in control subjects and in patand hypertriglyceridemia. 9 = feimmale controls; x hypertriglycerideiobese female patients; o = obese nu
group cholesterol synthesis wasand in the hypertriglyceridemtimes as high, as in the contaverage relative weights of thwere 1.69, 1.27, and 0.96, and s
weights were the same, it can
that obesity, particularly witldemia, effectively stimulates cthesis in man.
Figure 1 shows the positiibetween body weight and theof neutral, acidic, and totalcontrols exhibited a significantall parameters, the lighter flower acidic- and total-steroid X
10 - negative sterol-balance values than the heavi-o er males. However, the sex difference, which
was not seen in the obese patients because ofthe similar weight of the two sexes, disap-peared when fecal-steroid values were ex-
o pressed per kilogram of body weight, althougheven then the bile acid output was slightlylower in the women than in the men (table 2).
NEUTRAL The association between fecal steroids ando body weight tended to be less significant in
the hypertriglyceridemic than in the obesesubjects, because, particularly in one markedlyobese and hypertriglyceridemic patient, cho-lesterol elimination, both as bile acids and as
o neutral steroids, happened to be relativelyACIDIC low. Sterol balance, when expressed per
kilogram of body weight, was no longero significantly higher in the obese (- 14.9 ± 0.8
mg) than in the hypertriglyceridemic (-13.0 + 1.1 mg) or control subjects (-12.4 + 1.0mg). The positive correlation (r - 0.64) be-tween excess body weight and excess sterol
TOTAL balance (fig. 2) indicates that cholesterolsynthesis is enhanced over a wide range of
120 140 kg obesity. The average increment of cholesterolsynthesis per kilogram of adipose tissue wascalculated for the obese subjects by dividing
I1 neutral steroids the excess sterol balance by the excess bodypanel), and total weight. It was found to be 20 + 2 mg/kg/day,fc steroids; lowerjients with obesity which again demonstrates the effectiveness ofile controls; 8 - adipose tissue in enhancing cholesterol pro-mic patients; a duction in man, cholesterol synthesis in theaile patients. control subjects being only 12 mg/kg/day.
twice as high, However, the correlation between serum
iic subjects 1.3 cholesterol and sterol balance or excessrols. Since the balance (fig. 3) did not reach a significante three groups level in this small series, which indicates thatince their ideal the serum cholesterol concentration is notbe concluded determined solely by the overall rate of
hout hyperlipi- cholesterol synthesis. Neither body weight,tolesterol syn- excess weight, nor relative weight of the obese
group was correlated significantly with theve correlations serum cholesterol concentration.fecal excretion From table 3 it is seen that in threesteroids. The excessively obese subjects reduction of weightcorrelation for to near-normal values led to a markedemales having decrease in the elimination of fecal cholesterolTalues, and less- from the body. This indicates that the
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Lii
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Relationship between excess body weight and excesssterol balance in patients with obesity (o) and hyper-triglyceridemia (-).
abnormally high cholesterol synthesis occur-ring in obese subjects can be normalized byeffective weight reduction.
DiscussionThe results of the present study show that
cholesterol synthesis is normally proportionalto body size, obesity being especially potent in
-0.2
150L-1..0
EXCESS BALANCE g/DAY-0.7I
-1.5BALANCE,g /DAY
Figure 3
-1.2
-2.0
Relationship of the serum cholesterol concentration tosterol balance (o) and excess sterol balance (-) inobese subjects. Correlation coefficients (r = 0.54 and0.60) did not reach a statistically significant level.
Cii.culation, Volume XLIV, November 1971
stimulating this process. Thus, the markeddifference in cholesterol synthesis found be-tween the male and female control subjectsdisappeared when the values were expressedper kilogram of body weight. No sex differ-ence was seen in the obese patients, amongwhom the body weight happened to be similarin males and females (fig. 1). The fact that inour earlier series21 no difference (expressed inrelation to total body weight) was foundbetween men and women turned out, onretrospective study, to be due to the similarbody weights in the two groups.Only a few sterol-balance studies made with
accurate methods on human subjects have
Table 3Effect of Weight Reduction on Fecal SteroidExcretion in Three Obese SubfectsBody Collection Fecal steroids (mg/day)weight period(kg) (days) Acidic Neutral Total*
*Three determinations of dietary cholesterol on eachbody weight showed that the average intake had fallensignificantly between the two studies in cases 12 and19 (31 and 49 mg/day, respectively) and insignificantly(14 mg/day) in case 14.
0
0
00
o 00
00
00
0
0 ~~~~~~r=0.65
~~.0~~
0
300
E 250C)
E
200p
0 r= 0.54* r=0.60
CD
O ** 0
@00000 0 0
0
0 00
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been reported so far. Effects of dietary fats onfecal steroid excretion were studied by Connorand associates in six normocholesterolemicprisoners." The mean sterol-balance valuesfor two control periods on a cholesterol-freeliquid-formula diet (fat consisted of cocoabutter), one before and the other after a corn-oil diet, were -783 and -682 mg/day (neutralsteroids corrected for losses of ,B-sitosterol),respectively. Despite marked differences inthe diet, the figures are in good agreementwith the control value of the present study (-777 mg/day). The data did not appear to becorrelated with body weight. Grundy andAhrens`0 23 reported sterol-balance data onformula diets varying in cholesterol, plantsterol, and fat composition, for 15 hyper-cholesterolemic (type II, types as describedby Fredrickson and associates'2 ), one nor-mocholesterolemic, and four hypertriglycer-idemic (three type V and one type IV) sub-jects. The sterol balance ranged from -374to -749 mg/day for hypercholesterolemicsubjects and from -726 to -1833 mg/day for hyperglyceridemic subjects on a for-mula diet containing saturated fat; thedata appeared to bear some relation-ship to body weight. In 43 patients withfamilial hypercholesterolemia, sterol balance,fecal neutral steroids, and bile acids werefound to be correlated with body weight.9 Asin the present investigation, some but not allof the hyperglyceridemic patients exhibited ahigh bile acid production in the studies byGrundy and Ahrens20° 23 and by Kottke .24 Inthe latter series bile acid metabolism wasmeasured isotopically, and a marked interin-dividual heterogeneity in bile acid productionwas observed.Monkey adipose tissue synthesizes choles-
terol in vitro at a rate25 that would accountfor the increment revealed by sterol-balancedata in the obese subjects studied here. How-ever, more recent studies have indicated thathuman and rat adipocytes are not able to con-vert labeled glucose or acetate into cholesterol,and that adipose tissue is only a cholesterol-storage organ that receives its cholesterol fromcirculating lipoproteins or chylomicron.26 The
liver and intestinal mucosa,27 on the other hand,have been shown to be the sites where serumcholesterol is primarily synthesized, which sug-gests that these organs are responsible for theaugmented production of cholesterol in obe-sity. Studies with a labeled acetate-mevalonatemixture also indicated that synthesis wasmarkedly enhanced in obese patients and thatthis stimulation took place between acetateand mevalonate.10 Furthermore, the rapidappearance of newly synthesized radioactivecholesterol in the serum suggested that itoriginated from a rapidly equilibrating choles-terol pool ( s), supposedly situated primarilyin the liver and intestinal wall.27 Hypertriglyc-eridemic (type IV) subjects, who are usuallyobese and whose cholesterol synthesis in thepresent study was only moderately increased,have been shown by Salen et al.28 to have ahigh rate of intestinal cholesterol synthesis.The latter was minimal in hypercholesterol-emic (type II) patients, but it was markedlystimulated by interruption of the enterohepat-ic circulation of bile acids with cholestyra-mine; clofibrate inhibited synthesis in thecholestyramine-treated hypercholesterolemicpatients and in a case with hypertriglycer-idemia.The cholesterol ester turnover is also higher
in obese subjects than in lean ones and issignificantly correlated not only with bodyweight but also with serum cholesterol andtriglyceride concentrations.29 3 Nestel etal.,8 using the two-pool model for calculationof cholesterol metabolism, showed that choles-terol production, which bears no correlationto serum cholesterol, is increased by 22mg/day/kg of excess body weight. This is ingood agreement with the value of 20mg/day/kg obtained in the present study bydrect measurement of the fecal end productsof cholesterol metabolism.
Primarily enhanced elimination of choles-terol from the body, resulting, for instance,from treatment with cholestyramine or froman ileal bypass operation,,3Y is almostalways accompanied by a reduced level ofserum cholesterol. The magnitude of the latteris not correlated with the increment of fecal
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elimination, owing to a compensatory increasein the synthesis and possibly in the mobiliza-tion of tissue cholesterol.31 32 On the otherhand, primarily enhanced synthesis, such asobviously occurs in obesity, can be assumed toincrease the serum cholesterol level in almostevery case, although the magnitude of theincrease is not necessarily correlated with theenhancement of synthesis, because simulta-neous stimulation of cholesterol eliminationprevents this augmentation to an extent whichdiffers from one subject to another. Thiscompensatory increase of elimination isenough to keep the serum cholesterol levellow in some obese patients, while in otherselimination may be more or less defective, sothat hypercholesterolemia results. Thus, thelatter may accompany both reduced andenhanced synthesis; in familial hypercholes-terolemia the primary disorder appears to bedefective elimination of cholesterol, this beingsecondarily associated with a compensatorydecrease in cholesterol synthesis;9' 10, 21 inobesity it is synthesis that is primarilyenhanced, but in some cases augmentation ofelimination is not proportionate and hyper-cholesterolemia results.The variable response of elimination to
enhanced cholesterol synthesis in obesity mayexplain why the serum cholesterol levelusually shows only a weak correlation withbody weight or body fatness.1' 2 However,since obesity is frequent in modern society, itmay, as a potent factor enhancing cholesterolsynthesis, be a very important etiologic factorin hypercholesterolemia and hence in ischemicheart disease, even though, according to themore-recent epidemiologic studies,7 the as-sociation between the latter and obesity isrelatively weak. Weight reduction was ac-companied with a marked decrease in choles-terol synthesis in -the limited number ofsubjects studied. This therapeutic measure, socommonly recommended for prevention andtreatment of hypercholesterolemia and isch-emic heart disease, seems to be a veryeffective procedure as far as reduction ofcholesterol synthesis is concerned. Weightreduction has actually been reported toCirculation, Volume XLIV, Novemnber 1971
decrease the serum choiesterol level in obesesubjects,34 although in the new steady stateinitial values may be resumed.35
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