© 1995 American Heart Association, Inc.
Articles |
Effects of Different Phenotypes of Hyperlipoproteinemia and of Treatment With Fibric Acid Derivatives on the Rates of Cholesterol 7
-Hydroxylation in Humans
From the Departments of Internal Medicine and Chemistry (A.P.), University of Modena, Italy.
Correspondence to Marco Bertolotti, MD, Istituto di Patologia Medica, Policlinico, Via del Pozzo, 71, 41100 Modena, Italy.
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Abstract |
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Abstract Little is known about the relationships between hyperlipidemia and bile acid metabolism. However, hypolipidemic treatment with fibric acid derivatives has been shown to increase biliary cholesterol secretion, presumably by reducing bile acid synthesis. To clarify such relationships, we investigated the effects of different hyperlipoproteinemic conditions and of treatment with fibric acid derivatives on the rates of cholesterol 7
-hydroxylation (the limiting step of bile
acid synthesis) in humans. We studied 10 patients (aged 36 to 68 years)
with lipoprotein phenotype IIa and with a clinical diagnosis of
heterozygous familial hypercholesterolemia, a condition
of reduced activity of LDL receptors, and 11 patients (aged 48 to 70
years) with lipoprotein phenotype IIb or IV and clinical
diagnosis of familial combined hyperlipidemia, a
condition probably related to increased hepatic lipoprotein synthesis.
Cholesterol 7-hydroxylation rates were assayed in
vivo by tritium release assay after an intravenous
injection of [7-3H]cholesterol. The
results were compared by ANOVA to the values obtained in a group of 28
normolipidemic patients (aged 34 to 83 years), with age as the
covariate. Six patients were also studied after treatment with
gemfibrozil (900 to 1200 mg/d for 6 to 8 weeks) and 5 patients were
studied after treatment with bezafibrate (400 mg/d for 6 to 8 weeks).
Hydroxylation rates were 0.82±0.22 mmol/d in the familial
hypercholesterolemia group and 1.30±0.47 mmol/d in the
familial combined hyperlipidemia group
(P<.05 between the two groups and between patients with
familial combined hyperlipidemia and control subjects;
P=NS between patients with familial
hypercholesterolemia and control subjects, as
determined by ANOVA). Treatment with both gemfibrozil and bezafibrate
reduced serum cholesterol, slightly increased HDL
cholesterol, and significantly reduced serum
triglyceride and apo B concentrations.
Cholesterol 7-hydroxylation rates were significantly
reduced by nearly 55% both after gemfibrozil and after bezafibrate.
Our findings indirectly suggest that cholesterol
degradation to bile acid is independent of receptor-mediated uptake of
LDL by the liver. Hydroxylation rates seem to parallel serum levels of
triglyceride and apo B (particularly after fibrate
treatment), possibly suggesting a coordinate regulation of bile acid
and lipoprotein synthesis.
Key Words: familial hypercholesterolemia • familial combined hyperlipidemia • bile acid synthesis • gemfibrozil • bezafibrate
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Introduction |
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Cholesterol degradation to bile acids is a key event in the maintenance of cholesterol homeostasis in the liver and in the whole body.1 2 The rate-limiting step of the overall synthetic pathway is cholesterol 7
-hydroxylation; this
reaction is catalyzed by a microsomal enzyme, cholesterol
7-hydroxylase,3 and its rate appears to be regulated
mainly by feed-back inhibition exerted by hydrophobic bile acids
recirculating to the liver.4 5 Such regulation is
currently accepted to take place mainly at the level of gene
transcription.2 4 However, relatively little is known
about other aspects of cholesterol 7-hydroxylase regulation, such as
the role of the availability of intracellular free
cholesterol.2 4
Spontaneously occurring hyperlipidemias provide an interesting model to
investigate some of these issues. Familial hypercholesterolemia
(FH),6 7 in which the expression of receptors for apo B
and apo E (LDL receptors) is reduced,8 is accompanied by
decreased internalization of LDL cholesterol by means of the
receptor-mediated pathway; this condition might theoretically reduce
the availability of free cholesterol for further catabolization to bile
acid. The possibility of a preferential channeling of cholesterol
uptake by means of LDL receptors towards bile acid synthesis is
suggested by the fact that treatments primarily increasing bile acid
synthesis (eg, cholestyramine5 ) seem to upregulate LDL
receptor expression,9 whereas treatment with
chenodeoxycholic acid, which inhibits cholesterol
7-hydroxylation,5 is associated with increased serum
levels of LDL cholesterol,10 suggesting reduced LDL
receptor expression. Such findings support the view that internalized
LDL cholesterol and cholesterol recruitable for degradation to bile
acids belong to a common regulatory pool.
Other hyperlipidemic conditions may prove interesting from different points of view. Familial combined hyperlipidemia (FCH) is a condition characterized by the presence of multiple lipoprotein phenotypes (IIa, IIb, IV) among first-degree relatives or in the same subject on different occasions.7 11 12 13 Even though the underlying metabolic defect has not yet been fully elucidated, the rate of synthesis of VLDL apo B appears to be elevated in such patients, particularly in those with hypertriglyceridemia (phenotypes IIb and IV).14 15 Because hyperproduction of bile acids is a common finding in hypertriglyceridemic subjects,16 one might consider the possibilities of altered bile acid synthesis in patients with FCH who have the hypertriglyceridemic phenotype and of a coordinate regulation between production of bile acids and lipoprotein lipid and/or apoprotein in this disease.
Treatment with fibric acid derivatives, which are currently used as hypolipidemic agents,17 18 especially in conditions in which hypertriglyceridemia predominates, was consistently found to increase biliary cholesterol secretion and saturation,19 20 21 22 probably because of inhibition of bile acid synthesis. The finding has obvious implications with respect to the occurrence of cholesterol gallstones, and again suggests the possibility of a coordinate suppression of bile acid and lipoprotein production.
To examine possible regulatory effects on bile acid synthesis, we
undertook a series of studies to evaluate the rates of cholesterol
7-hydroxylation in vivo in patients with a clinical diagnosis of
heterozygous FH and in patients with a clinical diagnosis of FCH who
had the hypertriglyceridemic phenotype; furthermore, we looked at the
effects of two different fibric acid congeners,
bezafibrate23 (a typical fibric acid derivative) and
gemfibrozil24 (a structurally unrelated drug with
analogous pharmacological properties), on 7-hydroxylation rates.
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Methods |
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Patients
Twenty-one hyperlipidemic patients were studied. Their main clinical data are shown in the Table
. Ten of
them (patients 1 through 10) had primary isolated
hypercholesterolemia and lipoprotein phenotype
IIa; diagnosis of heterozygous FH was suggested by clinical features as
well as personal and family history.6 7
Diagnostic criteria included (1) elevated plasma total and
LDL cholesterol in the patient and in approximately 50% of
first-degree relatives and (2) presence of tendon xanthomas or
xanthelasma and corneal arcus, or manifestations of premature
arteriosclerosis, in the patient or first-degree
relatives.
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Eleven patients (subjects 11 through 21) had primary hypertriglyceridemia, with or without hypercholesterolemia (lipoprotein phenotypes IIb or IV), and with clinical and anamnestic features supporting a diagnosis of FCH.11 13 15 Diagnostic criteria included (1) elevated apo B levels, (2) presence of hyperlipidemia in approximately 50% of first-degree relatives (with at least one relative having hypercholesterolemia in the cases of patients with phenotype IV), and (3) premature arteriosclerosis in the patient or first-degree relatives.
Patients were admitted to the Department of Medicine of the University
of Modena as inpatients or day-hospital patients. All subjects were in
good general conditions and were nonobese. None was taking drugs
known to affect lipid metabolism. Clinical and laboratory
evaluation could rule out diabetes and alterations of hepatic,
intestinal, and thyroid function. Patients were instructed to follow a
hypolipidemic isocaloric diet adequate to maintain a constant body
weight. Evaluation of cholesterol 7-hydroxylation rates
was performed for the first time 4 to 8 weeks after initial evaluation.
Patients gave their consent to the design of the study, which was
approved by the Ethical Committee of the University of Modena.
In 6 patients (8, 12, 13, 14, 16, and 17) a study was performed after 6 to 8 weeks of treatment with gemfibrozil; the drug was taken, either as tablets or in granular form, as a daily dose of 1200 mg in two administrations (patient 13) or as a single bedtime dose of the 900-mg sustained-release preparation (patients 8, 12, 14, 16, and 17) (Lopid and Lopid TC, respectively; Parke Davis). Five patients (12, 18, 19, 20, and 21) were studied after 6 to 8 weeks of treatment with equipotent doses of bezafibrate administered as a 400-mg tablet of the sustained-release preparation (Bezalip Retard, Boehringer Mannheim Italia) as a single bedtime dose. Patient 12 was studied first during gemfibrozil treatment, then without treatment, and finally after bezafibrate. In the remaining patients the studies without and during drug treatment were randomly sequenced.
Laboratory Methods
[7-3H]Cholesterol (specific
activity, 3 to 10 mCi/mmol) was synthesized as
described.25 26 Cholesterol 7-hydroxylation
rates were assayed in vivo by tritium release assay, according to a
technique already validated both in vitro27 28 and in
vivo.5 26 Trace amounts of
[7-3H]cholesterol (200 to 350 µCi) were
dissolved in ethanol and then in 50 mL human albumin or
polygelin and subsequently injected intravenously after the
subjects had fasted overnight. Blood or urine samples were drawn at
fixed intervals after tracer administration for 5 to 6 days.
Because cholesterol 7-hydroxylation is a stereospecific
reaction, the amount of tritium released from the 7 position of the
molecule and joining the body water pool as [3H]water
reflects the extent of the 7-hydroxylation reaction. Erythrocyte or
urine samples underwent distillation, and aliquots of the distilled
water were assayed for radioactivity by liquid scintillation counting.
Serum was analyzed for the determination of plasma
cholesterol–specific activity after extraction, measured
as the radioactivity/mass ratio. The rates of cholesterol
7-hydroxylation were calculated as the ratio between the increment
of body water radioactivity in a fixed time interval (usually 60 to 72
hours after tracer) and the mean specific activity of serum
cholesterol in the same time interval. Total body water
volume was assumed to equal 60% of body weight, normalized to 70 kg. A
final correction was made to account for the degree of
stereospecificity of the label on the 7 position,26
which averaged 75% to 80% in the present study. Hydroxylation
rates were expressed as the amount of cholesterol
undergoing 7-hydroxylation per day.5 26 29
Hydroxylation rates assayed by means of the present technique
proved to correlate well with the values of total bile acid synthesis,
estimated by isotope dilution, in different
pathophysiological conditions.30
Routine laboratory evaluation was performed by automated analysis. Cholesterol and triglyceride concentrations were determined by enzymatic assay, and serum levels of apo B and apo A-I were assayed by radial immunodiffusion. Lipoprotein cholesterol was determined in the different density fractions by sequential ultracentrifugation of serum.
Statistical Evaluation
Data were expressed as mean±SD and the significance of
differences was evaluated according to Student's t test for
paired or independent data, as appropriate. Because
cholesterol 7-hydroxylation rates decrease with
aging,29 we planned to perform statistical
analysis to rule out the possible confounding effects of age in
the evaluation of differences between different patient groups.
Analysis was performed by ANOVA with age as the covariate, and
the values in the two groups of hyperlipidemic patients
were compared with each other and with previously published results
from a group of normolipidemic subjects with a wide age range (34 to 83
years).29 The equation of the regression line of
cholesterol 7-hydroxylation rates (expressed as mmol/d)
plotted versus age (years) in these subjects was
y=1.86-0.016x.29
Statistical analysis was conducted with the SPSS/PC statistical package on an IBM PS2 workstation. Significance was accepted for P<.05.
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Results |
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Cholesterol 7
-hydroxylation rates were 0.82±0.22
mmol/d in the FH group and 1.30±0.47 mmol/d in the FCH group
(P<.05 between the two groups, Student's t test
for independent data). When the values obtained in the two groups were
superimposed against the plot of 7-hydroxylation versus age for
normolipidemic subjects (Fig 1), a statistically
significant difference was detected by ANOVA among all groups (F=5.51,
P<.05), between patients with FCH and control subjects
(F=6.27, P<.05), and between patients with FH and patients
with FCH (F=7.53, P<.05). No difference was detected
between patients with FH and control subjects (F=1.47,
P=NS).
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) and in 11 subjects
with familial combined hyperlipidemia (FCH; 
) are
shown. Larger circles with error bars indicate mean±SD. The data were
superimposed against the regression line, with 95% confidence limits
(broken lines), calculated from the values of cholesterol
7
Fig 2 shows the effects of treatment with gemfibrozil or
bezafibrate on serum lipid levels and serum apo B in the subjects
studied.
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After gemfibrozil treatment, total cholesterol decreased from 6.54±0.75 mmol/L (253±29 mg/dL) (basal value) to 5.84±0.98 mmol/L (226±38 mg/dL) (P=NS, Student's t test for paired data). Total triglycerides decreased from 2.07±0.50 mmol/L (183±44 mg/dL) to 1.32±0.45 mmol/L (117±40 mg/dL) (P<.05) and HDL cholesterol increased slightly from 1.19±0.23 mmol/L (46±9 mg/dL) to 1.34±0.28 mmol/L (52±11 mg/dL) (P=NS). Serum apo B levels decreased significantly from 193±23 mg/dL to 140±42 mg/dL (P<.05).
After treatment with bezafibrate, total cholesterol was significantly reduced from 7.99±0.88 mmol/L (309±34 mg/dL) to 6.28±0.75 mmol/L (243±29 mg/dL) (P<.05). Triglycerides decreased from 2.32±1.04 mmol/L (205±92 mg/dL) to 1.31±0.55 mmol/L (116±49 mg/dL) (P<.05) and HDL cholesterol increased from 1.19±0.13 mmol/L (46±5 mg/dL) to 1.42±0.21 mmol/L (55±8 mg/dL) (P<.05). Serum apo B levels were significantly reduced from 198±25 mg/dL to 136±30 mg/dL (P<.05).
Serum levels of LDL cholesterol and VLDL cholesterol essentially paralleled those of total cholesterol and total triglycerides, respectively (data not shown), whereas the levels of apo A-I were increased, but not significantly, by either treatment (without gemfibrozil, 128±19 mg/dL; during gemfibrozil, 139±14 mg/dL; without bezafibrate, 137±8 mg/dL; during bezafibrate, 142±15 mg/dL).
Fig 3 shows the effects of gemfibrozil and bezafibrate
on cholesterol 7-hydroxylation rates.
Cholesterol 7-hydroxylation was significantly decreased
by an average of 57% after treatment with gemfibrozil (0.46±0.26
mmol/d with gemfibrozil treatment and 1.07±0.41 mmol/d with no
treatment; P<.05). Similarly, bezafibrate treatment
decreased 7-hydroxylation rates by 55% (0.74±0.27 mmol/d with
bezafibrate treatment and 1.63±0.48 mmol/d with no treatment;
P<.05).
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Discussion |
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The first set of studies was done to determine the possible effect of hyperlipidemic conditions on cholesterol 7
-hydroxylation, the limiting step of bile acid synthesis. Reduced
internalization of LDL cholesterol by defective receptors
in patients with FH might theoretically lead to reduced substrate
availability for bile acid formation. As shown in the present
study, this does not seem to be the case because 7-hydroxylation was
not significantly affected. Our findings are in agreement with data
obtained by use of isotope dilution to evaluate bile acid synthesis in
subjects with heterozygous FH31 ; furthermore, the
evidence, although scarce, from subjects with homozygous FH seems to
rule out a reduction of bile acid synthesis in such
patients.32 33 The fact that defects in bile acid
metabolism have been detected in particular subsets of
patients with FH34 might in any case suggest a certain
degree of inhomogeneity in FH in this respect. Thus, even if changes in bile acid production may affect LDL receptor expression,9 10 the opposite does not seem to take place, indicating that cholesterol degradation to bile acids does not depend on a normal function of LDL receptors. It was previously shown that hepatic uptake of LDL cholesterol by means of the receptor-independent pathway is markedly increased in the Watanabe heritable hyperlipidemic rabbit, an animal model of homozygous FH, leading to an internalization of even higher than normal amounts of LDL cholesterol.35 This mechanism might also ensure the availability of a sufficient amount of cholesterol for metabolic purposes when the LDL receptor pathway is impaired. Intake of chylomicron remnant cholesterol of alimentary origin might be another mechanism helping to maintain normal or high intrahepatic cholesterol levels.
However, FCH with the hypertriglyceridemic
phenotype, a condition associated with increased lipoprotein
and apo B production, was shown to be accompanied by a
significant increase in cholesterol 7-hydroxylation
rates. In previous studies, bile acid synthesis was shown to be
markedly increased in isolated
hypertriglyceridemia,16 36
whereas a lesser, not significant increase was found in combined
hyperlipidemia (phenotype IIb).36
Similarly, in another study the rates of bile acid synthesis evaluated
by isotope dilution in patients with a diagnosis of genetic
hypertriglyceridemia were found to be
significantly higher than normal in those with familial
hypertriglyceridemia, and were only
slightly elevated in those with FCH.37 The finding led the
authors of the latter study to hypothesize a coordinate regulation of
the rate-limiting enzymes of bile acid and triglyceride
synthesis; abnormal upregulation of this control system would in turn
be responsible for the changes observed in familial
hypertriglyceridemia. In a recent report
from our laboratory a significant correlation between
7-hydroxylation rates and serum triglyceride levels was
detected in normolipidemic subjects of different ages,29
indirectly supporting this view.
The present findings describe a significant increase of bile acid synthesis in patients with FCH when the results are evaluated with the interfering effect of age taken into account; this is at partial variance with the previously reported evidence, even if in absolute terms the rates of bile acid synthesis are only slightly higher compared with those observed in patients with the IIb phenotype36 and with FCH.37 Assuming that increased apo B production is the metabolic basis for the alterations observed in FCH, our data would also suggest a possible coordinate regulation between bile acid synthesis and hepatic production of apo B.
The findings on the effects of fibric acid derivatives are consistent with this view. The pharmacological effects of fibrates are not completely understood: activation of peripheral lipoprotein lipase is certainly the best characterized mechanism responsible for the reduction in serum lipids and for the increase in HDL cholesterol; in addition, an important role could be played by reduced hepatic synthesis of lipoprotein, as suggested,17 18 24 and in particular by decreased hepatic VLDL apo B production.38
However, an increase in biliary cholesterol secretion and
saturation has consistently been described with such
drugs.19 20 21 22 Little is known about the effects of fibrates
on bile acid production in human subjects, even if a reduction
might be expected from the data on cholesterol saturation.
Previous evidence with clofibrate, the oldest fibric acid derivative to
be used, showed a decrease of cholic acid synthesis in
vivo.39 40 Indirect data obtained by quantitation of fecal
acidic sterol output showed a decrease after treatment with
gemfibrozil20 41 ; likewise, preliminary in vitro findings
suggest a significant decrease of microsomal 7-hydroxylase activity
after treatment with bezafibrate.42
The present data show the first direct evidence of a significant
decrease in cholesterol 7-hydroxylation rates in vivo
after treatment with gemfibrozil and with bezafibrate. The fact that
both drugs suppressed hydroxylation rates by the same order of
magnitude (about 55%) appears to suggest a similar pharmacological
effect of both compounds at the level of hepatic
cholesterol balance. Such a marked reduction in the
limiting step of bile acid synthesis might reasonably account for an
increased availability of intracellular free cholesterol
recruitable for biliary secretion and, therefore, for the observed
changes in biliary saturation. Clearly, the mechanism whereby fibric
acid derivatives inhibit cholesterol 7-hydroxylation
cannot be speculated upon on the basis of the results of the
present study; transcriptional regulation of enzyme activity, as
well as posttranscriptional effects involving membrane interaction,
might be hypothesized.
In our patients, gemfibrozil and bezafibrate exerted similar effects on
plasma lipid and apolipoprotein concentrations; bezafibrate had a more
potent hypocholesterolemic effect, in agreement with
previous evidence,18 and increased HDL
cholesterol more markedly. At any rate the most
consistent and significant alterations were decreases in serum
triglyceride and apo B levels. Such changes, paralleling
the inhibitory effect on cholesterol
7-hydroxylation, again support the occurrence of a coordinate
regulation between the synthesis of bile acids and the hepatic
production not only of triglycerides, but also of
apo B to be incorporated into lipoprotein.
From the present series of data, coordinate regulation of gene
expression and/or specific activity of cholesterol
7-hydroxylase and of the enzyme limiting triglyceride
synthesis,37 and possibly of synthesis of apo B itself in
the liver, can therefore be expected, both in spontaneous conditions
(FCH) and after pharmacological treatment. Further studies on the
molecular levels of regulation of enzyme activity and apolipoprotein
production might provide a
pathophysiological basis for these findings.
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Acknowledgments |
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This work was partly supported by research funds of the University of Modena (MURST 60%).
Received February 13, 1995; accepted April 6, 1995.
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