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Fenofibrate Reduces Low Density
Lipoprotein Catabolism in
Hypertriglyceridemic Subjects
James Shepherd, Muriel J. Caslake, A. Ross Lorimer, Barry D. Vallance,
and Christopher J. Packard
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This study examines the kinetic basis for the increment in plasma low density
lipoprotein (LDL) levels that accompanies the fenofibrate treatment of severely hypertriglyceridemic (HTG) patients. Seven HTG men with a mean plasma triglyceride level
of 1470 mg/dl were treated for 6 weeks. During treatment, their plasma triglyceride
level fell by 77% and their cholesterol level by 41%. The fall in very low density
lipoprotein (VLDL) cholesterol level was reciprocated by increments in the cholesterol
level in both LDL and high density lipoproteins (HDL); the rise in HDL was confined to
HDL3. LDL catabolism was examined before and during therapy using native and
chemically modified tracers in an attempt to distinguish receptor-mediated from nonreceptor-mediated clearance. In their basal state, the hypertriglyceridemic subjects
overcatabolized both the native and the modified lipoprotein, implying that the nonreceptor pathways were hyperactive. The mean fractional clearance rate of LDL via the
receptor pathway was not significantly different from normal. Fenofibrate therapy
corrected the patients' hypercatabolism, reducing the receptor-independent fractional clearance of apo LDL by 50% (from 0.48 to 0.24 pools/day; p < 0.05). The mean
fractional catabolic activity of the receptor route did not change, but when the increment in the plasma apo LDL concentration was taken into account, it was clear that the
drug treatment was associated with an increase in the net amount cleared by the
receptor pathway and with a reduction of lipoprotein uptake into receptor-independent routes. (Arteriosclerosis 5:162-168, March/April 1985)
directly from the plasma,3 while others are remodeled1 to form low density lipoproteins (LDL). Imbalance between synthesis and catabolism in this system may lead to hypertriglyceridemia in which very
low density lipoproteins (VLDL) and possibly also
chylomicrons accumulate in the circulation. In severe cases, there is an associated decrease in circulating LDL and HDL levels. Patients like these have a
high risk of developing acute pancreatitis and therefore merit corrective intervention. The first line of
treatment is dietary modification. Where this fails, the
clinician may decide to initiate lipid-lowering drug
therapy, and among the agents available to him are
the recently introduced clofibrate analogues. They
seem to produce their effects 45 by activating the
enzyme lipoprotein lipase, promoting clearance of
the triglyceride-rich products and often altering the
circulating pools of LDL and HDL 6
We still do not understand why LDL levels are low
in severe hypertriglyceridemia nor why they rise
he metabolism of triglyceride-rich lipoproteins is
a complex process mediated by several enzyme
systems. It appears to occur in two stages.1 The first
involves binding of the particles to lipoprotein lipase
situated on the luminal endothelial surface of capillary beds. The enzyme hydrolyzes the lipoprotein
triglyceride core, releasing redundant surface coat
material which becomes incorporated into high density lipoproteins (HDL).2 The remnants produced by
lipolysis have one of two fates. Some are catabolized
T
From the University Departments of Biochemistry and Medical
Cardiology, Royal Infirmary, and the Department of Medicine,
Hairmyres Hospital, East Kilbride, Glasgow, Scotland.
This work was supported by Grant G 8111558SA from the
Medical Research Council and Grant K/MRS/50/C429 from the
Scottish Home and Health Department.
Address for reprints: Dr. James Shepherd, Department of
Pathological Biochemistry, Royal Infirmary, Glasgow G4 OSF,
Scotland.
Received May 21,1984; revision accepted November 30,1984.
162
FENOFIBRATE AND LDL CATABOLISM
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when treatment is started. These two questions are
addressed in the present investigation. Obviously,
the concentration of any plasma protein is governed
by its relative rates of synthesis and catabolism, and
preliminary studies7 have suggested that grossly hypertriglyceridemic individuals overcatabolize LDL. It
is known that this lipoprotein is cleared by at least
two distinct mechanisms.89 One mechanism is mediated by high-affinity receptors on cell membranes
and is thought to be responsible for the metered
delivery of cholesterol to tissues that need the sterol
for structural and metabolic purposes. When this
process is defective (for example in individuals suffering from familial hypercholesterolemia) more LDL
cholesterol is channelled into the alternative, poorly
regulated receptor-independent routes. Since these
subjects are predisposed to premature and accelerated vascular disease, receptor-independent mechanisms have been implicated in atherosclerosis.10
The relative contribution made by each of these
pathways to LDL catabolism as a whole can be assessed by using chemically modified LDL to trace
the receptor-independent routes. The present report
describes the derangement of LDL catabolism in
grossly hypertriglyceridemic subjects and follows the
response to fenofibrate therapy.1112
Methods
Subjects
Seven hypertriglyceridemic men were selected for
study on the basis of plasma triglyceride levels greater than 400 mg/dl and LDL cholesterol levels less
than 135 mg/dl. All had fasting chylomicronemia on
agarose gel electrophoresis and raised circulating
levels of VLDL as determined by the techniques described in the Lipid Research Clinics Manual of Laboratory Operations.13 None abused alcohol or presented clinical or biochemical evidence of hepatic,
endocrine, renal, or hematologic dysfunction. Specifically, they were neither hyperuricemic nor hyperglycemic (plasma glucose less than 120 mg/dl in the
fasting state). Throughout the study, the subjects
were instructed to eat their normal diet, an arrangement which maintained stable body weight (Table 1).
None was excessively obese or presented evidence
of coronary heart disease (angina at rest or during
exercise or previous myocardial infarction). Only one
subject had eruptive xanthomata.
All drug therapy known to affect lipoprotein metabolism was withdrawn 2 months before the study,
which was conducted in two phases. In the first
phase, plasma lipid and lipoprotein levels and the
turnover of radioiodinated native and chemically
modified LDL were measured. This was repeated in
the second phase, 6 weeks after start of a course of
fenofibrate therapy, given in a dose of 200 mg twice
daily (the fenofibrate was a gift from Nicholas Laboratories, Slough, U.K.). Thyroidal uptake of radioiodide was prevented by administration of Kl (360 mg
Shepherd et al.
163
daily in divided doses) for 3 days before and throughout the turnovers. The experimental protocol was in
accord with the requirements of the Ethical Committee of Glasgow Royal Infirmary, and written informed
consent was obtained from each volunteer.
Turnover Protocol
It is well known14 that LDL, particularly in hypertriglyceridemic subjects, is polydisperse, and therefore
it is inappropriate to use a fixed density interval to
prepare a representative tracer for kinetic studies.
Consequently, we used rate zonal ultracentrifugation to obtain a continuous spectral distribution of the
lipoprotein and permit selection of the major species
for radiolabeling. Fasting plasma from each volunteer was subjected to a preliminary separation in a
Beckman Ti 60 rotor (18 hours, 40,000 rpm, 10°) to
remove the chylomicrons and VLDL. Rate zonal ultracentrifugation of the d> 1.006 kg/liter infranatant
was performed according to the method of Patsch et
al.15 The peak fractions corresponding to the major
LDL species were concentrated by pressure filtration
(Amicon XM 100 filters, Amicon Corporation, Lexington, Massachusetts) to approximately 1.0 mg protein/ml. This was dialyzed extensively against 0.15 M
NaCI/0.01% Na, EDTA/0.01 M Tris HCI (pH 7.4).
Aliquots of the material were labeled separately with
125
I and 131I with the use of iodine monochloride.16
This resulted in incorporation of less than 5% of the
label into material soluble in chloroform/methanol
(1:1, vol/vol). The 13ll-labeled tracer was then treated
with 1,2 cyclohexanedione to block the arginyl residues on its protein moiety and provide a probe suitable for measuring receptor-independent LDL catabolism.1718 The properties of this tracer are
detailed in previous publications.1819 Each subject
received 25 /xCi of his 125l-native LDL and 25 ^iCi of
his 131l-cyclohexanedione-modified LDL by sequential intravenous injection.
A 10-minute blood sample was then collected;
thereafter, fasting plasma specimens were obtained
at daily intervals over the next 14 days. Plasma decay curves of each tracer were analyzed by the procedure of Matthews20 by using a two-compartment
model to obtain fractional clearance rates. The estimation error of these parameters was less than 5%.
On the assumption that the clearance of the modified
lipoprotein describes the activity of the receptorindependent catabolic pathways, receptor activity
was estimated from the difference between the fractional clearance rates of the two tracers.18
Plasma lipid and lipoprotein concentrations were
measured serially on five occasions during each
study phase according to the Lipid Research Clinics
Protocol.13 Additionally, measurements were made
of plasma HDLj and HDL, with an analytical ultracentrifugation technique.2122 At the end of each
study phase, the composition of LDL, isolated by rate
zonal ultracentrifugation, was determined by measuring protein, phospholipid, triglyceride, and free
164
ARTERIOSCLEROSIS VOL 5, No 2,
MARCH/APRIL 1985
Table 1. Effect of Fenoflbrate on the Plasma LIplds and LIpoprotelns of Six Hypertrlglyceridemic Men
Subject
AA
WA
GB
RB
WD
RR
JS
Mean ± SD
p (paired t test)
1140±370 170±35
400±53 180±60
750 ±195 210±20
3250 ±975 295 ±80
1000±20 210±35
1510±415 275 ±125
2230±130 1035 ±205
1470 ±905 335 ±285
Plasma cholesterol
(mg/dl)
Control
Drug
317±12
186+16
221±19
200±19
348±12
225±12
600±108 178±8
259±19
190±8
430±12
263±12
255 ±8
182 + 12
348±120 205 ±27
<0 .02
<0 .05
Plasma triglyceride
(mg/dl)
Weight (kg)
Age
(yr)
Height
(cm)
Control
Drug
40
36
37
38
48
46
67
178
175
172
176
168
175
171
82.6±0.2
74.8 ±0.4
77.1 ±0.3
76.2 ±0.3
60.3±0.1
77.1 ±0.5
66.7±0.1
80.3 ±0.3
73.7 ±0.2
78.3 ±0.2
78.0 ±0.4
60.8 ±0.3
76.7 ±0.2
65.8 ±0.2
Drug
Control
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and esterified cholesterol as outlined elsewhere.23
This information was used to calculate the plasma
LDL apoprotein (apo LDL) pool size by the procedure of Langer et al.24 The absolute rate of apo LDL
catabolism was then obtained from the product of the
fractional clearance rate (in pools/day) and plasma
pool size. Under the steady-state conditions of the
study, this was equal to the synthetic rate of the
apolipoprotein.
Results
Table 1 shows the lipid and lipoprotein profiles of
the subjects during the control and fenofibrate treat-
Table 2. Effects of Fenofibrate on LDL Composition (g/100 g)
Protein
Subject
C
F
Phospholipid
Triglyceride
C
C
F
33.2
36.5
36.9
29.6
32.9
25.1
47.5
30.7
29.3
24.8
27.7
30.6
33.5
47.0
29.2
37.2
±3.4
±6.8
<0 .01
AA
WA
GB
RB
WD
RR
JS
Mean
23.2
21.6
23.6
21.5
24.3
21.9
28.8
24.6
24.2
27.0
21.6
19.8
22.8
27.0
23.2
24.4
±2.1
±2.6
±SD
p (pair difference f test)
F
2.8
1.1
3.4
4.8
4.3
11.7
6.4
±4.2
C
2.2
1.3
1.8
2.5
1.2
3.7
1.5
3.6
2.3
11.9
Cholesteryl ester
Free cholesterol
2.1
5.9
4.4
3.7
3.0
1.8
3.4
±1.4
±1.3
F
F
C
35.2
41.1
38.3
41.7
36.8
43.2
14.5
40.3
30.7
39.8
42.8
43.5
32.1
16.6
30.8
40.1
±9.3
±3.8
<0 .05
2.8
3.1
4.8
3.1
4.7
5.6
3.8
4.1
±1.2
<0 .05
C = control phase; F = fenofibrate phase.
Table 3. Effects of Fenoflbrate on LDL Metabolism
Apo LDL plasma concentration
(mg/dl)
Apo LDL fractional clearance rate (pools/day)
A. Native minus CHD LDL
B. CHD LDL
Subject
Control
Drug
Control
Drug
Control
Drug
AA
WA
GB
RB
WD
RR
JS
Mean ± SD
p (paired ftest)
Reference
values*
71 ±10
82 + 6
46±4
22±2
80±6
70±11
26 + 4
57 ±25
74±5
82±5
92±5
66±3
87±6
81 ±12
58±3
77±12
0.13
0.09
0.27
0.15
0.10
0.26
0.36
0.19±0.10
0.22
0.17
0.18
0.15
0.17
0.21
0.21
0.19 ±0.03
0.35
0.31
0.33
0.90
0.20
0.46
0.84
0.48 ±0.27
0.26
0.25
0.16
0.27
0.18
0.21
0.32
0.24 ±0.06
<0.05
NS
<0.05
95±15
0.16±0. 06
0.19±0.03
"Taken from reference 26.
FENOFIBRATE AND LDL CATABOLISM
Shepherd et al.
165
Table 1. (Continued)
VLDL cholesterol
(mg/dl)
Control
Drug
31 ±4
320±12
54±16
31 ±8
46±4
217±39
542±112 54±4
39±8
101 ±66
70 ±31
290 ±62
108±4
217±8
209±150 54±25
<0. 02
LDL cholesterol
(mg/dl)
Control
Drug
85±16 100±12
124±12 120±8
70±19 132±12
35±1
85±8
70±12 100±10
120±27 135±27
21 ±1
50±8
74 ±35 104±27
<CI.02
HDL cholesterol
(mg/dl)
Control
Drug
54±3
39±6
58±4
46 + 4
46±4
39±1
43±1
22±5
46±14
35±3
77 ±2
46±1
23±11
19±1
35±12 50±16
<0 .01
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ment phases of the study. The drug affected all lipoprotein fractions in the plasma. Triglyceride levels fell
77% on average and there was a corresponding reduction in VLDL cholesterol (p < 0.02). This major
decrease in the circulating mass of triglyceride-rich
lipoproteins evoked reciprocal changes in the cholesterol-rich particles LDL and HDL. LDL cholesterol
increased from a subnormal value of 74 mg/dl into
the low normal range (p < 0.02). HDL cholesterol
also rose by about 40% (p < 0.01) so that the
LDL/HDL cholesterol ratio in the plasma was unchanged. Analytical ultracentrifugation revealed that
the increment in the high density fraction was confined to HDL3; the HDLj, which was initially low in
plasma concentration, remained unchanged.
Detailed analysis was made of the effects of treatment on LDL composition (Table 2) and on apo LDL
kinetics (Table 3). Before treatment, the LDL particles in these grossly hypertriglyceridemic subjects
were depleted in esterified cholesterol and relatively
enriched in triglyceride. Drug therapy, in addition to
raising the plasma LDL cholesterol concentration,
also perturbed the composition of the particles. Their
cholesteryl ester content rose 30% (p < 0.05), while
triglyceride fell approximately 60% (p < 0.05) as one
HDL3 mass
(mg/dl)
HDL2 mass
(mg/dl)
Control
Drug
8±1
25±11
10±8
26±10
44±13
36±10
21 ± 6
24±12
28±5
30±4
17±4
18+10
49±9
28±1
8±6
25±12
Control
Drug
161 ±51 273 ±30
240 ±31 262 ±34
133±17 228 ±30
114±21 241 ±14
157±22 183±16
238 ±28 323 ±21
90 ±24
63±19
162±54 225 ±77
<0 .05
NS
lipid presumably replaced the other in the hydrophobic core. In spherical particles like LDL, the ratio of
core to coat components (cholesteryl ester + triglyceride)/(phospholipid + protein) is an indicator of
size.25 Treatment with fenofibrate reduced the particles' coat phospholipid content by 22% (p < 0.01)
and increased the above ratio from 0.62 to 0.79.
Thus, therapy presumably enlarged the average
LDL particle size.
Only part of the rise in plasma LDL cholesterol was
due to the compositional changes seen in Table 2.
Apo LDL kinetics were also affected, leading to an
increment in the circulating mass of the lipoprotein
(Table 3). Fenofibrate therapy increased the apo
LDL concentration in the plasma by an average of
35% (p < 0.05), although there was variability within
the group. Patient WA, whose initial apo LDL concentration was near normal, showed no change in
this parameter, although there was a 300% increase
in RB, the patient who showed the greatest response
to therapy.
When the steady-state synthetic rate of apo LDL
was calculated, it was normal in the basal phase and
remained unaffected by fenofibrate treatment.28
Consequently, we expected that catabolism would
Table 3. (Continued)
Apo LDL absolute catabolic rate (mg/kg/day)
A. Nativei minus CHD LDL
B. CHD LDL
Apo LDL synthetic rate (mg/kg/day)
Control
Drug
Control
Drug
Control
Drug
3.7
3.1
5.0
1.3
3.2
7.3
3.8
3.9 ±1.9
6.6
5.6
6.6
3.9
5.9
6.8
4.9
5.8±1.1
9.9
10.8
6.1
8.1
6.4
12.8
8.8
9.0 ±2.4
7.7
8.2
5.9
7.1
6.3
6.8
7.5
7. 1 ±0.81
13.6
13.9
11.1
9.4
9.6
20.1
12.6
12.9 ±3.6
14.3
13.7
12.5
11.1
12.2
13.6
12.4
12.8+1.1
<0.05
<0.05
NS
6.0 ±1.2
7.7±1.7
13.3± 1.2
166
ARTERIOSCLEROSIS VOL 5, No 2,
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explain the changes in LDL. Before therapy, the
mean apo LDL total fractional clearance rate in the
subjects was about twice normal, although the values for this parameter varied over a fourfold range. In
general, a low plasma apo LDL pool was associated
with a high catabolic rate.
We used chemically modified (receptor-blocked)
LDL in an attempt to uncover the mechanism responsible for the hypercatabolism. On the assumption that 1,2 cyclohexanedione-treated LDL traces
the activity of pathways which do not involve the high
affinity receptor, it was possible to calculate18 the
contributions made by the receptor and nonreceptor
routes in these subjects. In the basal state the average fractional clearance rate of the lipoprotein via its
high affinity receptor was normal. Conversely, in only
one subject was the clearance rate by nonreceptor
mechanisms comparable to values obtained in normal individuals in our laboratory (Table 3). On average, it was increased 2.5-fold.
Fenofibrate therapy did not change apo LDL fractional catabolism via the receptor pathway but did
reduce the activities of the alternate mechanisms to
normal. So, in the group as a whole, the increase in
plasma apo LDL concentrations that followed fenofibrate therapy arose from the suppression of the receptor-independent catabolism. Since, as was noted
earlier, the turnover rate of the apoprotein (in
mg/kg/day) did not change, there apparently was a
redistribution of the amounts channeled into each
pathway during therapy. Table 3 shows that the absolute amount of LDL cleared by the receptor route
increased significantly and that concomitantly there
was a fall in that component handled by other, receptor-independent mechanisms.
Discussion
In severely hypertriglyceridemic subjects, plasma
LDL characteristically is low in concentration and abnormal in composition 627 (Tables 1 and 2). It has
been suggested28 that the reduced plasma level of
LDL derives from a defect in its synthesis from precursor VLDL. However, the present investigation
and earlier data from Sigurdsson et al.7 do not support this view, but show that apo LDL production
rates are normal. Rather, hypercatabolism is responsible for the effect. In theory, either the receptor pathway, or alternative mechanisms, or both might contribute to this effect and it is now possible to assess
the relative activities of each by using an LDL tracer
modified to inhibit the tracer's interaction with the
high affinity receptor on cell membranes. In this
study, we chose 1,2 cyclohexanedione as the modifying agent. This probe has been characterized elsewhere.18' 19 It gives the same value for receptor-independent LDL catabolism as lysine-modified,
hydroxyethylated LDL in normal individuals29 and as
glycosylated LDL in heterozygous familial hypercholesterolemic subjects.1830 Its use here suggested
that our severely hypertriglyceridemic patients over-
MARCH/APRIL 1985
catabolized LDL as a result of the hyperactivity of
their receptor-independent pathways; the mean
fractional clearance by the receptor route was normal (Table 3).
Therefore, in these patients the balance between
the activities of both catabolic routes was deranged
so that the uptake of lipoprotein into the nonreceptor
pathway was disproportionately high. The factor(s)
responsible for the increment in receptor-independent LDL catabolism are not known and, indeed,
the mechanisms and tissues involved in the normal
operation of the pathway are not established. Certainly, pinocytosis makes a contribution, but this is
probably small. In a previous study,31 we suggested
that the monocyte-macrophage system may play an
important part. In support of this view, Ginsberg and
his colleagues32 showed that clearance of LDL by the
nonreceptor pathway is accelerated in patients with
myeloproliferative disorders. Since grossly hypertriglyceridemic subjects commonly exhibit hepatosplenomegaly, it is tempting to speculate that an increase in LDL catabolism by the reticuloendothelial
cells of these organs may be partly responsible for
the low levels of the lipoprotein circulating in the
bloodstream of these patients.
The above changes in LDL metabolism seen in
hypertriglyceridemic patients are accompanied by
significant alterations in the composition of the particles6' M which become smaller, denser, and enriched
in triglyceride relative to cholesteryl ester (Table 2).
The mechanisms responsible for these effects are
not yet established, although it has been suggested
by Deckelbaum and his colleagues27 that these effects are caused by the combined actions of cholesteryl ester transfer protein and plasma lipases.
These authors envisage that in the presence of a
large circulating mass of triglyceride-rich lipoproteins, the distribution of neutral lipid within the lipoprotein spectrum is distorted so that VLDL becomes
relatively cholesteryl ester-enriched by changing a
component of its hydrophobic triglyceride core into
LDL and HDL. The triglyceride content of the latter is
thereby enhanced, so that both become better substrates for lipase which shrinks them to particles of
smaller than normal size.
Recent studies33 have indicated that low lipoprotein lipase activities may be crucial to the development of severe hypertriglyceridemia in nonobese
subjects. This primarily results in high plasma concentrations of VLDL and chylomicrons, even after an
overnight fast, but clearly the other lipoproteins in the
bloodstream are also affected. If the perturbation in
LDL and HDL is secondary to altered VLDL metabolism, a reduction in the level of plasma triglyceride
and VLDL should restore to normal both the composition and metabolism of these denser lipoproteins.
The clofibrate analogues are potent stimulators of
lipoprotein lipase activity4 and these analogues markedly reduced triglyceride and VLDL levels in hypertriglyceridemic subjects (Table 2). Simultaneously,
both the composition (Table 2) and metabolism of
FENOFIBRATE AND LDL CATABOLISM
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LDL (Table 3) reverted to normal. The cholesterol/triglyceride and cholesterol/protein ratios in the particle increased during fenofibrate therapy, as did the
ratio of core/coat components, an index of the particle's size. Additionally, both the fractional and absolute amounts of LDL that were cleared into the receptor-independent pathways fell to values approaching
those found in normal subjects28 and so, in the face
of maintained synthesis, the plasma LDL concentration rose. Concomitantly, there was a significant increment in the amount of LDL cleared into the receptor route. This usually implies an expanded cellular
requirement for cholesterol and is consistent with the
finding that fenofibrate inhibits the action of 3-hydroxy-3-methylglutaryl CoA reductase34 and therefore presumably suppresses endogenous sterol synthesis. The response of the receptor pathway to
fenofibrate therapy is similar to that which we observed35 in a group of Type II hyperiipoproteinemic
subjects prescribed an alternative clofibrate analogue, bezafibrate.
It should be noted that interpretation of our observations on these grossly hypertriglyceridemic subjects is based on our previous experiences with 1,2
cyclohexanedione-treated LDL in normal and hypercholesterolemic individuals. It is possible that the abnormal structure of LDL in the present group may
produce aberrant behavior of the chemically modified probe. So, mechanisms other than hyperactivity
of receptor-independent pathways may be responsible for the observed rapid catabolism of the cyclohexanedione-treated tracer. These mechanisms include the incomplete receptor-blocking of the
hypertriglyceridemic LDL and the generation of a
probe that is recognizably different from normal to
receptor-independent pathways.
Many of the chlorophenoxyisobutyric acid derivatives increase plasma HDL levels in humans, and
Table 1 shows that fenofibrate produced the same
effect. On average, HDL cholesterol rose by 42% (p
< 0.01) in the seven hypertriglyceridemic subjects
as a result of an increase in plasma HDL,. HDL,,
which was originally low in these patients, was not
affected by the drug. Although the kinetic changes
responsible for these effects were not measured, it is
possible to make inferences from an earlier study36
designed to examine the influence of nicotinic acid
on HDL metabolism in Type IV hyperiipoproteinemic
subjects. In that situation, HDLj rose after a decrease in the fractional clearances of both A apolipoproteins. By extrapolation, it may be that fenofibrate
decreases the catabolism of not only of LDL but also
of HDL in our hypertriglyceridemic individuals. Certainly, evidence from the literature37'M would indicate
that the catabolism of LDL and HDL are linked in
some obscure way so that the clearance rates of
both fractions respond to metabolic perturbations in
concert.
In a previous publication35 we proposed that the
primary action of clofibrate and its analogues can be
adequately explained on the basis of their effects on
Shepherd et al.
167
two key enzymes in lipoprotein metabolism — lipoprotein lipase and 3-hydroxy-3-methylglutaryl CoA
reductase. The results of the present study remain
consistent with that view and provide a working
hypothesis to explain the actions of these drugs in
the treatment of the various hyperlipoproteinemias.
Acknowledgments
We thank Linda Coyle and Ann McKinnon for excellent secretarial assistance.
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• lipid-lowering drugs
Fenofibrate reduces low density lipoprotein catabolism in hypertriglyceridemic subjects.
J Shepherd, M J Caslake, A R Lorimer, B D Vallance and C J Packard
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Arterioscler Thromb Vasc Biol. 1985;5:162-168
doi: 10.1161/01.ATV.5.2.162
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