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Original Studies |
Departments of Medicine (E.R.C., M.H.C., E.A., A.M.A., M.A.B., P.H.S., D.L.R.-J.) and Chemical Pathology (P.J.L., A.S.W.), St. Thomas’ Hospital, and the Medical Research Council Lipoprotein Team, Hammersmith Hospital, Clinical Sciences Center (R.P.N.), London, United Kingdom SE1 7EH
Address all correspondence and requests for reprints to: Dr. E. Christ, Department of Diabetology and Endocrinology, 44th floor, bâtiment de liaison, Hôpital Universitaire de Genève, CH 1211 Genèva 14, Switzerland. E-mail: EmanuellChrist{at}hcuge.ch
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Plasma lipid concentrations are dependent on the secretion and clearance rate of the apolipoprotein B (apoB)-containing lipoproteins [very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and LDL]. As VLDL apoB is the precursor of IDL and LDL apoB, lipid kinetics are dependent on VLDL apoB metabolism. Hepatic overproduction of VLDL apoB has been implicated in a number of hyperlipidemic disorders known to be related to premature atherosclerosis (8, 9, 10, 11). Adults with GH deficiency have an increased hepatic secretion rate and a reduced catabolism of VLDL apoB compared to age-, sex-, and body mass index (BMI)-matched control subjects (12), suggesting that the hyperlipidemic condition of these patients and consequently the increased risk for atherosclerosis may be in part related to a disordered VLDL apoB metabolism.
GH has important effects on intrahepatic substrate availability (i.e. TG and cholesterol esters), the most important determinant of VLDL apoB secretion (13, 14). Its lipolytic effect by stimulating hormone-sensitive lipase and possibly a decreased in situ reesterification of FFA in the peripheral tissues leads to an increase in nonesterified free fatty acid (FFA) flux to the liver and, hence, by increased hepatic esterification to an increase in intrahepatic TG and cholesterol esters (15). This, in turn, may stimulate VLDL apoB secretion.
The clearance of VLDL apoB depends partly on the activity of lipoprotein lipase (LPL), which hydrolyzes TG and promotes the formation of TG-depleted apoB particles: IDL and LDL. Evidence concerning the effect of GH on LPL is contradictory. GH increases total postheparin LPL activity in rats (16), but in humans GH appears to reduce total plasma postheparin LPL (17) and adipose tissue LPL activity (18). In addition, VLDL apoB clearance may be influenced by the removal of partially TG-depleted VLDL particles via the LDL receptor, LDL receptor-related protein (LRP), or the recently described VLDL receptor pathway (19). In humans, the expression of the hepatic LDL receptor is enhanced by GH treatment (20), whereas the effects of GH on LRP and VLDL receptor are not known.
In hypophysectomized rats, GH replacement therapy stimulates the secretion of VLDL particles that are rapidly cleared without entering the delipidation cascade (15). The underlying mechanism appears to be an increased hepatic production of apoB48 and apoE, which are known to promote direct VLDL clearance (15). In humans, unlike rats, apoB48 originates entirely from the gut. It is as yet unknown whether the proposed effects of GH on lipoprotein metabolism in rats apply to humans. Using a stable isotope method, we aimed, therefore, to investigate VLDL apoB kinetics in adults with GH deficiency before and after 3 months of GH replacement therapy in a randomized, double blind, placebo-controlled trial. In addition, the association between changes in VLDL apoB metabolism and changes in lipid substrate were investigated.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Fourteen patients with adult GH deficiency (eight women and six
men) volunteered for the study. The clinical characteristics of these
patients are summarized in Table 1
. All
had multiple pituitary deficiencies, had suffered from GH deficiency
for at least 1 yr, and were receiving stable conventional replacement
therapy. GH deficiency was defined as a peak GH of less than 3 mU/L
during an insulin provocation test with nadir plasma glucose less than
2.2 mmol/L. None of the patients had diabetes mellitus or abnormal
liver function, or were taking drugs known to affect lipid metabolism.
Patients were asked to maintain their diet unchanged through the study,
which was confirmed by 24-h dietary recall and assessment by a
dietitian. All patients provided informed written consent, and the
study was approved by St. Thomas’ Hospital ethics committee.
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The study was randomized, double blind, and placebo controlled. Patients were instructed in self-administration of GH using a pen device (Genotropin-pen, Pharmacia-Upjohn, Milton-Keynes, UK) and injected GH (Genotropin, Pharmacia-Upjohn, Milton-Keynes, UK; 0.018 IU/kg·day for the first week, followed by 0.036 IU/kg·day for the remainder of the study) or placebo sc at bedtime.
Identical metabolic investigations were performed before and after 3
months of GH or placebo treatment. All subjects were admitted to the
metabolic ward at 0830 h after a 12-h overnight fast. They were
studied in a semirecumbent position and allowed to drink water. An
indwelling cannula was placed in a superficial vein of the antecubital
fossa for administration of the stable isotope tracer, and another was
placed in the contralateral arm for blood sampling. The blood-sampling
schedule is outlined in Fig. 1. At the
beginning of the study, 10 mL ethylenediamine tetraacetate (EDTA)
plasma were collected for measurement of TC, TG, apoE phenotype, high
density lipoprotein (HDL) cholesterol, hemoglobin A1C
(HbA1C), and mevalonic acid (MVA), and 10 mL serum were
collected for measurement of hormone [insulin-like growth factor I
(IGF-I) and insulin] and IGF-binding protein-3 (IGFBP-3)
concentrations. [1-13C]Leucine (15 mg/mL; 13C
enrichment, 99%; Tracer Technologies, Sommerville, MA) was
administered as a primed (1 mg/kg) constant infusion (1 mg/kg·h) for
9 h. Five-milliliter EDTA plasma samples were collected for VLDL
apoB enrichment at baseline and at 30-min intervals throughout the
study. Five-milliliter lithium heparin samples were taken at baseline
and after 15, 30, 45, 60, 120, 240, 360, 480, and 540 min to determine
13C enrichment of 
-ketoisocaproate (KIC), the
deaminated product of leucine that provides a measure of intracellular
leucine enrichment (21). At baseline and after 2, 4, 6, 8, and 9 h
of infusion, 10 mL blood were collected into an EDTA (0.34 mol/L) tube
to determine FFA, VLDL TG, VLDL-C, and VLDL apoB concentrations. Plasma
volume was measured by a standardized radionuclide dilution technique
(22). Briefly, autologous plasma containing 1.85 kilobecquerels/kg BW
125I-labeled human albumin (Amersham, Aylesbury, UK) was
injected, with blood samples taken 10, 20, and 30 min after injection.
Five-milliliter aliquots were counted for 10 min using a 
-counter
(LKB Wallac, Bromma, Sweden) with channel settings of
20–83 keV for 125I counting. Plasma volume was
determined by extrapolating the 125I counts to zero time by
linear regression.
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Body weight was measured on an electronic balance with subjects wearing light clothes and without shoes. Height was assessed by a stadiometer. Bioelectrical impedance analysis was measured in the erect position after voiding, using a body fat analyzer TBF-105 (Tanita Corp., Tokyo, Japan). Fat mass and lean body mass were calculated using a preprogrammed equation based upon densitometric data in a healthy population (23).
Isolation and measurement of isotopic enrichment of VLDL apoB
All EDTA plasma samples were stored at 4 C and analyzed within
24 h of collection. A 2-mL aliquot of plasma was overlaid with 3
mL sodium chloride density solution (density = 1.006 kg/L) and
ultracentrifuged for 16 h at 147,000 x g
(Centrikon T-2070 ultracentrifuge, Kontron Instruments Ltd., Zurich, Switzerland). The supernatant containing VLDL was
isolated by aspiration. ApoB was precipitated by the tetramethylurea
method. This method has been demonstrated, by polyacrylamide gradient
electrophoresis, to be highly specific (specificity, 97%) for apoB in
our laboratory (9) and others (24). The precipitate was delipidated by
incubation with 3 mL ether-ethanol solution (1:3, vol/vol) at -20 C
for 12 h. After recentrifugation (2,000 rpm, 30 min, 4 C), the
supernatant was removed by aspiration. The delipidated apoB precipitate
was dried under oxygen-free nitrogen (BOC, Guildford, UK) for 20 min at
25 C and then hydrolyzed in 2 mL 6 mol/L hydrochloric acid. The samples
were heated for 24 h at 115 C to ensure complete hydrolysis and
were reconstituted in 0.5 mL 50% acetic acid. Amino acids were eluted
by cation exchange chromatography (70-µm pore size filter plastic
columns, Bioconnections, Leeds, UK; and H+ form cation exchange resin,
Bio-Rad, Richmond, VA) using 2 mL 3 mol/L ammonia. The eluted amino
acids were frozen (-70 C), lyophilized, and stored at -20 C until
derivatization. The samples were derivatized using 100 µL
acetonitrile and 100 µL
N-methyl-N-(tert-butyldimethylsilyl)-trifluoroacetamide
(Aldrich, Dorset, UK) to form the
bis(tert-butyldimethylsilyl) derivative. Excess reagent was
removed by blowing down under oxygen-free nitrogen, and the sample was
reconstituted in 100 µL decane for gas chromatography-mass
spectrometry. Isotopic enrichment was determined by selected ion
monitoring of fragments with mass to charge ratios (m/z) of 303 and 302
using a gas chromatograph-mass spectrometer (VG Biotech TRIO-2, VG
Biotech Ltd., Altrincham, UK) in the electron impact ionization
mode. The quinoxalinol (tert-butyldimethylsilyl) derivative
of KIC was prepared, and isotope enrichment was determined by
selected ion monitoring of fragments at m/z 259 and 260 (GCMS analysis,
5890A, Hewlett-Packard Co., Bracknell, UK). Analytical
precision of the method (coefficient of variation) has been shown to be
less than 8% for isotopic enrichment of leucine and KIC (9).
Quantification of VLDL apoB and other analytes
The VLDL apoB concentration was determined by immunoturbimetry (Immunoturb Kit, Immuno Ltd., Dunton Green, UK) (25); the interassay CV was 4%. This method yields results comparable to those obtained using the Lowry method (25). Plasma TC and TG concentrations were measured by an enzymatic method (Boehringer Mannheim, Mannheim, Germany) using a Cobas Fara II analyzer (Roche, Welwyn Garden City, UK). HDL-C was separated by precipitation of apoB-containing lipoproteins with dextran sulfate/magnesium chloride and measured enzymatically. LDL-C was measured enzymatically (Boehringer Mannheim) after ultracentrifugation for 20 h (density = 1.063 kg/L). HbA1C was measured by anion exchange liquid chromatography (interassay CV, 8%). The plasma immunoreactive insulin concentration was determined by double antibody RIA (26) (interassay CV, 6%). Serum IGF-I concentrations were measured by a double antibody RIA after ethanol-hydrochloric acid extraction (27). The interassay CVs were 10%, 9%, and 8% at 13, 35, and 173 nmol/L, respectively. Serum IGFBP-3 was determined by a two-site immunoradiometric assay (Diagnostics Systems Laboratories, Inc., Webster, TX). The interassay CVs were 1.9%, 0.5%, and 0.6% for IGFBP-3 concentrations of 76.9, 21.5, and 8.03 ng/mL, respectively. Plasma FFA concentrations were measured enzymatically (FFA-kit, Wako Chemicals GmbH, Neuss, Germany; interassay CV, 3.6%). The plasma MVA concentration was measured using capillary gas chromatography-electron capture mass spectrometry (28) (interassay CV, 6.7%). The apoE phenotype was determined by isoelectric focusing (29).
Calculation of VLDL apoB secretion and clearance rates
VLDL apoB enrichment with [13C]leucine and
[13C]KIC enrichment (precursor pool) were calculated
using the following formula (30): enrichment (E)t = [
Rt - R0/(1 + Rt -
R0)] x 100, where Rt is the
13C/12C ratio at time t and R0 is
the 13C/12C ratio at baseline before the tracer
infusion. The fractional catabolic rate (FCR) and fractional secretion
rate (FSR) of VLDL were estimated by a compartmental model with an
intrahepatic delay function using SAMM II software (SAMM, Seattle, WA).
The precursor compartment for the incorporation of
[13C]leucine into the VLDL particles (forcing function)
was the steady state tracer/tracee ratio of KIC. The FSR of VLDL is
subject to an intrahepatic delay. The catabolic rate of VLDL from
plasma is expressed as the FCR. Throughout the study the patients were
in steady state, as shown by constant VLDL apoB concentrations. In this
case, the FSR equals the FCR. The model parameters (intrahepatic delay
and FCR) were estimated from the tracer/tracee ratio of VLDL apoB. A
total of 19 time points over the 9-h tracer infusion were included in
the mathematical analysis.
The absolute VLDL apoB secretion rate was calculated as the product of FCR and the VLDL apoB pool size divided by body weight. Pool size was determined as the product of plasma volume and VLDL apoB concentration taken as the mean of six samples taken during the study, and MCR was calculated as the product of FCR and plasma volume.
Data presentation and statistics
As the patients age ranged from 23–72 yr in age, the age-dependent values (IGF-I, IGFBP-3) were transformed into SD units by the following formula: observed IGF value minus mean value of the age-matched healthy population divided by the SD of the age-matched healthy population. Results were expressed as the mean ± SEM. Skewed variables (plasma and VLDL TG concentration, VLDL apoB concentration, VLDL apoB pool size, FCR, and VLDL apoB secretion and clearance rates) were examined after log transformation. Unpaired t testing was used for between-group comparisons, and paired t testing was used for within-group comparisons.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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)The patients in the GH-treated and placebo groups were well matched in terms of age, sex, duration of hypopituitarism, BMI, and apoE phenotype. Eleven patients were overweight (BMI, >25 kg/m2): 6 in the placebo group and 5 in the GH-treated group. During the study period, GH was well tolerated, and there was no need for a dose reduction in the treated group.
Body composition (Fig. 2)
Total body weight did not significantly change in either group. All seven patients with GH treatment exhibited an increase in lean body mass (47.0 ± 4.4 to 50.5 ± 4.8 kg, mean ± SEM; P < 0.01). Fat mass decreased in all GH-treated patients (26.4 ± 2.7 to 23.0 ± 2.5 kg, mean ± SEM; P < 0.05). No significant changes could be measured in the placebo group.
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)There were no significant differences in fasting plasma lipid profile between the two groups before treatment. Eleven of a total of 14 patients were hyperlipidemic (TC >5.5 mmol/L or TG >2.3 mmol/L): 6 in the placebo group and 5 in the GH-treated group. GH replacement therapy significantly decreased total plasma cholesterol concentrations (P < 0.02), LDL-C concentrations (P < 0.02), and VLDL-C/VLDL apoB ratios (P < 0.005) and significantly increased VLDL TG/VLDL-C ratios (P < 0.005), whereas no significant changes were observed after placebo treatment.
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)Before treatment, these variables were not statistically different in the GH-treated group compared with the placebo group. Mean IGF-I concentrations were at the lower end of the normal range in both groups and increased 2.9 ± 0.5-fold in the GH-treated group (P < 0.001). IGFBP-3 concentrations increased 2.0 ± 0.1-fold (P < 0.001) after GH treatment, whereas no significant changes were observed in the placebo group. Before treatment, fasting insulin levels and HbA1C were not significantly different between the GH-treated and placebo groups. After GH replacement therapy fasting, insulin concentrations increased 1.8 ± 0.6-fold (P < 0.04), and HbA1C increased from 5.0 ± 0.2% to 5.3 ± 0.2% (P < 0.001). No significant change was observed in the placebo group.
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There was no difference in the values of MVA and mean FFA concentration (average of six consecutive samples taken during the study) between the two groups before treatment. No significant changes in either variable were seen after GH or placebo treatment (MVA: placebo group, 7.4 ± 1.0 vs. 5.3 ± 1.0 ng/mL, mean ± SEM; GH-treated group, 8.9 ± 3.1 vs. 6.8 ± 4.2 ng/mL; FFA: placebo group, 1.12 ± 0.1 vs. 0.96 ± 0.1 mmol/L, mean ± SEM; GH-treated group, 1.02 ± 0.13 vs. 1.03 ± 0.16 mmol/L).
Kinetic characteristic of VLDL apoB metabolism (Table 4)
ApoB kinetics were in steady state, as supported by the fact that
VLDL apoB concentrations did not show a significant change at selected
time points throughout the study (data not shown). Precursor pool
enrichment as measured by [13C]KIC occurred rapidly
and remained constant throughout the study periods (Fig. 3, a and b). [13C]Leucine
plateau enrichment of VLDL apoB had not been reached after 9 h in
the placebo group on both occasions or in the GH-treated group before
treatment, whereas plateau enrichment was achieved after 7 h of
infusion following GH replacement therapy (Fig. 3, a and b).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Cummings et al. reported an increased VLDL apoB secretion rate and a decreased VLDL apoB catabolism in untreated adults with GH deficiency compared with age-, sex-, and BMI-matched healthy control subjects (12). In the present study GH replacement therapy led to a reversal of the decreased VLDL apoB catabolism but further increased VLDL apoB secretion. This is an unexpected finding, indicating that the beneficial effect of GH on hepatic uptake of VLDL and LDL clearance may be offset by increased VLDL secretion. This finding may explain the variable effects of GH replacement therapy on the serum lipoprotein profile observed in some studies (31). One possible explanation for this finding may relate to the duration of GH replacement therapy. Short term GH therapy increases insulin resistance and may contribute to increased VLDL apoB secretion, but long term GH replacement therapy administered for more than 6 months reduces insulin resistance, which, in turn, may decrease VLDL apoB secretion (32).
The increase in the VLDL apoB secretion rate may be explained firstly by the relative increase in intrahepatic lipid substrate, which has been shown to stimulate hepatic VLDL apoB secretion (13, 14). In the present study GH replacement therapy led to a reduction in fat mass consistent with the results of previous studies (31). Indirect evidence from studies using a computer tomography x-ray technique suggests that GH exerts its action preferentially on visceral fat mass (33). It is, therefore, conceivable that FFA appear initially in the portal circulation and are directly cleared by the liver, reesterified to cholesterol esters and TG, which are available to stimulate hepatic VLDL apoB secretion. The lack of a significant change in FFA concentrations in the present study may be due to the fact that GH may directly stimulate hepatic FFA extraction of the portal vene (15), which is not reflected by peripheral measurements of FFA concentrations. Alternatively, it is conceivable that GH leads to an overall increase in FFA flux, which can only be detected by FFA turnover studies using labeled FFA. In addition, the increase in VLDL apoB catabolism observed in this study may have led to an increased uptake of apoB-containing lipoproteins (VLDL, IDL, and LDL) by the liver. The core lipids of these recycled particles can, in turn, stimulate VLDL apoB secretion (34). In starved rats, recycled TG have been shown to account for up to 80% of the newly secreted VLDL TG (35). Secondly, insulin resistance is known to be associated with an increase in VLDL apoB secretion in part due to an increased hepatic lipid substrate (36). The clinical features of insulin resistance include central obesity with an increase in intraabdominal adiposity, characteristic findings of adult GH deficiency (31). Studies using the euglycemic, hyperinsulinemic clamp technique have confirmed the insulin-resistant state of patients with adult GH deficiency and have shown that short term GH replacement therapy further increases insulin resistance (32). In keeping with these findings, high fasting insulin concentrations (a surrogate marker of insulin resistance) before and a significant increase in insulin concentrations after GH treatment were measured in the present study. Thirdly, an increase in circulating glucose concentrations, as seen by a significant increase in HbA1C, may have contributed to the observed increase in the VLDL apoB secretion rate after GH replacement therapy (34). Glucose can be metabolized to glycerol and, via acetyl coenzyme A, to TG, thereby, enhancing the substrate supply (34). MVA concentrations, a precursor of cholesterol and a surrogate marker for endogenous cholesterol synthesis (28), did not significantly change after GH replacement therapy, suggesting that increased endogenous cholesterol synthesis did not substantially contribute to an increased intrahepatic cholesterol pool and hence to an increased VLDL apoB secretion rate in the present study. This is in contrast to our previous study (37), which reported a decrease in MVA concentrations after GH therapy. One explanation for this discrepancy is the smaller sample size in the current study, as a tendency towards decreased MVA concentrations after GH therapy could be observed. Alternatively, a possible stimulatory role of GH on the activity and expression of hydroxy-methylglutaryl(HMG)-coenzyme A reductase, the key enzyme of cholesterol synthesis (38), could be counterbalanced by up-regulation of LDL receptor (20) which may lead to a decrease in HMG-coenzyme A reductase activity and, hence, to a decrease in cholesterol synthesis. The opposing effects of these two mechanism could explain the lack of change in MVA concentrations in the current study.
In man, VLDL particles are normally removed from the vascular compartment through two pathways (36): complete hydrolysis of TG in VLDL particles leading to the production of IDL and eventually LDL particles (LDL pathway) or direct hepatic removal of partially delipidated VLDL particles via a receptor (LDL receptor, LRP, and/or VLDL receptor)-mediated pathway (non-LDL pathway). The increased VLDL apoB clearance rate observed after GH replacement therapy could be explained 1) by an increase in the conversion of VLDL to LDL (LDL pathway), and/or 2) by an increase in direct hepatic removal of VLDL (non-LDL pathway). LPL activity is critical for the first step in the delipidation cascade. However, this enzyme operates normally at only half-maximum capacity (39). In addition, GH decreases the total plasma postheparin LPL activity (16) and adipose tissue LPL activity (18) in humans. Based on these observations it appears unlikely that the present finding of an increase in VLDL apoB clearance can be explained by a change in LPL activity. If the observed VLDL apoB clearance rate is associated with an increase in VLDL conversion to LDL, the reduction in TC and LDL-C concentrations after GH replacement therapy in this and previous studies (31) can only be explained by an increase in LDL apoB removal that exceeded the increase in conversion from VLDL to LDL. This would be supported by the fact that in vivo and in vitro studies have shown that GH up-regulates hepatic LDL receptors (20). Alternatively, the observed increase in VLDL apoB catabolism could be explained by an increase in direct hepatic uptake of VLDL (non-LDL pathway). As direct hepatic VLDL removal is also in part LDL receptor mediated (19), GH-induced up-regulation of LDL receptor would support this hypothesis.
VLDL particles are cholesterol depleted after GH replacement therapy, as seen by a decrease in the VLDL-C/VLDL apoB ratio and a relative increase in the VLDL-TG/VLDL-C ratio. Using multicompartmental modelling of VLDL subfractions, Packard et al. (19) have shown that the composition of VLDL particles can have a direct impact on their metabolic fate and atherogenic potential: large, TG-rich VLDL particles do not form LDL to a significant degree, whereas most of cholesterol-rich VLDL particles are converted to LDL (19) and are therefore potentially more atherogenic. In addition, LDL receptors appear to be responsible for the removal of the cholesterol-rich VLDL particles, whereas TG-rich VLDL are probably directly removed by LDL receptor-related protein and/or VLDL receptor (19). We infer, therefore, that the cholesterol depletion of the VLDL particles could be related to an increase in LDL receptor-mediated direct hepatic uptake of this subset of VLDL particles, thereby decreasing the conversion to LDL.
A number of assumptions are made in the metabolic model. It assumes
that plasma KIC is in equilibrium with intrahepatic leucine and
reflects the enrichment of hepatic leucine transfer ribonucleic acid,
which is necessary for the production of apoB. This assumption is
supported by experimental work in dogs showing similar enrichment of
leucine extracted from hepatic tissue and plasma KIC (40). In
addition, plateau VLDL apoB enrichment has been shown to correlate well
with KIC enrichment in humans (41) and has been successfully used in
humans in different mathematical models (42). Furthermore, this model
assumes that steady state isotope enrichment of the precursor pool is
constant and maximal at the beginning of the study and remains stable.
In our study a primed constant tracer infusion was used (42) with the
aim of labeling the precursor pool rapidly to a plateau level. In
practice, the isotope enrichment of the precursor pool (KIC) occurs
within about 30–45 min of tracer infusion and remains stable
thereafter. The model applied to the VLDL apoB enrichment data in this
study assumes that VLDL particles are homogeneous. Packard et
al. have, however, described VLDL subspecies with distinct kinetic
properties (19) and have derived a multicompartmental model. In this
study apoB enrichment in VLDL subfractions was not determined. However,
monocompartmental models yield similar results as multicompartmental
models (41), and the kinetic behavior of VLDL subfractions can be
deduced on the basis of changes in the VLDL lipid content.
In conclusion, GH increases lipoprotein flux in humans consistent with findings in rats. This study suggests that GH replacement therapy improves the lipid profile by increasing the removal of VLDL particles. Although GH therapy stimulates VLDL apoB secretion by increasing intrahepatic lipid availability, we speculate that this is counterbalanced by its effect in up-regulating LDL-receptors and modifying VLDL composition. We hypothesize that the improved lipid profile, in particular the decrease in cholesterol-rich VLDL particles, and the increased VLDL clearance may contribute to the antiatherogenic action of GH. This kinetic study revealed a profound effect of GH on VLDL apoB metabolism despite no significant changes in plasma VLDL-C, VLDL TG, and VLDL apoB concentrations. This emphasizes the importance of turnover studies for understanding lipoprotein disorders in conditions such as adult GH deficiency. Further metabolic studies are required to examine the long term effects of GH replacement therapy on VLDL apoB metabolism and the kinetic behavior of other lipoprotein classes, particularly LDL, before and after GH replacement therapy to fully understand the effects of GH on lipoprotein metabolism.
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Acknowledgments |
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Footnotes |
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Received June 24, 1998.
Revised September 23, 1998.
Accepted September 29, 1998.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-hydroxylase in the rat. J Clin Invest. 99:2239–2245.[Medline]
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