ARTICLES

Abnormal High-Density Lipoproteins in Overweight

Adolescents With Atherogenic Dyslipidemia
AUTHORS: Aida Medina-Urrutia, MSc,a Juan G. JuarezRojas, BSc,a Guillermo Cardoso-Saldaa, PhD,a Esteban
Jorge-Galarza, MSc,a Rosalinda Posadas-Snchez, MSc,a
Rocio Martnez-Alvarado, MD,a Nac Caracas-Portilla,
MD,a Enrique Mendoza Prez, MD,a and Carlos PosadasRomero, MDa
aDepartment of Endocrinology, Instituto Nacional de Cardiologa
Ignacio Chvez, Mexico City, Mexico

KEY WORDS
obesity, adolescent health, cardiovascular risk factors,
lipoproteins, preventive medicine
ABBREVIATIONS
LDLlow-density lipoprotein
HDLhigh-density lipoprotein
apoapolipoprotein
IRinsulin resistance
HOMAhomeostasis model assessment
SR-BIscavenger receptor class B type I
www.pediatrics.org/cgi/doi/10.1542/peds.2010-1395
doi:10.1542/peds.2010-1395
Accepted for publication Feb 8, 2011
Address correspondence to Carlos Posadas-Romero, MD, Juan
Badiano No 1 Col Seccin XVI, Tlalpan, CP 14080.
E-mail: cposadasr@yahoo.com.
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright 2011 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated that they
have no personal nancial relationships relevant to this article
to disclose.

PEDIATRICS Volume 127, Number 6, June 2011

WHATS KNOWN ON THIS SUBJECT: Atherogenic dyslipidemia is

a marker of qualitative and functional high-density lipoprotein
(HDL) abnormalities in obese adults. Cholesterol efux, an
atheroprotective function of HDL, is inversely related to carotid
intima-media thickness, independent of HDL cholesterol and
apolipoprotein AI concentrations, suggesting it as a predictor of
cardiovascular risk.
WHAT THIS STUDY ADDS: Atherogenic dyslipidemia identies
obese adolescents who, aside from a general adverse
cardiovascular risk factor prole, show quantitative, qualitative,
and cholesterol efux abnormalities; therefore, these adolescents
should be the target of aggressive prevention programs and lipid
management guidelines.

abstract
OBJECTIVE: This study aimed to evaluate high-density lipoprotein functionality and the cardiovascular risk factor prole in the overweight
pediatric population. We hypothesized that overweight adolescents
with low high-density lipoprotein cholesterol and elevated triglyceride
plasma levels have metabolic abnormalities and dysfunctional highdensity lipoprotein particles, similar to those reported in adults.
PATIENTS AND METHODS: Overweight adolescents with (group 1 [n
21]) and without (group 2 [n 36]) atherogenic dyslipidemia (highdensity lipoprotein cholesterol: 40 mg/dL and triglycerides: 150
mg/dL) and normal-weight normolipidemic subjects, as a reference
(group 3 [n 36]), were included. The cardiovascular risk factor
prole (lipids, lipoproteins, high-sensitivity C-reactive protein, and insulin), high-density lipoprotein subclass distribution, composition, and
cholesterol efux capacity were studied.
RESULTS: Group 1 adolescents showed abnormalities in high-density
lipoprotein subclass distribution and high-density lipoprotein chemical composition, as well as a signicantly lower capacity to promote
cholesterol efux (14.8 2.8, 16.5 3.8, 20.4 3.5, for groups 1, 2 and
3, respectively). High-density lipoprotein2a (R2 0.212, 0.472, P
.0001) and the Tanner score (R2 0.054, 0.253, P .02) were the
independent predictors of cholesterol efux. Group 1 also showed a
higher degree of cardiovascular abnormalities (an adverse lipoprotein
prole, greater insulin resistance and systemic inammation; and
lower low-density lipoprotein size) than group 2, even after BMI and
Tanner score adjustment.
CONCLUSIONS: This study suggests that atherogenic dyslipidemia
identies overweight adolescents with quantitative, qualitative, and
functional high-density lipoprotein abnormalities. Atherogenic dyslipidemia seems to be a marker of an increased risk for developing cardiovascular disease and indicates that those adolescents should be a
target of aggressive prevention programs and lipid management
guidelines. Pediatrics 2011;127:e1521e1527

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e1521

Although clinical atherosclerotic coronary artery disease does not occur until
the fourth or fth decade of life, it is
known that atherosclerosis already is
present in youth,1 and its initial stages
are associated with dyslipidemia.2 An association between increased low-density
lipoprotein (LDL) cholesterol and cardiovascular risk is well established.3 Epidemiologic studies also have consistently
shown that low plasma levels of highdensity lipoprotein (HDL) cholesterol is
an important independent risk factor for
coronary disease.4 However, it has been
reported that some HDL characteristics
may be more important than HDL cholesterol levels in predicting future coronary
disease.5 HDL is a heterogeneous group
of large (HDL2b and HDL2a) and small
(HDL3a, HDL3b, and HDL3c) lipoprotein
particles6 that differ in size, lipid composition, density, and function.7 Under normal conditions, the antiatherogenic effect of both large and small HDL particles
is likely attributable to its central role in
reverse cholesterol transport and to
their antioxidant, anti-inamatory, and
anti-thrombotic actions that may contribute to the prevention of atherosclerosis development and progression.8
Childhood obesity is one of the most
serious and urgent health problems in
both developed and emerging economies.9 Atherogenic dyslipidemia,
which is characterized by high triglycerides, low HDL cholesterol concentrations, and small dense LDL particles, is
commonly seen in obese children and
adolescents.10 In addition, abnormalities in the HDL subclass distribution
and chemical composition have both
been shown in adults11,12 and children13,14 with obesity, insulin resistance, and type 2 diabetes. In adults,
lower levels of large particles and increased levels of small HDL are associated with increased coronary disease
prevalence and increased recurrence
of coronary events.5 In children, adiposity and its adverse metabolic proe1522

MEDINA-URRUTIA et al

le have been found to be associated

with increased carotid intima-media
thickness and endothelial dysfunction,15 2 early events in atherogenesis.
Cholesterol efux from cells is an early
step in the reverse cholesterol transport from peripheral cells to the liver
for excretion or recycling, a process
considered to be one of the most important HDL atheroprotective mechanisms.16 Of note, cholesterol efux is
inversely related to carotid intimamedia thickness, independently of HDL
cholesterol and apolipoprotein (apo)
AI concentrations,17 suggesting that
cholesterol efux capacity may be a
predictor of cardiovascular risk. Although studies in adults have shown
that atherogenic dyslipidemia identies obese subjects with a generalized
metabolic disorder,11,12 qualitative lipoprotein abnormalities, and dysfunctional HDL particles with reduced capacity to promote cholesterol efux
from cells,18 it is unknown whether this
phenotype also is present in the overweight pediatric population with this
lipid-lipoprotein disorder. We hypothesized that overweight adolescents with
low HDL cholesterol and elevated triglyceride levels have other metabolic
abnormalities and dysfunctional HDL
particles similar to those reported in
adults. To test this hypothesis, we evaluated HDL subclass distribution and
composition, cholesterol efux capacity, and insulin and inammatory
markers in overweight adolescents
with and without atherogenic dyslipidemia and in normal-weight subjects.

METHODS
A cross-sectional survey to investigate
cardiovascular risk factors in adolescents was conducted in 510 adolescents attending a junior high school in
Mexico City.13 Weight, height, waist circumference, and blood pressure were
measured according to standard procedures.13 BMI was calculated as

weight (in kilograms) divided by the

square of height (in meters) and used
as an indicator of body mass status,
and overweight and obesity were diagnosed according to Cole et al.19 Sexual
maturity was evaluated by Tanner
score.20
Venous blood samples were obtained
from 350 adolescents after a 12-hour
fast. All those with overweight or obesity were categorized as adolescents
with excess body weight and were divided into 2 groups: group 1 (n 21),
whose subjects had atherogenic dyslipidemia (HDL cholesterol 40 mg/dL
and triglycerides 150 mg/dL); and
group 2 (n 36), whose subjects had
normal HDL cholesterol and triglycerides. A third group (n 36) of a similar
age and gender distribution, with normal lipid values and BMI between the
25th and 50th centiles, was included as
a reference. None of the subjects were
receiving vitamin supplementation or
a specic diet at the time of the study,
and none had clinical evidence of diabetes or thyroid, renal, or liver disease. The protocol was approved by
the institutional review board of the Instituto Nacional de Cardiologa, Ignacio Chvez. Parental informed consent
and adolescent assent were obtained
from all participants.
Biochemical Analyses
Plasma glucose, total cholesterol, triglycerides, and HDL cholesterol were
measured using standard enzymatic
procedures in a Hitachi 902 analyzer
(Hitachi LTD, Tokyo, Japan). Accuracy
and precision were evaluated periodically by the Centers for Disease Control and Prevention (Atlanta, GA). LDL
cholesterol was estimated by using
the Friedewald formula. Total highsensitive C-reactive protein, apoB, and
apoAI levels were determined by immunonephelometry on a BN Pro Spec
nephelometer (Dade Behring, Marburg, Germany), with an interassay co-

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ARTICLES

efcient of variation of less than 6%.

Plasma insulin concentrations were
determined by a radioimmunometric
assay (Coat-A-count; Diagnostic Products, Los Angeles, CA), and insulin resistance (IR) was estimated by the homeostasis model assessment (HOMA).
LDL Size and HDL Subclasses
Distribution
LDL size was determined in plasma by
a modication of the method of Krauss
and Bruke.21 For HDL subclasses, total
HDL was isolated from the plasma of
each adolescent by sequential ultracentrifugation in a density of 1.21 g/mL
at 4C in a Beckman TL-100 ultracentrifuge. The resulting total HDL was dialyzated against phosphate buffer (pH
7.4), loaded into native 4% to 25% polyacrylamide gel electrophoresis gels,
and analyzed by automated densitometry, as previously described.13 The coefcient of variation for each subclass
was less than 10%.

TABLE 1 Clinical and Biochemical Characteristics of the Study Subjects

Boys/Girls, %
Tanner, %, 2/34/5
Age, means SD, y
BMI, means SD, kg/m2
Waist, means SD, cm
Systolic blood pressure, means SD,
mm Hg
Diastolic blood pressure, means SD,
mm Hg
Total cholesterol, means SD, mg/dL
LDL cholesterol, means SD, mg/dL
HDL cholesterol, means SD, mg/dL
Triglycerides, means SD, mg/dL
nonHDL cholesterol, means SD
apoAI, means SD, mg/dL
ApoB, means SD, mg/dL
ApoB-to-apoAI ratio, means SD
Total cholesteroltoHDL cholesterol ratio,
means SD
LDL size, means SD, nm
C-reactive protein, means SD, mg/L
Glucose, means SD, mg/dL
Insulin, means SD, mU/L
HOMA-IR, means SD

Dyslipidemic
Overweight,
Group 1, n 21

Normolipidemic
Overweight,
Group 2, n 36

Normolipidemic
Normal Weight,
Group 3, n 36

52/48
0/79/21
13.3 0.9
29.8 3.8a,b
90.0 9.4a
111.3 8.4a

47/53
0/77/23
13.1 0.8
27.0 2.9a
84.8 10.6a
109.4 8.1a

53/47
6/84/10
13.1 1.0
19.7 0.7
66.5 3.8
101.6 8.5

69.4 5.6a,b

64.3 5.5

62.6 4.8

151.9 24.0b
90.4 19.3a,b
31.1 5.5a,b
189.7 40.4a,b
120.7 21.3a,b
109.3 19.7a,b
78.5 13.7a,b
0.74 0.1a,b
4.9 0.6a,b

141.7 23.3
78.0 18.7
46.0 5.4a
110.4 39.2a
95.7 20.7
134.0 19.0
63.5 13.2
0.48 0.1
3.1 0.6

147.5 17.7
80.9 14.4
51.6 1.6
81.5 22.4
93.9 15.6
137.8 22.4
57.8 14.3
0.42 0.08
2.8 0.4

26.6 0.6a,b
0.8 1.1
85.0 6.2
19.8 8.2a,b
4.3 2.0a,b

27.2 0.6
0.9 1.1
88.6 6.0
14.4 8.0a
3.1 1.9a

27.4 0.6
0.9 1.2
85.9 7.0
9.0 3.6
1.9 0.8

P .01 vs group 3 (analysis of covariance).

P .05 vs group 2 (analysis of covariance). For insulin and HOMA-IR, P values of the difference between groups 1 and 2
were adjusted for BMI and Tanner score. Blood pressure and lipid variables were adjusted for BMI, Tanner score, and
HOMA-IR.

Characterization of HDL
Total protein, total cholesterol, free
cholesterol, phospholipid, and triglyceride contents of isolated HDL were determined using commercially available enzymatic assays in a Hitachi 902
analyzer. Cholesteryl esters were calculated by multiplying the difference
between total and free cholesterol by
1.67.22 Total lipoprotein mass was calculated as the sum of total protein,
cholesteryl esters, free cholesterol,
phospholipids, and triglycerides. Apo
content (apoAI, apoAIV, and apoE) was
evaluated semiquantitatively by sodium dodecyl sulfate polyacrylamide
gel electrophoresis.23
Cholesterol Efux Assay
Cellular cholesterol efux was determined using Fu5AH rat hepatoma cells
according to the procedure described
by de la Llera Moya et al,24 with slight
modications. Briey, Fu5AH cells
were maintained in minimal essential
PEDIATRICS Volume 127, Number 6, June 2011

medium containing 5% of bovine serum, 250 000 cells per well were
placed on 24-well plates, and 24 hours
after plating radiolabeled cholesterol
(1,2-3H cholesterol; American Radiolabeled Chemicals, Inc, St Louis, MO) was
added (0.5 Ci per well). Cells were
then washed and incubated for 18
hours in minimal essential medium
with 0.5% of bovine serum albumin. Finally, cells were washed and incubated at 37C for 4 hours with 2.0%
diluted serum or isolated total HDL
fractions (20 g HDL-protein/mL), prepared by sequential ultracentrifugation, as previously described. Radioactivity was measured in medium and
cells, and the percentage of cholesterol efux was calculated. All determinations were made in triplicate. As an
internal control, a total serum and isolated total HDL were included in each
plate, obtaining coefcients of variation of 3.3% and 5.3%, respectively.

Statistical Methods
Statistical comparisons were performed using SPSS for Windows (version 9.0; SPSS, Chicago, IL). Results are
expressed as means SD for continuous variables, and skewed variables
were previously log transformed. P
values less than 0.05 were considered
signicant. Between-group differences
in continuous variables were analyzed
by analysis of covariance. Pearson correlation coefcients were calculated
to evaluate relationships between variables, and multivariate stepwise linear
regression analysis was performed to
determine the relative contribution of
the variables studied to the cholesterol efux.

RESULTS
Age, gender, and Tanner stage distribution were similar across groups (Table 1). Group 1 showed a statistically

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TABLE 2 HDL Subclass Distribution and Total HDL Composition by Group

HDL subclass distribution, proportion SD

HDL2b, %
HDL2a, %
HDL3a, %
HDL3b, %
HDL3c, %
HDL size, nm
HDL composition, proportion SD
Total protein, %
Phospholipids, %
Triglycerides, %
Cholesteryl ester, %
Free cholesterol, %
HDL-phospholipidtoapoAI ratio
HDL-phospholipidtoHDL cholesterol ratio

Dyslipidemic
Overweight,
Group 1, n 21

Normolipidemic
Overweight,
Group 2, n 36

Normolipidemic
Normal Weight,
Group 3, n 36

9.8 2.5a,b
16.6 2.7a,b
27.8 1.6a
25.7 2.4a
20.0 2.7a,b
8.6 0.1a,b

11.0 2.4a
19.8 2.6a
28.3 1.6a
24.8 2.3a
16.1 2.6
8.7 0.1a

14.1 2.7
22.7 2.5
26.7 2.1
22.2 2.0
14.2 3.3
8.8 0.2

50.3 3.0a,b
25.6 2.1
5.1 0.9a,b
16.1 2.0a,b
2.9 0.5a,b
45.4 16.8a,b
1.7 0.9a,b

47.2 2.9
26.9 2.1
3.3 0.9
19.2 1.9
3.4 0.5a
58.5 16.4
2.8 0.9

45.1 5.2
27.4 2.7
3.1 1.0
20.6 2.2
3.8 0.5
62.0 19.2
3.0 0.7

HDL subclasses are expressed as the relative proportion of total HDL protein SD. HDL composition was estimated as the
relative proportion of HDL total mass, and HDL-phospholipid to apoAI and HDL-phospholipid to HDL cholesterol were
calculated as molar ratios.
a P .01 vs group 3 (analysis of covariance).
b P .05 vs group 2 (analysis of covariance); P values of the difference between groups 1 and 2 were adjusted for BMI,
Tanner score, and HOMA-RI.

signicantly higher BMI than group 2,

and unadjusted waist circumference
had the same tendency, but it was not
signicantly different when adjusted
for BMI. Apart from expected differences in levels of HDL cholesterol and
plasma triglycerides, group 1 adolescents had signicantly higher levels of
plasma total cholesterol, LDL cholesterol, nonHDL cholesterol, and apoB,
as well as higher values for the total
cholesteroltoHDL cholesterol and
apoB-to-apoAI ratios, whereas their
LDL size and apoAI concentrations
were lower than in group 2; the differences between groups 1 and 2 were all
signicant after adjustment for BMI,
Tanner score, and HOMA-IR. Even in adjusted analyses, plasma concentrations of high-sensitivity C-reactive protein and glucose were not signicantly
different between groups 1 and 2, but
insulin and HOMA-IR showed a statistically signicant difference.
As shown in Table 2, groups 1 and 2
had an abnormal HDL subclass distribution, with lower proportions of large
(HDL2b and HDL2a), and higher proportions of small (HDL3b and HDL3c) sube1524

MEDINA-URRUTIA et al

populations. As a consequence, the

mean HDL size was signicantly decreased, compared with group 3.
These differences were more pronounced in overweight dyslipidemic
subjects. This latter group also had an
abnormal HDL chemical composition,
characterized by triglyceride and

protein-enriched particles, with lower

proportions of cholesteryl esters, free
cholesterol, and phospholipids, as reected by the molar ratios of HDLphospholipidstoapoAI and HDLto
phospholipidstoHDL cholesterol. We
found no differences for apo-HDL composition among groups (data not
shown).
Serum from group 1 (Fig 1) had a signicantly lower cholesterol efux capacity, compared with group 2 (14.8
2.8% vs 16.5 3.8%; P .05) and
group 3 (14.8 2.8% vs 20.4 3.5%; P
.01) adolescents. Although cholesterol efux was lower in group 2 than
in group 3, the difference did not reach
statistical signicance. To ensure that
the differences observed were not a
consequence of the lower HDL cholesterol levels in group 1, cholesterol efux experiments also were conducted
using the same concentration of isolated total HDL fractions from groups 1
and 3 (20 g HDL-protein/mL) and similar incubation conditions as for total
serum. The results conrmed a lower
efux capacity in dyslipidemic adoles-

FIGURE 1
Cholesterol efux assays were carried out using a monolayer of cultured cells (Fu5AH rat
hepatoma cells) and whole serum as cholesterol acceptor. P values of the difference between
groups 1 and 2 were adjusted for BMI, Tanner score, and HOMA-RI. Analysis of covariance was
used.

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ARTICLES

TABLE 3 Simple and Multivariate Correlation Analysis of Biochemical Variables and Cholesterol
Efux in All the Adolescents Studied
Univariate analysis

Tanner
Triglycerides
HDL cholesterol
Total cholesterol to HDL cholesterol
Insulin
HOMA-IR
HDL2b, %
HDL2a, %
HDL3a , %
HDL3b, %
HDL3c, %
HDL size, nm
HDLtotal protein, %
HDL-phospholipids, %
HDL-triglycerides, %
HDLcholesteryl ester, %
HDLfree cholesterol, %
HDL-phospholipidtoapoAI ratio
HDL-phospholipidtoHDL cholesterol ratio

Multivariate analysis
2

0.258
0.313
0.452
0.315
0.283
0.301
0.397
0.465
0.163
0.421
0.372
0.426
0.285
0.293
0.115
0.216
0.350
0.348
0.304

.03
.01
.0001
.01
.005
.003
.0001
.0001
NS
.0001
.0001
.0001
.005
.05
NS
.05
.001
.001
.003

0.054a

0.253

0.248b

0.509

.0001

0.212a

0.472

.0001

P
.02

R indicates the Pearson correlation coefcient; R2 indicates the regression coefcient in stepwise correlation analysis. NS
indicates not signicant.
a Excludes HDL cholesterol.
b Includes all the variables, with P .05 at the unvaried analysis.

cents (4.6 0.5% vs 7.01 0.6% for

groups 1 and 3, respectively; P .001).
To assess the relationships of cellular
cholesterol efux with biochemical
and the HDL-related variables, a correlation analysis was performed (Table
3). We observed a direct correlation
between cholesterol efux and HDL
cholesterol, HDL2b, HDL2a, HDL size, HDL
content of phospholipids, cholesteryl
esters, free cholesterol, and the HDLphospholipidtoapoAI and HDL-phospholipidtoHDL cholesterol molar ratios. An inverse correlation was found
with sexual maturity (Tanner stage),
plasma triglycerides, total cholesteroltoHDL cholesterol ratio, insulin,
HOMA-IR, HDL3b, HDL3c, and the content
of protein in the HDL particle. The independence of the associations was determined by multiple linear regression
analyses. When all variables signicantly related in the univariate analysis were entered into the model
(Model b), HDL cholesterol was the
only independent predictor of cholesterol efux (R2 0.248, 0.509, P
PEDIATRICS Volume 127, Number 6, June 2011

.0001). However, when the effect of

the HDL-related variables was analyzed excluding HDL cholesterol from
de model (Model a), the proportion
of HDL2a (R2 0.212, 0.472, P
.0001) and Tanner score (R2 0.054,
0.253, P .02) were the independent predictors.

DISCUSSION
Cholesterol in peripheral tissues is derived from local synthesis and direct
uptake of circulating lipoproteins.
Most peripheral cells lack the capacity
to catabolize cholesterol and can only
dispose of it by efux to extracellular
acceptors such as HDL. Reverse cholesterol transport is a complex process by which cellular cholesterol
excess in peripheral tissues is transported by HDL to the liver for excretion
in the bile and feces, and it is thought
to be the major mechanism by which
HDL protects against atherosclerotic
cardiovascular disease.7,8,25 Cholesterol
efux, the rst step of the reverse cholesterol transport process, is mediated

by a variety of lipid transporter molecules, including adenosine triphosphate binding cassette transporter A
and G and scavenger receptor class B
type I (SR-BI).25 Adenosine triphosphate
binding cassette transporter A1 mediates the efux to small lipid poor HDL,
whereas SR-BImediates the efux to mature phospholipid rich HDL.26
In adults, Brites et al18 reported that,
compared with control subjects, adult
subjects with low HDL cholesterol and
high triglycerides showed a reduced
capacity to promote cholesterol efux
from Fu5AH cells using either whole
serum or isolated HDL fractions. Another study conducted in adults27
found that cholesterol efux from
Fu5AH system to serum was preserved
in hypertriglyceridemic subjects with
normal HDL cholesterol; however, in
those with high triglycerides and low
HDL cholesterol a signicantly reduced
capacity of serum to promote cholesterol efux was observed. The reduced
cholesterol efux in our group of overweight adolescents with atherogenic
dyslipidemia is in agreement with
these studies in adults.18,27 The remarkable similarity between our results
and those reported in adults demonstrates that the abnormal HDL efux
capacity already is present in dyslipidemic overweight adolescents. Together, these results indicate that HDL
from adolescents and adults with
atherogenic dyslipidemia are not only
low but also dysfunctional. The relevance of our ndings is highlighted by
a study17 suggesting that cholesterol
efux capacity may be an independent
predictor of cardiovascular risk, even
after adjusting for HDL cholesterol and
apoAI values. The prognostic implications of the HDL abnormalities found in
our group of overweight dyslipidemic
subjects are not known but may contribute to a higher cardiovascular risk.
The ability of HDL to promote cholesterol efux may be affected by HDL size,

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e1525

changes in the HDL lipid and protein

content, and by a number of HDL chemical modications. In vitro studies using the SR-BI model have shown that
large, phospholipid-rich HDL stimulated more cell cholesterol efux from
Fu5AH cells than small, lipid-poor HDL
particles.26,28 This is in line with our observation of a lower cholesterol efux
in group 1 adolescents, who had a
lower proportion of large HDL2 and HDL
particles with low phospholipid content. In fact, the multivariate analysis
performed in the whole population
studied showed that HDL cholesterol
concentration was the most important
variable signicantly and independently associated with cholesterol efux, explaining approximately 25% of
its variance (Table 3). When HDL cholesterol was not entered in the multivariate model, HDL2a emerged as an independently related variable to
cholesterol efux. This nding is in
agreement with the positive correlations observed between SR-BI cholesterol efux and mature HDL particles.26
It also is possible that HDL chemical
modications like oxidation, nitration,
and partial hydrolysis of apoAI, known
to occur in states of obesity and insulin
resistance,29 might have contributed
to the efux reduction in the overweight dyslipidemic adolescents.
In addition to physicochemical and
functional HDL abnormalities, overweight dyslipidemic adolescents
showed an adverse cardiovascular
risk factor prole, characterized by
high levels of insulin resistance
(HOMA-IR), systolic and diastolic blood

pressure, nonHDL cholesterol, small

LDL, and total cholesteroltoHDL cholesterol and apoB-to-apoAI ratios. Results of many studies have shown that
all these disorders are good predictors of cardiovascular disease. Moreover, a recent prospective study30
found that a high apoB-to-apoAI ratio
during childhood was superior to conventional lipid measurements in predicting an abnormal intima-media
thickness. Therefore, the present
study may have important clinical implications in the face of the worldwide
epidemic of overweight and obesity.
The results clearly indicate that the
prevalence of elevated plasma triglycerides combined with a low HDL cholesterol in overweight adolescents
uncovers a generalized metabolic disorder commonly associated with increased risk of developing diabetes
and cardiovascular disease. These adolescents represent a high-risk group
that should be targeted for aggressive
global prevention programs.
Our study has some potential limitations. First, SR-BI promotes both the
cell cholesterol efux to HDL and the
selective cholesterol uptake from HDL.
Thus, the movement of cholesterol via
SR-BI is bidirectional, and the net
movement of cholesterol via this receptor depends on the direction of the
cholesterol gradient.16 Therefore, as
described in Methods, we used Fu5AH
cells loaded with a large amount of
cholesterol to determine only cholesterol efux. Second, the removal of
cholesterol from arterial macrophage
foam cells is believed to be a critical

mechanism by which HDL protects

against development and progression
of atherosclerosis, but studies in vitro
have shown that SR-BI only has a minor
role in this process. Nonetheless, the
Fu5AH system (expressing SR-BI) is a
validated method that allows the assessment of the HDL capacity to promote cholesterol efux.

CONCLUSIONS
It is known that lipoprotein levels track
strongly from childhood and adolescence to adulthood, and abnormal lipoprotein concentrations in early life
may induce arterial changes that contribute to adult atherosclerosis. Our
results show that the simple measurement of HDL cholesterol and triglycerides allows for the identication of
overweight adolescents with a global
adverse atherogenic prole, including
physicochemical and functional abnormalities of HDL that may increase their
risk of future development of diabetes
and cardiovascular disease.

ACKNOWLEDGMENTS
We are grateful to the school authorities and to the adolescents and their
parents for making this study possible.
The authors also thank Dr Margarita
de la Llera-Moya and Dr George H.
Rothblat for providing the Fu-5AH cells
and for their assistance in the preparation of the cholesterol efux assays.
We also appreciate the kind collaboration of Maria del Carmen Gonzlez
Salazar for collecting anthropometric
measurements.

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e1527

Abnormal High-Density Lipoproteins in Overweight Adolescents With

Atherogenic Dyslipidemia
Aida Medina-Urrutia, Juan G. Juarez-Rojas, Guillermo Cardoso-Saldaa, Esteban
Jorge-Galarza, Rosalinda Posadas-Snchez, Rocio Martnez-Alvarado, Nac
Caracas-Portilla, Enrique Mendoza Prez and Carlos Posadas-Romero
Pediatrics 2011;127;e1521; originally published online May 9, 2011;
DOI: 10.1542/peds.2010-1395
Updated Information &
Services

including high resolution figures, can be found at:

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References

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html#ref-list-1

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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright 2011 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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Abnormal High-Density Lipoproteins in Overweight Adolescents With

Atherogenic Dyslipidemia
Aida Medina-Urrutia, Juan G. Juarez-Rojas, Guillermo Cardoso-Saldaa, Esteban
Jorge-Galarza, Rosalinda Posadas-Snchez, Rocio Martnez-Alvarado, Nac
Caracas-Portilla, Enrique Mendoza Prez and Carlos Posadas-Romero
Pediatrics 2011;127;e1521; originally published online May 9, 2011;
DOI: 10.1542/peds.2010-1395

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/127/6/e1521.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2011 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from pediatrics.aappublications.org by guest on June 25, 2015