Available online at www.sciencedirect.com
Nutrition Research 30 (2010) 689 – 694
www.nrjournal.com
Orange juice decreases low-density lipoprotein cholesterol in
hypercholesterolemic subjects and improves lipid transfer to high-density
lipoprotein in normal and hypercholesterolemic subjects
Thais B. Cesar a , Nancy P. Aptekmann b , Milena P. Araujo a ,
Carmen C. Vinagre b , Raul C. Maranhão b,⁎
b
a
Food and Nutrition Department, Sao Paulo State University (UNESP), São Paulo, SP, Brazil
Lipid Metabolism Laboratory, the Heart Institute (InCor), University of São Paulo Medical School Hospital - USP, São Paulo, SP, Brazil
Received 16 June 2010; revised 9 September 2010; accepted 13 September 2010
Abstract
Orange juice (OJ) is regularly consumed worldwide, but its effects on plasma lipids have rarely
been explored. This study hypothesized that consumption of OJ concentrate would improve lipid
levels and lipid metabolism, which are important in high-density lipoprotein (HDL) function in
normolipidemic (NC) and hypercholesterolemic (HCH) subjects. Fourteen HCH and 31 NC adults
consumed 750 mL/day OJ concentrate (1:6 OJ/water) for 60 days. Eight control subjects did not
consume OJ for 60 days. Plasma was collected before and on the last day for biochemical analysis
and an in vitro assay of transfers of radioactively labeled free-cholesterol, cholesteryl esters,
phospholipids, and triglycerides from lipoprotein-like nanoemulsions to HDL. Orange juice
consumption decreased low-density lipoprotein cholesterol (160 ± 17 to 141 ± 26 mg/dL, P b .01) in
the HCH group but not in the NC group. HDL-cholesterol and triglycerides remained unchanged in
both groups. Free-cholesterol transfer to HDL increased (HCH: 4.4 ± 2 to 5.6 ± 1%, NC: 3.2 ± 2 to
6.2 ± 1%, Pb .05) whereas triglyceride (HCH 4.9 ± 1 to 3.1 ± 1%, NC 4.4 ± 1 to 3.4 ± 1%, Pb .05)
and phospholipid (HCH 21.6 ± 2 to 18.6 ± 3%, NC 20.2 ± 2 to 18.4 ± 2%, P b .05) transfers
decreased in both groups. Cholesteryl-ester transfer decreased only in HCH (3.6 ± 1 to 3.1 ± 1%, P b
.05), but not in NC. In control subjects, plasma lipids and transfers were unaltered for 60 days. Thus,
by decreasing atherogenic low-density lipoprotein cholesterol in HCH and increasing HDL ability to
take up free cholesterol in HCH and NC, OJ may be beneficial to both groups as free-cholesterol
transfer to HDL is crucial for cholesterol esterification and reverse cholesterol transport.
© 2010 Elsevier Inc. All rights reserved.
Keywords:
Abbreviations:
Cholesterol; Orange juice; Human lipoproteins; Nanoparticles; Lipid transfer
apo A1, Apolipoprotein A-I; apo B, Apolipoprotein B; HDL, High-density lipoprotein; LDL, Low-density
lipoprotein; NC, Normocholesterolemics subjects; OJ, Orange juice; PMF, Polymethoxylated flavones; PON1,
Paraoxonase 1.
1. Introduction
⁎ Corresponding author. Laboratório de Metabolismo de Lípides,
Instituto do Coração do HC-FMUSP, Av. Dr. Enéas de Carvalho Aguiar,
Subsolo, 05403-000 São Paulo, SP, Brazil. Tel.: +55 11 30695951; fax: +55
11 3069 5574.
E-mail address: [email protected] (R.C. Maranhão).
0271-5317/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.nutres.2010.09.006
Orange juice (OJ) consumption has become a worldwide
dietary habit and, as a result, the consumption of frozen
concentrated juice has increased steadily over the years. Not
surprisingly, the market share of this product is now much
greater than that of fresh fruit, especially in developed
countries [1]. The concentrated product has a greater
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T.B. Cesar et al. / Nutrition Research 30 (2010) 689–694
flavonoid content; such as polymethoxylated flavones
(PMF), hesperitin and naringin, when compared to fresh
juice. This is due to the manufacturing grinding process
which uses the entire fruit to produce the juice [2]. Pectin and
essential oils contained in the peel are also found in greater
amounts in the concentrated juice [2].
In animal studies, supplementation with PMF, hesperitin,
and naringin reduced low-density lipoprotein (LDL) cholesterol, apolipoprotein B (apo B), and triglycerides [3,4]. The
few studies involving OJ consumption or orange extract of
flavonoids have reported beneficial effects on plasma lipids
[5,6]. In hypercholesterolemic subjects, consuming 750 mL
orange juice daily increased high-density lipoprotein (HDL)
cholesterol concentrations by 21% [5].
High-density lipoprotein, as other lipoprotein classes, is
synthesized in the liver or intestinal cells. However, it can
also be synthesized in the intravascular compartment as well
[7]. Apolipoprotein A1 (apo A1), which is synthesized by the
liver or by the small intestine, receives phospholipids and
cholesterol from cell membranes and from apo B containing
lipoproteins in the plasma [8]. This results in discoidal HDL;
which is converted to a larger, spherical HDL through
cholesterol esterification by lecithin:cholesterol acyltransferase, using apo A1 as a cofactor [8,9]. Cholesterol
esterification occurs mostly in the HDL fraction and is a
key process for cholesterol plasma pool stabilization [9].
Lipid transfer is facilitated by the so-called transfer
proteins, cholesteryl ester transfer protein and phospholipid
transfer protein, and involves all lipoprotein classes [10]. The
transfer of lipids to HDL is an essential metabolic step for
reverse cholesterol transport in which cholesterol from
peripheral tissues is shuttled back to the liver and excreted
in the bile. Lipid transfer also determines HDL composition
and, thus, the adhesion to the lipoprotein surface of proteins
related with HDL atheroprotection, such as the antioxidative,
anti-inflammatory, antiapoptotic, vasodilatory, antithrombotic, and anti-infection functions of the lipoprotein [11,12].
Despite the great importance of OJ as a widely consumed
dietary item, its effects on serum lipids have rarely been
investigated. The importance of alterations in the plasma
lipid profile and lipid metabolism in atherogenesis is well
established. This study investigated whether the ingestion of
considerably large amounts of concentrated OJ could affect
the lipid profile of hypercholesterolemic and normolipidemic
subjects. Furthermore, it was hypothesized that OJ consumption would improve the transfer of lipids (freecholesterol, cholesteryl esters, phospholipids and triglycerides) to HDL.
evaluated on the first and last day of the 60-day period of
orange juice consumption (750 mL/d). To monitor seasonal
variations, blood samples were collected at a 60-day interval
for biochemical analysis from a non OJ consuming control
group of 8 subjects: 3 normocholesterolemic (2 men and 1
women) and 5 hypercholesterolemic (1 man and 4 women)
individuals. An estimate by dietary inquiry of daily diet
composition of all participants is in Table 1.
Data on their physical characteristics are presented in
Table 2. The following inclusion criteria were observed:
little or no consumption of OJ, no vitamin or mineral
supplementation, no lipid-lowering medication or hormone
replacement therapy, fasting glucose below 100 mg/dL and
no kidney diseases, no alcohol drinking, no thyroid
problems, and no diabetes or any other metabolic diseases.
Both NC and HCH subjects were submitted to a 60-day
period of dietary supplementation with 750 mL/d frozen
concentrated OJ/water at 1:6 dilution, consumed at breakfast,
lunch, and dinner. Food intake of each participant was
assessed by means of a 3-day dietary inquiry before and after
the experimental period as previously described [13]. Food
intake was described in terms of portion sizes, and the
individual sugar and oil intake was calculated from the
questionnaire. Estimates of dietary energy and nutrient
intake obtained with the 24-hour recalls and food frequency
questionnaires were calculated by the NUTRI software,
version 2.5 (CIS, School of Medicine, Federal University of
São Paulo, SP, Brazil). Concentrated OJ was furnished to the
participants on a weekly basis. A dietitian maintained contact
with the participants to ensure comprehension of and
compliance with the dietary regimens. Participants were
advised not to change their normal diet or physical activities
during the study period.
The study protocol was approved by the Ethics
Committee of the Pharmaceutical Science Department of
the Sao Paulo State University. An informed written consent
was obtained from each participant.
2.2. Supplementation with orange juice
2. Methods and materials
A single batch of frozen concentrated OJ (65° Brix) was
provided by Citrosuco-Fischer Group S/A company (Matão,
Brazil). The OJ was stored in 900 mL bottles at 20°C.
Participants received one bottle of concentrated juice per
week and instructed on how to dilute it to 12° Brix for
consumption (1:6 OJ/water). No sugar was added. The
flavonoid content in 750 mL of OJ (chilled from concentrate)
was 42 mg of hesperitin and 12 mg of naringin [2]. Each
daily serving of OJ contained approximately 258 mg of
vitamin C, 135 μg of folate, 64 g of total sugar (2:1:1 of
sucrose:fructose:glucose), and 1.36 MJ (1318 KJ).
2.1. Participant subjects and study design
2.3. Plasma lipid determinations
Thirty-one normocholesterolemic (NC; 12 males and 19
females) and 14 hypercholesterolemic (HCH; 6 males and
8 females, with LDL cholesterol N130 mg/dL) subjects were
Blood samples were collected in tubes without anticoagulant, on day zero and on day 60 of the OJ supplementation
period. Serum was separated by centrifugation at 2500 rpm
T.B. Cesar et al. / Nutrition Research 30 (2010) 689–694
691
Table 1
Estimate by dietary inquiry of daily diet composition of NC (n = 31), HCH (n = 14) and control (n = 8) groups on the first and last day of the 60-day period of
orange juice consumption (750 mL/d)
Nutrients
NC
First day
Energy (KJ)
Total fat (g)
Saturated fat acid (g)
Cholesterol (mg)
Protein (g)
Carbohydrate (g)
Control a
HCH
6088 ± 1803
56 ± 30
2±1
523 ± 251
87 ± 43
204 ± 47
Last day
8381 ± 1987
55 ± 15
2±1
478 ± 284
78 ± 29
348 ± 91 b
b
First day
Last day
First day
Last day
7569 ± 3259
57 ± 28
1.5 ± 1
419 ± 185
95 ± 48
249 ± 97
8464 ± 1845
51 ± 19
2±1
352 ± 314
84 ± 36
340 ± 58 b
9192 ± 2540
76 ± 34
2±1
302 ± 179
104 ± 34
284 ± 105
9217 ±
68 ±
2±
350 ±
117 ±
269 ±
3268
30
1
273
63
101
Values are expressed as means ± SD.
a
Subjects did not drink orange juice or orange-derived products.
b
Comparison between first and last day in the same group (P b .001).
for 15 minutes and then stored at −80°C for 10 days for
biochemical analysis. Total plasma cholesterol and triglycerides were determined after a 12 h fast with commercial
enzymatic kits (CHOD_PAP, Merck, Darmstadt, Germany
and Abbott Laboratories, Abbott Park, Ill, respectively).
High-density lipoprotein cholesterol was determined by the
same method after precipitating LDL and very low-density
lipoprotein with MgCl2, and phosphotungstic acid. Lowdensity lipoprotein was estimated by the Friedewald
equation [14].
2.4. Assay for the lipid transfer from the donor
nanoemulsion to HDL
Blood samples were collected in tubes containing 0.1 %
EDTA as anticoagulant. Plasma was separated by centrifugation at 2500 rpm for 15 minutes and then stored at −80°C
until analysis. The nanoemulsion was prepared from lipid
mixtures composed of 40 mg cholesteryl oleate, 20 mg egg
phosphaditylcholine, 1 mg triolein and 0.5 mg cholesterol
purchased from Sigma (St Louis, Mo). Radioactive lipids
were purchased from Amersham International (Little
Chalfont, Buckinghamshire, UK) and were added to the
lipid mixtures. Two sets of nanoemulsions were prepared:
one labeled with 3H-cholesteryl oleate and 14C-cholesterol
and the other with 14C-phosphatidylcholine and 3H-triolein.
Lipid emulsification by prolonged ultrasonic irradiation in an
aqueous media and a two-step ultracentrifugation procedure
of the crude emulsion and addition of KBr to adjust density
in order to obtain the nanoemulsion was carried out as
described by Maranhão et al [15].
The in vitro assay of the transfer of the radioactive lipid
nanoemulsion to the HDL fraction has been described
elsewhere [16]. Briefly, the assay consisted of a 1-hour
incubation period for the 2 sets of nanoemulsions with plasma
followed by chemical precipitation of the apo B containing
lipoproteins and the nanoemulsion. The supernatant containing the HDL fraction was transferred to vials with scintillation
solution and radioactivity was counted in a Packard 1660 TR
model Liquid Scintillation Analyzer (Palo Alto, CA). The
transfer to HDL of the nanoemulsion lipids was calculated as
a percentage of the radioactivity of a given labeled lipid in the
nanoemulsion found in the HDL plasma fraction.
2.5. Paraoxonase 1 activity
Paraoxonase 1 (PON1) activity was measured by adding
serum to 1 mL Tris-HCl buffer (100 mmol/L, pH 8.0)
Table 2
Physical characteristics and serum laboratorial data of normocholesterolemic (NC, n = 31), hypercholesterolemic (HCH, n = 14) and control (n = 8) groups on the
first and last day of a 60-day period of orange juice consumption (750 mL/d) a
Variables
NC
First day
Last day
First day
Last day
First day
Last day
Age (y)
Body mass index (kg/m2)
Waist circumference (cm)
Cholesterol (mg/dL)
Total
LDL
HDL
Triglycerides (mg/dL)
35.8 ± 11.6
24 ± 4
83 ± 10
35.8 ± 11.6
24 ± 4
84 ± 11
42.3 ± 14.2
28 ± 5
96 ± 13
42.3 ± 14.2
28 ± 5
96 ± 13
44 ± 12
30 ± 6
99 ± 13
44 ± 12
30 ± 5
99 ± 14
174 ± 26
101 ± 17
50 ± 13
104 ± 51
168 ± 38
98 ± 31
48 ± 11
113 ± 56
229 ± 21
160 ± 17
43 ± 7
130 ± 43
211 ±
141 ±
45 ±
146 ±
30 ⁎
26 †
7
52
212 ± 28
142 ± 26
44 ± 13
128 ± 53
221 ± 40
147 ± 36
44 ± 12
161 ± 64 ⁎
a
HCH
Control
Values expressed as means ± SD. Blood samples taken on day 0 and on day 60 to control for seasonal variations. Comparison between first and last day in
the same group.
⁎ P b .01.
†
P = .007.
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T.B. Cesar et al. / Nutrition Research 30 (2010) 689–694
containing 2 mmol/L CaCl2 and 5.5 mmol/L paraoxon
(Sigma). The generation of p-nitrophenol was measured at
405 nm, at 37°C, for 6 minutes in 1-minute intervals, in a
Bio-Rad Benchmark Microplate Reader (Nippon Bio-Rad,
Tokyo, Japan) [17].
2.6. Statistical analyses
All values are expressed as means ± SD. The paired
Student t test was used to compare the means obtained
before and after the experiment period for the 3 groups.
Statistical analysis of the data was obtained with the Sigma
Stat software version 3.11 (Sigma Stat for Windows, Systat
Software Inc, San Jose, Calif). Statistical significance was set
at P b .05.
3. Results
An energy intake increase of about 38% occurred after the
introduction of the OJ in the NC subjects (Table 1). After the
OJ intake period, the NC and HCH subjects presented an
increase in the ingestion of carbohydrates of 77% and 55%,
respectively (P b .001).
Body mass index and waist circumference of the subjects
of the three study groups were not altered during the study
period, as can be seen in Table 2.
OJ supplementation had no effect on LDL or HDLcholesterol or triglycerides in the NC subjects. However, in
the HCH subjects, there was a 12% decrease in LDLcholesterol after the OJ intake period; whereas HDLcholesterol and triglycerides remained unchanged (Table 2).
In the NC subjects, OJ intake elicited a 48% increase in
free cholesterol transfer and 9% decrease in the transfer of
phospholipids (P b .001). As for the transfer of core lipids in
this group, the triglyceride transfer diminished by 23%, but
the cholesteryl ester transfer remained unaffected by OJ
(Table 3).
In the HCH subjects, free cholesterol transfer increased by
22%; whereas the phospholipid transfer decreased 10% (P b
.05), triglyceride transfer diminished 23% and cholesteryl
ester transfer decreased 14% (P b .01) after OJ consumption
(Table 3).
The activity of the antioxidative enzyme PON1 decreased
only in the NC subjects and was unchanged in the HCH
subjects (Table 3).
In the control group, the lipid profile and transfer of lipids
to HDL and PON1 activity were similar at the first
evaluation and second evaluation after 60 days, without
OJ consumption.
4. Discussion
In this study, the ingestion of 750 mL/day of OJ
concentrate for two months resulted in a reduction of LDLcholesterol in HCH subjects; whereas in NC subjects, this
reduction was not statistically significant. In both groups,
serum triglycerides and HDL-cholesterol were unchanged.
It was recently shown that 500 mL/day of OJ associated
with aerobic training decreased LDL-C levels and increased
HDL-C in normolipidemic, overweight, middle-aged
women. However, these effects were not observed in
women under the same aerobic training program who did
not consume orange juice [18]. Kurowska et al [5] reported
that consuming 250 or 500 mL/d of orange juice did not alter
lipid levels in hypercholesterolemic subjects. However, the
consumption of 750 mL/day, in contrast with our data, did not
decrease LDL-cholesterol levels but increased HDL-cholesterol. On the other hand, plasma triglycerides increased, an
undesirable effect which was not observed in our study. Roza
et al [6] supplemented hypercholesterolemic subjects with
PMFs extracted from orange peels. They reported that
supplementation lead to a reduction of both LDL-cholesterol
and triglycerides but did not significantly alter HDLcholesterol. In studies performed in rats, the hypocholesteromic effect of PMFs were obtained by inhibiting 3Hydroxy-3-methyl-glutaryl coenzyme A reductase and
increasing the expression of LDL receptors in the liver
[3,4]. This is essentially the same mechanism whereby
cholesterol reduction is achieved through treatment with
Table 3
Lipid values (cholesterol ester, phospholipids, triglycerides, and free cholesterol) transferred from a donor nanoemulsion to HDL and Paraoxonase (PON1)
activity of normocholesterolemic (NC, n = 31), hypercholesterolemic (HCH, n = 14) and controls (n = 8) obtained in the first and in the last day of a 60-day of
orange juice consumption (750 mL/day) a period
Lipd Transfer to the
HDL Fraction %
Phospholipids
Free cholesterol
Cholesteryl esters
Triacylglycerols
PON1 (nmol/mL/min)
NC
First day
20.2 ± 2
3.2 ± 2
3.1 ± 1
4.4 ± 1
64 ± 44
HCH
Last day
††
18.4 ± 2
6.2 ± 1 ††
3.0 ± 1
3.4 ± 1 ††
54 ± 42 †
Control
First day
Last day
First day
Last day
21.6 ± 2
4.0 ± 2
3.6 ± 1
4.9 ± 1
38 ± 25
18.6 ± 3 ⁎
5.6 ± 1 ⁎
3.1 ± 1 †
3.1 ± 1 †
40 ± 17
18.9 ± 1
6.7 ± 1
3.9 ± 1
4.9 ± 1
97 ± 43
18.6 ±
6.0 ±
3.6 ±
4.4 ±
96 ±
a
Values expressed as means ± SD. Comparison between first and last day in the same group.
⁎ P b .05.
†
P b .01.
††
P b .001.
3
2
1
1
46
T.B. Cesar et al. / Nutrition Research 30 (2010) 689–694
statins. The reduction in LDL-cholesterol elicited by OJ
consumption in the HCH group cannot be ascribed to changes
in dietary cholesterol: those changes were not detected in the
dietary questionnaire and slight changes in cholesterol intake
are unlikely to influence LDL-cholesterol levels.
As hypothesized, in respect to the lipid transfers to HDL,
OJ consumption elicited marked changes in this process
despite the HDL cholesterol remaining unchanged. The most
relevant change occurred in the transfer of free cholesterol,
which increased in both the HCH and NC groups. As is
commonly known, the free form of cholesterol is unstable
and is stored in cells in its esterified form. In the plasma,
cholesterol is esterified by lecithin:cholesterol acyltransferase [8]. This reaction occurs mainly in HDL and apo A1, the
main HDL apolipoprotein, being the cofactor. Substrate free
cholesterol is transferred to HDL by transfer from other
lipoprotein classes or from cells, by the adenosine
triphosphate-binding cassette transporter A1 complex mediated by the cholesterol efflux after hydrolysis of the
esterified form, the initial step of reverse cholesterol
transport [19,20]. Therefore, despite our findings of
increased free cholesterol transfer to HDL, which may be
interpreted as a favorable effect of OJ intake, it appears to
assist in the esterification process.
A further potential benefit of OJ consumption on lipid
transfers (which occurred in both the NC and HCH subjects
in our study) was the decreased triglyceride transfer to HDL.
Increase in triglyceride transfer to HDL, as occurs in
hypertriglyceridemia, may determine a greater instability of
the lipoprotein particles, which, in turn, may affect HDL
antiatherogenic properties [21]. Hepatic lipase hydrolyzes
triglyceride-enriched HDL to form small dense HDL
particles. Such small dense HDL particles of abnormal
composition (high triglyceride/cholesteryl ester ratio) have a
shorter half-life in the plasma than larger HDL particles. As a
result of this, HDL levels fall [21]. Therefore, a decrease in
triglyceride transfer to HDL may be a favorable effect of OJ
consumption. The reduction of phospholipids by OJ intake is
complex to interpret, as is the reduction of cholesteryl ester
transfer in the HCH group. A recent study reported that HDL
enrichment with phospholipids may facilitate reverse
cholesterol transport [22].
Alterations in lipid transfer can be ascribed to changes in
the action of cholesteryl ester transfer protein and phospholipid transfer protein; the status of lipoprotein composition
and concentration [23]. This last factor can be discarded
since study subjects of both groups did not have their HDLcholesterol affected by the orange juice intake. As PMFs
contained in OJ concentrate may affect lipid regulatory
proteins such as 3-Hydroxy-3-methyl-glutaryl coenzyme A
reductase in the liver, the possibility may exist that PMFs
may also influence the hepatic synthesis of transfer proteins.
It should be noted that those transfer changes did not alter
PON1 activity. Paraoxonase 1 is associated with the HDL
fraction and is related to the antioxidant functions of HDL
[24]. The fact that no alterations of the enzyme activity were
693
found suggests that whatever changes occurred in HDL
composition as a consequence of the changes in lipid
transfer to the lipoprotein were not sufficient to influence
enzyme activity.
Recruitment difficulties and drop-outs were limitations to
this study, thus the HCH group was pronouncedly smaller
than the NC group. As there are clear OJ dose-response
effects, lower OJ intakes should also be tested. Differences
in fructose and glucose intake, eventually resulting from the
introduction of OJ supplementation, did not cause changes
in triglycerides.
In conclusion, OJ consumption leads to a reduction of
LDL-cholesterol in HCH, an effect that is undoubtedly antiatherogenic. On the other hand, OJ consumption did not alter
HDL-cholesterol. Nonetheless, the changes in HDL metabolism by OJ, i.e., the increase in the transfer of freecholesterol and the decrease in transfer of triglycerides, may
favor HDL function in cholesterol reverse transport and
cholesterol esterification. These changes may also protect the
lipoprotein from rapid degradation in the plasma and prevent
a fall in HDL-cholesterol levels. These effects were observed
regardless of the presence of hypercholesterolemia or not.
Considering the results of this study, the effects of OJ
consumption can be considered beneficial to both subjects
with normal lipids and those with hypercholesterolemia.
Acknowledgment
This study received support from the Citrosuco-Fischer
Group S/A, São Paulo, Brazil. Maranhão is a Research
Awardee of the National Scientific and Technology Council,
Brasília, Brazil.
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