VOLUME 16 NUMBER 6 | JUNE 2008 | www.obesityjournal.org
nature publishing group
Obesity-related Changes in High-density
Arshag D. Mooradian1, Michael J. Haas1, Kent R. Wehmeier1 and Norman C.W. Wong2
Obesity is associated with a 3-or-more-fold increase in the risk of fatal and nonfatal myocardial infarction (1–6). The
American Heart Association has reclassified obesity as a major, modifiable risk factor for coronary heart disease (7). The
increased prevalence of premature coronary heart disease in obesity is attributed to multiple factors (8–10).
A principal contributor to this serious morbidity is the alterations in plasma lipid and lipoprotein levels. The dyslipidemia
of obesity is commonly manifested as high plasma triglyceride levels, low high-density lipoprotein cholesterol (HDLc),
and normal low-density lipoprotein cholesterol (LDLc) with preponderance of small dense LDL particles (7–10). However,
there is a considerable heterogeneity of plasma lipid profile in overweight and obese people. The precise cause of this
heterogeneity is not entirely clear but has been partly attributed to the degree of visceral adiposity and insulin resistance.
The emergence of glucose intolerance or a genetic predisposition to familial combined hyperlipidemia will further modify
the plasma lipid phenotype in obese people (11–15).
Obesity (2008) 16, 1152–1160. doi:10.1038/oby.2008.202
The major lipoprotein constituents of
HDL are apolipoprotein A-I (apo A-I)
and apo A-II. Whereas apo A-I has car-
dioprotective properties, apo A-II has
been associated with increased risk of
atherosclerosis in animal models (16,17).
Metabolic and nutritional correlates of
obesity commonly alter the production
of apo A-I and other lipoproteins.
In this review, the obesity-related
changes in HDL metabolism will be
reviewed and the potential mechanisms
contributing to these changes will be
discussed. The direct and indirect effects
of interventions targeting body weight
reduction will also be discussed briefly.
Biological functions of HDl anD
Heterogeneity of HDL can be catego-
rized either based on its lipid composi-
tion, a major determinant of its size and
density, or based on apoprotein compo-
sition. HDL2, HDL3 and pre-βHDL rep-
resent the largest most buoyant to smaller
and denser HDL particles, respectively
(16–18). The other categorization of HDL
based on apoprotein content identifies the
HDL that is mostly apo A-I or a mixture
of apo A-I and apo A-II, referred to as
LpA-I and the LpA-I:A-II, respectively.
Additional minor apolipoprotein compo-
nents of HDL are apo Cs (i.e., C-I, C-II,
and C-III) and apo E. The latter is a ligand
for hepatic LDL and apo E receptors and
mediates the uptake of a subgroup of
HDL particles such as HDL1. Apo C-I is
an activator of lecithin-cholesterol acyl-
transferase (LCAT), apo C-II activates
lipoprotein lipase (LPL), and apo C-III is
an inhibitor of hepatic lipase (HL) (18).
Although HDL2 is considered more
cardioprotective than HDL3, there
remains considerable uncertainty regard-
ing the role of each HDL species. Simi-
larly, the role of apo A-II in promoting
or inhibiting cholesterol efflux is also
controversial. The potential deleterious
effects of apo A-II include inhibition of
LCAT and hepatic cholesterol uptake
through its effects on scavenger receptor
class B type 1 receptor (18). However, apo
A-II also has potential beneficial effects
such as inhibition of cholesteryl-ester
transfer protein (CETP) and increasing
HL activity (18).
The cardioprotective effects of HDLc
and apo A-I have been attributed to mul-
tiple mechanisms (16–18). These mecha-
nisms will be discussed briefly.
reverse cholesterol transport
At the present time, reverse choles-
terol transport (RCT) is considered to
be the principal mechanism by which
HDL decelerates atherosclerotic process
(16–18). A schematic diagram showing
the major steps in the RCT is shown in
Figure 1. The process starts when the
nascent HDL particle composed mostly
of apo A-I takes up the cholesterol that
is exported from target tissues either by
diffusion or more importantly through
the action of ATP-binding cassette trans-
porter A1 (Figure 1). Subsequently, the
free cholesterol is esterified by LCAT, and
the HDL particle changes in geometry
from discoidal to spherical in shape. The
spherical HDL, namely HDL3, continues
to grow forming HDL2 by accepting addi-
tional cholesterol. The HDL2 transfers
1Department of Medicine, University of Florida College of Medicine, Jacksonville, Florida, USA; 2Faculty of Medicine, Departments of Medicine and Biochemistry and
Molecular Biology, University of Calgary, Calgary, Alberta, Canada. Correspondence: Arshag D. Mooradian (email@example.com)
Received 21 June 2007; accepted 11 August 2007; published online 3 April 2008. doi:10.1038/oby.2008.202
obesity | VOLUME 16 NUMBER 6 | JUNE 2008 1153
cholesterol to other lipoproteins such as
LDL and the very LDL (VLDL) through
the CETP or accepts free cholesterol and
phospholipids from hydrolysis of VLDL
mediated by LPL and facilitated by phos-
pholipid transfer protein (PLTP). Choles-
terol transferred off the HDL2 is replaced
by triglycerides. The hydrolysis of this
triglyceride by HL and the hydrolysis
of phospholipids by endothelial lipase
accelerate the renal clearance of the apo
A-I by cubulin, an endocytic receptor.
The cholesterol ester in the hydrophobic
core of the HDL particle is taken up in
the liver through the scavenger receptor
class B type 1 receptor. The apo A-I that
is released either re-enters the RCT cycle
or undergoes metabolic degradation or
It is noteworthy that the level of HDLc
does not predict the efficiency of RCT or
the cardio-protectiveness of HDL. Thus,
inhibition of CETP and the attendant
increase in HDLc level failed to reduce
cardiovascular events (19). In addition, a
common CETP promoter polymorphism
which leads to a significant decrease in
CETP gene transcription and thereby
leading to higher HDLc levels is para-
doxically associated with increased inci-
dence of coronary disease (20). These
observations underscore the importance
of understanding the metabolic pathway
regulating HDLc as a determinant of its
effects on coronary artery disease.
other atheroprotective mechanisms
One of the principal properties of HDL
that imparts cardioprotective function
is that it has antioxidant activity. This
has been demonstrated by the ability of
HDL to bind transition metals, and its
association with two enzymes, namely
paraoxonase and platelet activating factor-
Another important cardioprotective
feature of HDL is its anti-inflammatory
activity. This could be partly related to
its antioxidative potential or to its abil-
ity to increase intracellular ceramide
through inhibition of sphingosine kinase
(16–18). Recent proteomic analysis of
HDL implicated protease inhibition
and complement activation in the anti-
inflammatory properties of HDL particle
(21). Additional cardioprotective prop-
erties of HDL include scavenging toxic
by-products of LDL oxidation such as
botic and fibrinolytic activity through
promotion of protein C, and inhibition
of LDL retention through apo E-related
effects. (For more detailed review of the
topic, see refs. 16–18,22,23). The rela-
tive importance of each cardioprotec-
tive property of HDL is not known. It is
noteworthy that in vivo modification of
HDL may impair its function or render
it proatherogenic (24,25). The concen-
tration of HDLc may not reflect the true
functional attributes of this lipoprotein.
epiDemiology of low HDl in
Low HDLc is a common lipid disorder
in obesity especially in the context of
metabolic syndrome. The prevalence of
this syndrome is high especially in certain
ethnic groups (26–29). In a study of 8,814
men and women (>20 years old) partici-
pating in the Third National Health and
Nutrition Examination Survey (NHANES
III), there was 24% prevalence of meta-
bolic syndrome as defined by the National
Cholesterol Education Program (NCEP)
(27). The prevalence increases with age,
and 33–45% of subjects >50 years meet
the criteria for the metabolic syndrome
(28). Among NHANES III participants
with diabetes who were >50 years old, the
prevalence of metabolic syndrome was
86.0%, while 26% of normoglycemic indi-
viduals had metabolic syndrome accord-
ing to the NCEP definition (28). The most
common component of the metabolic
syndrome in US adults ≥20 years was
obesity (39%) followed immediately by
the low HDLc level (37%) (26,30).
The prevalence of low HDLc among
overweight and obese individuals is
variable. In obese people with a BMI >
30, the prevalence of low HDLc (<45 in
women and <35 mg/dl in men) is 40.6%
in women and 31.1% in men (31).
Low plasma HDLc level in obesity
can occur in the presence or absence of
hypertriglyceridemia. It is estimated that
~50% of obese people without hypertrig-
lyceridemia have reduced HDLc (32). The
pathophysiology of low HDLc in this
large subgroup of individuals is probably
distinct from those who have high plasma
effect of oBesity on HDl
metaBolism anD rct
In obesity, the reduced plasma HDLc
levels have been attributed to increased
fractional clearance of HDL secondary to
depletion of its cholesterol (33,34).
Several key enzymes involved in HDL
metabolism are altered in obese people
with insulin resistance (Table 1). Some of
these changes are further accentuated in
type 2 diabetes where in addition to insu-
lin resistance, relative or absolute insulin
deficiency may augment the abnormali-
ties in RCT. Cellular cholesterol efflux
figure 1 Reverse cholesterol transport and high-density lipoprotein (HDL) metabolism.
Phosholipid (PL) and free-cholesterol (FC) are taken up by preβ-1 HDL utilizing the transporter
ATP-binding cassette protein A1 (ABCA1) to form HDLα-4 (α-4). FC is converted to cholesterol
ester (CE) by lecithin-cholesterol acyltransferase (LCAT), lipids are released by lipoprotein
lipase (LPL) and hepatic lipase (HL), and the HDL is converted to larger, less-dense
lipoproteins forming HDLα-2 and HDLα-1. CE is taken up by liver parenchymal cells via scavenger
receptor-B1 (SR-B1). Both free-apolipoprotein A-I (apo A-I) and preβ-1 HDL are catabolized
in the kidney after binding to the cubulin receptor. EL, endothelial lipase; PLTP, phospholipids
VOLUME 16 NUMBER 6 | JUNE 2008 | www.obesityjournal.org
to normocholesterolemic normotrig-
lyceridemic diabetic plasma is probably
impaired, partly because of impaired
actions of the cholesterol transporter
ATP-binding cassette transporter A1
and scavenger receptor class B type 1
However, the capacity of plasma to
facilitate cholesterol efflux from cultured
fibroblasts can be modulated by con-
founding variables that are commonly
found in people with diabetes. Thus, cho-
lesterol efflux to plasma may be increased
in type 1 diabetic subjects with moder-
ate hypercholesterolemia (35). Similarly,
cholesterol efflux may be increased in
type 2 diabetic subjects with hypertrig-
lyceridemia with associated increased
PLTP activity (36,37). PLTP promotes
the formation of nascent pre-βHDL par-
ticles that are the initial acceptors of cell-
derived cholesterol (36,37). Increased
HDLc and apo A-I in the subset of type
1 diabetic subjects with hypercholester-
olemia, and increased PLTP activity in
those with hypertriglyceridemia, may
effectively counteract the other diabetes-
related changes that inhibit cholesterol
efflux. Thus, cholesterol efflux studies
should be interpreted in the light of over-
all plasma lipid profile and other risks of
Insulin resistance is also associated
with a decreased postheparin plasma
LPL/HL ratio. This change contributes to
the low HDLc levels in obesity because
LPL activity promotes lipid availability
for HDL while HL hydrolyzes the HDL
triglyceride and phospholipids and ren-
ders the HDL particle more susceptible
to metabolic clearance (33).
The LCAT-mediated esterification of
cholesterol is either modestly increased
or unaltered in obese subjects with insu-
lin resistance while the CETP activity is
increased. The latter change depletes
HDL of its cholesterol and contributes
to lowering of HDL levels. It is notewor-
thy that neither CETP nor PLTP activ-
ity is independently associated with
insulin sensitivity, and PLTP activity is
increased as a result of the association of
plasma PLTP with plasma triglycerides
(33). It is not known whether hepatic
metabolism of HDL-derived cholesterol
and subsequent hepatobiliary transport
is altered in insulin resistance or in type
2 diabetes (33).
An important metabolic trigger for
reduced HDLc levels in obesity and
insulin resistance is the increased VLDL
production, at least partly because of
increased fatty acid flux to the liver (14).
This change promotes exchange of trig-
lyceride for HDLc ester through the
action of CETP. The triglyceride-enriched
HDL is then hydrolyzed through HL or
LPL, and apo A-I dissociates from smaller
HDL, is filtered by the glomerulus, and
degraded in renal tubular cells (17,18)
(Figure 2). The relative importance of this
pathway in individuals who do not have
increased VLDL production or hyper-
triglyceridemia is not known. It appears
that 50% of obese normotriglyceridemic
individuals have low HDLc levels (32).
In this population, the degree of adipos-
ity and insulin resistance continues to
be a major predictor of low HDLc. One
potential cause is the inability of insulin
to upregulate the apo A-I production in
those with insulin resistance (17,38,39).
It is also possible that insulin resistance
and low HDLc levels may have a common
mediator such as tumor necrosis factor-α
that is implicated in both obesity-related
insulin resistance and is found to down-
regulate the apo A-I gene expression and
can lower serum HDLc levels (40,41).
Serum leptin, adiponectin and highly
sensitive C-reactive protein levels did
not appear to be predictors of low HDLc
levels in normotriglyceridemic obese
Heterogeneity of HDLc turnover in
subjects with reduced concentrations of
plasma HDLc was demonstrated previ-
ously by Le and Ginsburg (42). In the
latter study, subjects with low HDLc
without hypertriglyceridemia had sig-
nificantly reduced HDLc production
rate while the fractional clearance rate
was not altered. The decreased HDLc
production rate could be the result of
either decreased apo A-I production
or decreased cholesterol ester assembly
figure 2 Remodeling of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) by
cholesteryl-ester transfer protein (CETP). Cholesterol esters (CEs) are transferred to LDL from
HDLα-1 (α-1) by the enzyme CETP in exchange for triglyceride (TG), changing the density of both
lipoproteins. HDL can then be taken up by the liver or catabolized and cleared by the kidney. apo
A-I, apolipoprotein A-I; HL, hepatic lipase; LPL, lipoprotein lipase; SR-B1, scavenger receptor-B1;
VLDL, very low-density lipoprotein.
table 1 obesity or insulin resistance-related alterations in reverse cholesterol
transport and HDl metabolism
I Reduced efflux of cholesterol from peripheral cells; more pronounced in type 2 diabetes
unless the plasma triglyceride level is high and PLTP activity is increased
IIAbnormal HDL remodeling
IIIUnaltered esterification of cholesterol by LCAT
IV Increased uptake of HDL cholesterol by SR-B1 possibly secondary to high HL activity
V CETP mediated transfer of cholesterol to apo B containing lipoproteins may be increased
CETP, cholesteryl-ester transfer protein; HDL, high-density lipoprotein; HL, hepatic lipase; LCAT, lecithin-
cholesterol acyltransferase; PLTP, phospholipid transfer protein; SR-B1, scavenger receptor-B1.
obesity | VOLUME 16 NUMBER 6 | JUNE 2008 1155
on nascent HDL. A host of metabolic
changes commonly found in obese peo-
ple can alter apo A-I production. The
effects of these variables on the molecu-
lar mechanisms of reduced apo A-I in
obesity will be discussed.
effect of oBesity-relateD
cHanges on apo a-i expression
The literature on the effect of the meta-
bolic changes commonly associated with
obesity on apo A-I production is extensive
(Table 2). Obesity is associated with insu-
lin resistance, hyperinsulinemia, carbohy-
drate intolerance, increased production of
adipokines and inflammatory cytokines,
changes in prostaglandin metabolism, and
neuroendocrine hormonal changes that
affect apo A-I production.
Insulin signaling and glucose metab-
olism are important modulators of apo
A-I production. Studies in vivo and in
hepatocyte cell cultures have shown that
glucose suppresses and insulin upregu-
lates the expression of apo A-I protein
and its mRNA (38,39). These changes
occur at the transcriptional level where
the apo A-I promoter activity is sup-
pressed by dextrose and stimulated by
insulin in a dose-dependent fashion (38).
A 50-base pair fragment spanning nucle-
otides −425 to −376 within the promoter
mediates the effects of both dextrose
and insulin. Within this DNA frag-
ment, between −411 and −404, there is
an insulin response core element. Muta-
tion of this motif abolishes the effects of
both insulin and dextrose. However,
it is likely that there are additional
within the promoter (38).
The stimulatory effect of insulin on
apo A-I promoter is also observed with
insulinomimetics such as bisperoxo
(1, 10-phenathroline) oxovanadate (bpv)
and the protein kinase C activator phor-
bol ester phorbol-12, 13-dibutyrate (39).
However, insulin sensitization with thiaz-
olidendiones may not always be sufficient
to induce apo A-I expression (43,44).
Moreover, insulin therapy fails to cor-
rect the metabolic abnormalities of apo
A-I in people with type 2 diabetes (45).
Another argument against a direct role of
insulin resistance is the observation that
insulin resistance and hyperinsulinemia
induced with a high-fructose diet in rats
is associated with increased apo A-I lev-
els (46). Similarly, aging in rats is associ-
ated with increased expression of apo A-I
although it is accompanied with insulin
resistance (47). These observations may
well be species-specific or may be viewed
as suggestive evidence that insulin resis-
tance per se is not a direct cause of low
apo A-I and HDLc in obesity. It is note-
worthy that observational data derived
from the Lipid Research Clinics indicate
that HDLc rises after the age of 40 years
in white men and in white women who
are nonsex hormone users (48).
The potential mediators of insulin
resistance in obesity include increased
plasma free-fatty acid concentrations
or increased muscle and hepatic tissue
content of triglycerides, increased pro-
duction of leptin, inflammatory cytok-
ines such as tumor necrosis factor-α, and
possibly other yet unidentified humoral
The free-fatty acid may have a dir-
ect albeit a modest effect on apo A-I
production. Free-fatty acid treatment
of human hepatoma cell line Hep G2
abolishes insulin activation of apo A-I
promoter. However, basal apo A-I gene
expression is not altered (50).
Another potential mediator of insulin
resistance is leptin (49). Plasma leptin
levels correlate with body adiposity and
hyperleptinemia occurs in diet-induced
models of insulin resistance (51,52).
However, treatment of HepG2 cells with
leptin over a wide concentration range
(0–100 ng/ml) does not alter apo A-I
promoter activity, apo A-I protein syn-
thesis, or apo A-I mRNA levels (A.D.M.
and M.J.H., unpublished data). These
observations do not support a role of lep-
tin in contributing to the obesity-related
reduction in apo A-I levels.
Inflammatory cytokines are impli-
cated in obesity-related insulin resis-
tance (49). Tumor necrosis factor-α
and interleukin-1β reduce apo A-I
gene expression in a dose-dependent
manner (40). This effect occurs at the
trans criptional level through reduc-
tion in apo A-I promoter activity and is
mediated through extracellular-signal
regulated kinase and c-jun-N-terminal
kinase signaling and a cytokine respon-
sive element within site A of the pro-
Prostanoids are implicated in insu-
lin signaling in the liver and therefore
may modulate the apo A-I expression.
In addition, some prostanoids are
ligands of peroxisome proliferator–
activator receptors (53), and peroxisome
proliferator–activator receptors are
implicated in the regulation of apo A-I
expression (54). Decreasing prostaglan-
din synthesis through cyclooxygenase
inhibition with indomethacin down-
regulates apo A-I protein and mRNA
expression at a transcriptional level (55).
This effect could not be attributed to
either arachidonic acid excess or to a
deficiency in various prostanoids tested
including prostaglandin I2, thrombox-
ane B2, (±) 5-HETE or (±) 12-HETE,
and prostaglandin E1 and E2 (55). Thus,
the underlying mechanism of indo-
methacin-related downregulation of
apo A-I expression is not known.
Obesity-related reduction in apo A-I
is not only related to increased plasma
table 2 obesity-related metabolic changes that may alter hepatic apo a-i gene
Metabolic variables Effect on apo A-I References
Insulin resistance Inhibit38,39
Increased FFA Inhibit insulin-mediated effects50
No effect on basal rate of transcription
No effect A.D.M. and M.J.H.,
apo A-I, apolipoprotein A-I; FFA, free-fatty acid; IL-1β, interleukin-1β; TNF-α, tumor necrosis factor-α.
VOLUME 16 NUMBER 6 | JUNE 2008 | www.obesityjournal.org
clearance of the protein but also is the
result of down regulation of apo A-I pro-
duction. Although the precise nature for
this change is not known it is likely that
increased cytokine production and pos-
sibly impaired insulin signaling or car-
bohydrate intolerance may contribute
significantly to the inhibition of apo A-I
effect of nutrient intake on
HDlc anD apo a-i
The effect of obesity on HDLc and apo A-I
levels is modulated by nutrient consump-
tion. Total caloric intake and consump-
tion of specific nutrients have significant
effects on plasma HDLc concentration.
Since medical nutrition therapy consti-
tutes the cornerstone of obesity manage-
ment, it is essential to understand the
mechanisms underlying the changes in
HDLc level in response to alterations in
effect of caloric intake
Total energy flux has an important role in
modulating the plasma levels of HDLc.
In addition, weight loss is associated with
increased LPL levels and LCAT activity
that contribute to the increased choles-
terol esterification and RCT (56).
A meta-analysis of 70 studies indi-
cated that reduced caloric intake during
a weight reducing program is associated
with a temporary decline in HDLc (57).
Once a stable weight is achieved, HDLc
is increased. It is estimated that for every
kilogram decrease in body weight, a
0.35 mg/dl (0.009-mmol/l) increase in
HDLc occurs for subjects at a stabilized
body weight, while HDLc will decrease
by 0.27 mg/dl (0.007-mmol/l)/kg lost in
subjects actively losing weight (57).
In some studies where pharmaco-
logic agents were used for weight loss,
the rise in HDLc is more favorable than
what would be expected from weight
loss secondary to caloric restriction
alone. In clinical trials with appetite
suppressant sibutramine, a loss of
10 lb (4.5 kg) was associated with 20.7%
increase in HDLc while total choles-
terol was decreased by 16% and LDLc
decreased by 12% (58).
Selective CB1-receptor blockade with
rimonabant significantly reduces body
weight and improves the lipid profile (59).
As compared with placebo, rimonabant
at a dose of 20 mg was associated with
a mean weight loss of 5.4 kg along with
~10.0% increase in HDLc (59). Although
most of the effect on HDLc may well be
the result of weight loss and specifically
loss of abdominal fat, rimonabant may
have direct effects on apo AI production;
some laboratory experiments suggest that
endocannabinoids may have suppressive
effect on apo A-I gene transcription (60).
Orlistat, a gastrointestinal lipase inhibi-
tor that reduces dietary fat absorption by
30%, promotes modest weight loss of
~5% of body weight, reduces the LDLc
levels but is not associated with increased
plasma levels of HDLc (61,62). The lack
of favorable change in HDLc level after
orlistat treatment could be secondary to
limited weight reduction or more likely
related to the altered nutrient absorp-
tion notably reduced saturated fatty acid
influx. The latter is known to be an impor-
tant modulator of HDLc levels (16).
Gastric reduction surgery is an effec-
tive weight loss treatment for obesity. It
is associated with reduction in caloric
consumption as well as in changes in
neuroendocrine hormones of the gut.
The effect of these changes on HDL
physiology is not well studied. However,
in the Swedish Obese Subjects Study, a
10-year follow-up of individuals under-
going bariatric surgery has found that all
cardiovascular risk factors except hyper-
cholesterolemia improved in the surgical
patients (63). In these studies, the body
weight in the control group increased
by 0.1% after 2 years of follow-up while
it decreased by 23.4% in the surgery
group (63). After 10 years, the weight
had increased by 1.6% in controls and
decreased by 16.1% in surgery group (63).
Recovery from hypertension, diabetes,
hypertriglyceridemia, a low HDLc level,
and hyperuricemia was more frequent
in the surgical group than in the control
group, both at 2 and 10 years of follow-up.
Hypercholesterolemia did not improve
significantly in the surgical group.
Caloric restriction to achieve desirable
body weight either with life style changes
alone or when coupled with pharmaco-
logic or surgical interventions may have
cardio-protective effects (64,65).
effect of Dietary composition
The response of plasma lipids to dietary
changes depends on genetic factors and
the individual’s lipid phenotype (66).
Overall, replacing saturated fat with car-
bohydrate in the diet is associated with
reduced HDLc along with reduced LDLc
and increased triglycerides levels (67–71).
Conversely, replacement of dietary car-
bohydrate with fat results in lower trig-
lyceride and higher HDLc concentrations
if the body weight is not altered. Thus, a
diet rich in glycemic load is associated
with reduced HDLc levels (69)
The effect of replacing saturated fat with
monounsaturated or polyunsaturated fat
on HDLc is less dramatic. In general,
reducing dietary intake of saturated fat
is associated with reduced plasma cho-
lesterol content of various lipoproteins
including HDL (67–70). The reduced
cholesterol content of HDL accelerates
The mechanisms by which saturated
fatty acids and cholesterol raise plasma
HDLc do not involve transcriptional reg-
ulation of the apo A-I gene (50). Under
basal conditions, free-fatty acid treat-
ment of HepG2 cells do not alter apo A-I
mRNA or its protein levels but they can
abolish insulin and transcription factor
Sp-1-stimulated activation of the apo A-I
promoter (50). In contrast, unsaturated
fatty acids had no effect on Sp1-mediated
induction of the apo A-I promoter. The
overall contribution of these changes
in apo A-I gene transcription to overall
changes of HDLc is probably small. In
contrast, the changes in HDLc turnover
are more important. Thus, polyunsatu-
rated fatty acids upregulate hepatic scav-
enger receptor class B type 1 expression,
increase HDLc ester transport to the liver,
and as a consequence, plasma HDLc level
is reduced (72). It is noteworthy that diets
enriched in saturated fatty acids, unlike
diets enriched in unsaturated fatty acids,
are associated with increased HDLc and
in apo A-II levels but not in apo A-I lev-
els (73). This effect is gender specific. In
general, men may have a more favorable
lipoprotein response to a low fat, low
cholesterol diet than postmenopausal
women (74,75). The selective changes
in apo AI and AII provide an addi-
tional rationale for the current dietary
obesity | VOLUME 16 NUMBER 6 | JUNE 2008 1157
recommendations of limiting intake of
saturated fat in the diet.
The triglyceride-lowering effect of
omega-3 fat consumption is well estab-
lished (76). Sometimes, omega-3 fatty
acid–related decrease in plasma triglycer-
ide level is associated with a modest reduc-
tion in HDLc possibly through increasing
the fractional catabolic rate of medium-
sized HDL particles (76). However, clini-
cal trials with a purified omega-3 fatty acid
formulation, namely Omacor, have shown
either a modest increase or no change in
plasma HDLc levels. It is possible that the
increased fractional catabolic clearance of
HDLc is counterbalanced and sometimes
superseded by the reduced CETP-mediated
exchange of HDL-cholesterol ester for
The effect of monounsaturated fatty
acids on apo A-I expression in liver is
comparable with the effects of polyun-
saturated fatty acids (78). Trans-fatty
acids or hydrogenated fat–enriched diets
increase LDLc levels, and either decrease
or have no effect on HDLc and apo A-I
The effect of monosaccharides
other than glucose on apo A-I gene
expression has not been well studied.
Fructose-enriched diets may increase
cardiovascular risk factors, especially
in hyperinsulinemic men (83). How-
ever, consumption of fructose as high as
60 g/day incorporated in the normal diets
of 13 type 2 diabetic patients did not sig-
nificantly alter fasting serum lipids and
apo A-I and B-100 levels (84).
The effect of dietary protein on HDLc
is not well studied (85,86). Some proteins
such as soy protein have a unique, albeit,
modest direct effects on HDLc (87,88).
Often it is not possible to determine the
effects of protein independently of the
effects of changing the proportions of
fat and carbohydrates in the diet (85).
Replacing carbohydrates with protein in
the Optimal Macro-Nutrient Intake Heart
Trial to Prevent Heart Disease (OMNI-
Heart) have shown modest improvements
in blood pressure and HDLc levels (89).
This is probably the result of limiting the
glycemic load rather than a consequence
of increasing the protein load (69).
Commonly used nutritional supple-
ments also affect HDLc metabolism.
Large doses of antioxidant vitamins may
partially blunt HDLc induction by sim-
vastatin and niacin combination therapy
(90). The apo A-I promoter is sensitive to
the oxidative state of the cell and some
antioxidants, at high concentrations,
can suppress apo A-I promoter activity
(91). Apo A-I gene transcription is also
affected by large doses of vitamin D (92)
and vitamin A (93). Optimal concentra-
tion of these vitamins are needed for apo
A-I gene expression. The relationship
between vitamin D, HDLc, and obesity
has been the subject of several epidemio-
logic studies. Parikh et al. in a cohort of
300 otherwise healthy individuals showed
an inverse relationship between body
mass index as well as fat mass when com-
pared with serum 25-hydroxyvitamin D
and 1,25-dihydroxyvitamin D (94). The
same inverse relationship of adiposity
and 25-hydroxyvitamin D was found
in a follow-up study (95). Using data
derived from NHANES III, Ford et al.
found that as serum 25-hydroxyvitamin
D levels rose, the prevalence of low HDLc
declined (96). A similar observation was
made in untreated subjects with polycys-
tic ovary syndrome, a disease associated
with insulin resistance. In the latter study,
25-hydroxyvitamin D levels were directly
correlated with serum HDLc (97).
Alcoholic beverages have significant
effects on HDLc. Moderate alcohol con-
sumption (1–2 drinks/day) may decrease
cardiovascular disease risk. This favorable
effect may be partly related to improved
plasma lipid profile with increased con-
centrations of HDLc (98,99). In addition,
treatment of hepatoma cells in culture
with alcohol significantly increases apo
A-I production while decreasing apo B
effect of exercise
Most programs targeting body weight
reduction include an exercise compo-
nent. Exercise increases HDLc levels
especially in people with high baseline
HDLc (>60 mg/dl) (101). In general, a rel-
atively high intensity exercise is required
for significant changes in plasma HDLc
concentrations. The magnitude of the
change in HDLc may depend on genetic
factors notably the genotypes of CETP
and endothelial lipase (102,103).
Although the effect of exercise is gen-
erally modest, it should be encouraged
because it helps maintain weight loss
and can also improve insulin sensitivity
independent of weight loss.
The low plasma HDLc concentrations
in obese people could be the result of a
number of metabolic changes. For sim-
plification purposes these changes can
be categorized into two general groups;
(i) increased fractional clearance of HDL
secondary to reduced cholesterol content,
and (ii) reduced production of the main
cardioprotective apoprotein, notably apo
A-I. Although low HDLc levels in obese
people are commonly a concomitant of
hypertriglyceridemia, it can occur inde-
pendently of elevated serum triglyceride
levels. In some obese subjects, the low
HDLc concentration may be secondary
to elevated serum levels of inflammatory
Recent observations with agents that
interfere with cholesterol ester transfer
suggest that the mechanistic determinant
of HDLc levels is an important predictor
of its cardioprotective properties. To this
end, caloric intake and select nutrients
play an important role in modulating
both the fractional clearance rate as well
as the rate of apo A-I gene expression.
Understanding the mechanisms of low
HDL in obesity will help in the develop-
ment of interventions that reduce the risk
of cardiovascular disease in people with
The authors declared no conflict of interest.
© 2008 The Obesity Society
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