Abdominal Obesity Insulin Resistance Health Essay

Published: 2021-07-09 23:00:03
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Authors:
Femke Tavernea, Patrick Couturea, Benoît Lamarchea*
aInstitute of Nutraceuticals and Functional Foods, Laval University, Quebec, Canada
Short title: Cholesterol homeostasis in metabolic syndrome
*Corresponding author and request for reprints:
Benoît Lamarche
Institute of Nutraceuticals and Functional Foods, Laval University
2440, boul. Hochelaga
Québec (Qc) Canada G1V 0A6
Phone: (418) 656-2131 ext. 4355
Fax: (418) 656-5877
e-mail address: [email protected]
KEY WORDS:
cholesterol homeostasis, abdominal obesity, insulin resistance, metabolic syndrome
*Manuscript
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Abstract
Reducing low-density lipoprotein-cholesterol (LDL-C) concentrations is the primary
therapeutic target for the prevention of coronary heart disease (CHD). However, several
other cardiometabolic risk factors such as the ones associated with metabolic syndrome also
predict an increased risk of CHD, often in the absence of elevated LDL-C concentrations.
Evidence is now emerging to suggest that whole-body cholesterol homeostasis, which is
perturbed in metabolic syndrome, may be related to the risk of CHD, independent of
concurrent variations in LDL-C. Studies have suggested that metabolic syndrome is
associated with an increased endogenous synthesis of cholesterol and reduced intestinal
cholesterol absorption. Both abdominal obesity and insulin resistance have been associated
with the subtle disruptions in cholesterol homeostasis seen in metabolic syndrome. This
review examines how abdominal obesity and insulin resistance may each contribute to
perturbations in whole-body cholesterol homeostasis in the context of metabolic syndrome.
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1. Introduction
Coronary heart disease (CHD) remains to date among the major causes of death in Western
societies [1-3]. Elevated plasma LDL-cholesterol concentrations are one of the most
important predictors of CHD risk and this is why reducing LDL-cholesterol is considered the
primary therapeutic goal to manage one’s risk of CHD [4, 5]. Statins are drugs of first choice
to lower LDL-cholesterol in both primary and secondary prevention of CHD. Meta-analyses
have also shown that statin treatment in primary prevention may lower cardiovascular
deaths by 11% [6]. In secondary prevention, LDL-cholesterol lowering with statins has been
shown to reduce mortality from CHD by 23% [7]. On the other hand, a large proportion of
patients on statins continue to develop CHD, thereby emphasizing the notion that an
elevated plasma LDL-cholesterol concentration is not the only risk factor to consider and
treat as part of a strategy to reduce CHD risk [8].
Accordingly, several studies have shown that men and women may still be at considerable
risk of CHD not based on their plasma LDL-cholesterol levels but rather on the number of
atherogenic LDL particles and their partitioning as large and small LDL [9]. Men with an
increased proportion of small LDL particles have been shown to have a 4-fold increase in risk
of ischemic heart disease (IHD), even in the presence of relatively normal plasma LDLcholesterol
levels [10]. We have also shown that men with increased LDL-cholesterol but low
apolipoprotein B levels (apoB), did not have an increased risk of IHD, whereas men with
both high LDL-cholesterol and high apoB levels had a significant 2-fold increase in IHD risk
[11]. These findings can be explained by the fact that plasma LDL-cholesterol only reflects
the mass of cholesterol that is found within the LDL fraction in plasma [5]. Plasma apoB
concentrations, which reflect the number of atherogenic particles in the plasma, including
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VLDL and IDL, are a better predictor of CHD risk than plasma LDL-cholesterol concentrations
[12-15].
Research has also shown that metabolic syndrome was associated with a 2-fold increase in
cardiovascular outcomes and a 1.5-fold increase in all-cause mortality [16]. Metabolic
syndrome has also been related to the risk of type 2 diabetes and cancer [17]. Various
clinical criteria to identify patients with MetS have been proposed and it is beyond the scope
of this review to discuss the value and relevance of these criteria [18]. In general, it is well
accepted that metabolic syndrome is a pro-thrombotic, pro-inflammatory state generally
characterized by abdominal obesity, insulin resistance, hypertension as well as blood lipid
disorders including high triglycerides and low HDL cholesterol, high apoB and small dense
LDL-cholesterol [19]. The escalating prevalence of metabolic syndrome in western countries
has a tremendous impact on the burden of these diseases. For example, in US adults the
prevalence of metabolic syndrome reached almost 25% in 2003, ranging from 6.7% in adults
between 20-29 until almost 45% in adults over 60 years of age [20]. It must be stressed that
a high plasma concentration of LDL-cholesterol is not considered a key feature of metabolic
syndrome and abdominal obesity [21]. On the other hand, both abdominal obesity and
metabolic syndrome are associated with a high concentration of small dense LDL particles [9,
22, 23]. Studies have also suggested that subtle disruptions in cholesterol homeostasis seen
with obesity, insulin resistance states and metabolic syndrome may play a key etiological
role in atherosclerosis and subsequent CVD thereby emphasizing the importance of
characterizing further whole-body LDL and cholesterol homeostasis beyond just cholesterol
concentrations. This paper provides an overview of the limited yet exciting literature on
cholesterol homeostasis as it relates to metabolic syndrome, abdominal obesity and insulin
resistance.
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2. Cholesterol homeostasis
Whole-body cholesterol homeostasis may be defined as the balance between endogenous
cholesterol synthesis, intestinal cholesterol absorption and whole-body cholesterol
clearance. As with many inter-related metabolic pathways cholesterol homeostasis is finely
tuned, all of the processes being counter-regulated by one another to achieve balanced
cholesterol concentrations in the body. While the liver is responsible for a significant
proportion of cholesterol produced endogenously (approximately 25%), many other tissues
and organs including the intestine also contribute to cholesterol synthesis [24].
Statins exert their cholesterol lowering effects by blocking cholesterol synthesis. This in turn
up-regulates the expression of LDL-receptors that accelerate the clearance of LDL. Because
the whole-body cholesterol pool is being reduced with statin treatment, absorption in the
gut is up-regulated to compensate, although not fully, for this loss of cholesterol. Studies
have shown repeatedly that statin treatment is indeed associated with an enhanced
cholesterol absorption in the gut [25]. On the other hand, pharmacological or dietary
treatments that inhibit cholesterol absorption in the gut such as ezitimibe or dietary
phytosterols are associated with a compensatory increase in endogenous cholesterol
synthesis [25]. These observations underscore the inter-relationship between the various
pathways and mechanisms involved in the maintenance of whole-body cholesterol
homeostasis.
In the following sections, we will first briefly review the methods that are used to measure
cholesterol homeostasis in humans. We will then review the available data pertaining to
cholesterol homeostasis in metabolic syndrome, abdominal obesity and insulin resistance as
well as its association with CHD risk.
2.1. Measurement of cholesterol homeostasis
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The various processes regulating cholesterol homeostasis can be measured directly with
isotopes or indirectly with surrogate markers. The gold standard measurement of
cholesterol homeostasis has traditionally used cholesterol labelled with radioisotope but
more reliable techniques are now based on the use of stable isotopes and mass
spectrometry [26]. Using radioisotopes, one can assess cholesterol absorption or synthesis
by various methods including balance methods, single dose isotopic feeding, dual isotope
plasma ratio, continuous isotope feeding and intestinal perfusion. Every method has its own
strengths and limitations, and it is beyond the scope of this review to discuss these
techniques in detail (see review by Matthan and Lichtenstein [27] and Stellaard and Kuipers
[26]). It must be stressed that the use of radiolabeled isotope is no longer allowed in some
countries due to ethical considerations on exposing participants to radiation. Also,
radioisotopes cannot be used in older populations and children and are very costly.
Stable isotope methods label cholesterol as a tracer with a stable isotope given to
participants orally, intravenously or a combination of those two. Incorporation of the tracer
is measured in either blood or faecal samples by gas chromatography and mass
spectrometry (GC-MS) to derive various measures of cholesterol homeostasis. Methods
based on stable isotopes use the dual isotope plasma ratio or continuous isotope feeding
approaches [26, 27]. These methods involve labour-intense processes to purify the
cholesterol and its tracer prior to analysis. Their use may also be limited by availability of
specific tracers for research. Collection of faecal samples may be a limitation in some cases.
On the other hand, continuous infusion methods can assess cholesterol absorption over
time and this is a significant strength. The stable isotope techniques are also extremely
precise, sensitive and safe [27, 28].
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Intestinal cholesterol absorption and endogenous synthesis can also be estimated using
surrogate markers in plasma such as non-cholesterol sterols, stanols and phytosterols.
Recognized surrogate markers of endogenous cholesterol synthesis are plasma cholestenol,
desmosterol, lathosterol and squalene concentrations [29, 30]. These molecules are
sequential precursors in the cholesterol biogenesis pathway and have been validated as
relatively strong correlates of isotopically measured cholesterol synthesis [29, 31]. Plasma
lathosterol concentrations have been shown to correlate particularly strongly with direct
measures of cholesterol endogenous synthesis [32]. Intestinal cholesterol absorption can
also be assessed using surrogate markers, i.e. plasma cholesterol metabolites (cholestanol)
and plant-sterols (campesterol, beta-sitosterol) [27, 29, 30]. Campesterol and beta-sitosterol
are plant-derived sterols, or phytosterols, that are present in small quantity in westernized
diets. Phytosterols have a higher affinity for micelles in the intestine than cholesterol and
are absorbed through similar pathways in the gut. Their rate of absorption, however, is
about a thousand times lower than that of cholesterol [33]. Unlike cholesterol, phytosterols
are not synthesized in the human body, and therefore their plasma concentrations can be
used to reflect the capacity of the body to absorb cholesterol [32].
Researchers have developed and adapted methods to measure cholesterol homeostasis
surrogate markers in blood plasma by capillary gas-liquid chromatography (GLC) [29, 30, 32,
33]. A major strength of this method is that it is technically both fast and relatively simple.
This is the reason why it currently represents the only method available to assess cholesterol
homeostasis in large-scale clinical trials and epidemiological studies. Indirect methods based
on surrogate markers are limited by the fact that they do not provide actual rates of
cholesterol synthesis and absorption. Surrogate markers only reflect the balance between
cholesterol synthesis and absorption in the body. Furthermore, the validity of using plasma
phytosterol concentrations as surrogates of cholesterol absorption becomes questionable
8
when there are significant variations in the intake of plant sterols by participants over time
or when participants have genetic disorders like phytosterolemia [27].
2.2. Association between cholesterol homeostasis markers and CHD risk
The study of the association between surrogate markers of cholesterol homeostasis and
CHD risk is emerging and has become of great interest as preliminary data suggest that such
markers may predict CHD risk independent of other traditional risk factors including plasma
LDL-cholesterol concentrations. Matthan et al. [30] have shown using retrospective data
from the Framingham Offspring Study Cycle-6 (N = 155 cases and 414 controls respectively)
that plasma concentrations of cholesterol synthesis surrogates (desmosterol and
lathosterol) and of cholesterol absorption surrogates (campesterol, beta-sitosterol and
cholestanol) were significantly correlated with the risk of CHD. Specifically, a 1-SD increase in
cholesterol synthesis surrogates was associated with an approximately 40% lower odds of
having CHD. In contrast, a 1-SD increase in each of the cholesterol absorption surrogates
was associated with a 147%, 87% and 57% increase in the risk of CHD respectively. Surrogate
markers were expressed per mole of plasma cholesterol and therefore their associations
with CHD risk were to some extent independent of variations in plasma cholesterol
concentration. Cases and controls were matched for age, body mass index (BMI) and systolic
blood pressure and no significant difference in waist circumference was observed between
cases and controls. Furthermore, associations were significant even after adjustment for
medication use, diabetes and diastolic blood pressure. Results from a smaller case-control
study in non-diabetic subjects (N=66 cases and 111 controls respectively) indicated that an
increased plasma lathosterol-to-cholesterol ratio and a reduced campesterol-to-cholesterol
ratio both predicted lower odds ratios for CHD [34]. Taken together, these results suggest
that enhanced endogenous cholesterol synthesis and reduced intestinal cholesterol
9
absorption may be associated with a lower risk of CHD, independent of several traditional
risk factors, including plasma cholesterol concentrations.
These are not consistent findings, however. Escurriol et al. [33] have shown in a nested casecontrol
study (N=299 cases and 584 controls) that having moderately elevated plasma betasitosterol
levels reflecting increased cholesterol absorption was associated with a reduced
risk of having CHD, subjects in the highest beta-sitosterol-to-cholesterol tertile showing a
41% lower odds ratio for CHD than those in the lowest tertile. Associations were weaker for
plasma campesterol. These results are consistent with the findings from the Longitudinal
Aging Study Amsterdam (LASA) by Fassbender et al. [35], who showed in a cohort of 1242
elderly Dutch subjects (>65 years) that increased plasma beta-sitosterol concentrations were
associated with a significant 22% reduction in the risk of CHD. Variations in the plasma
concentration of other plant sterol and surrogate markers of endogenous cholesterol
synthesis showed no significant association with CHD risk [35]. A 22-year prospective study
of 232 men (mean age 60 years) at high risk of CHD suggested that lower cholesterol
synthesis and higher absorption profiles were associated with lower total and CHD mortality
[36]. Finally, the Coronary Risk factors for Atherosclerosis in women study (CORA) is a
retrospective study of 186 cases and 231 controls with comparable plasma LDL-cholesterol
concentrations that showed no association between plasma phytosterol concentrations and
the risk of CHD [37].
Inconsistent associations in these studies between cholesterol homeostasis surrogates and
CHD risk can be attributed to a number of factors. First and foremost, the variety in study
designs (cross-sectional vs. prospective, nested case control vs. population-based) and in
study outcomes (total cardiovascular vs. coronary heart disease) can explain many of the
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inconsistencies between studies. The age and gender of patients in these studies may also
have confounded results.
Another key point to emphasize pertains to the fact that various groups of subjects are
compared to each other in epidemiological studies in the absence of any treatment. It is well
accepted that statin treatment inhibits endogenous cholesterol synthesis, which in turn is
associated with increased intestinal cholesterol absorption, and that overall this is also
associated with a lower risk of CHD. That certainly does not imply that increasing cholesterol
absorption per se may be beneficial from a cardiovascular health perspective. Data suggest
that assessing surrogates of endogenous cholesterol synthesis at baseline may identify
patients in whom statin may not reduce the risk of recurrent coronary events. Specifically,
Finnish researchers investigated how plasma cholestanol concentrations at baseline
modulated the effectiveness of statin treatment in a subsample of 868 patients with
coronary heart disease from the Scandinavian Simvastatin Survival Study (4S). The mean
reduction in the risk of coronary events in 4S was 34% [38]. Sub-analyses showed that this
reduction in the risk of recurrent coronary events was significant among patients in the
lowest quartile of plasma cholestanol concentrations at baseline (-37% reduction in risk) but
not among those in the highest quartile (+16%). These findings suggested that CHD patients
CHD with a high absorption and low synthesis of cholesterol may not benefit from statin
treatment alone [39]. The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)
[40], which investigated the association between plasma markers of cholesterol synthesis
(desmosterol, lathosterol) and cholesterol absorption (campesterol, beta-sitosterol) at
baseline and after treatment with pravastatin in elderly male and female patients at risk of
CHD, came to a different conclusion. Pravastatin reduced concentrations of the cholesterol
synthesis markers desmosterol (-12% in cases vs. -11% in controls) and lathosterol (-50% in
cases vs. -56% in controls) and increased the concentrations of the cholesterol absorption
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markers campesterol (48% in cases vs. 51% in controls) and beta-sitosterol (25% in cases vs.
26% in controls). Because these changes were similar between cases and controls, it was
suggested that inter-individual variations in cholesterol homeostasis in response to
treatment do not explain differences in CHD outcomes between patients treated with
pravastatin [40]. Therefore, the extent to which the magnitude of the change in the
cholesterol synthesis and absorption profile of any given individual with treatment predicts
different CHD outcomes needs to be further investigated.
It is virtually impossible based on the available data from these epidemiological studies to
conclude which cholesterol homeostasis profile (high vs. low endogenous cholesterol
synthesis, high vs. low cholesterol absorption) is more favourable from a cardiovascular
standpoint. Other evidence from association studies may be helpful in trying to address that
question. The following sections will review the emerging yet limited literature on the interrelationship
between cholesterol homeostasis, metabolic syndrome, obesity and insulin
resistance. We will also discuss potential clinical implications from a cardiovascular health
point of having high vs. low cholesterol synthesis and absorption profiles in these states.
2.3. Cholesterol homeostasis in metabolic syndrome
Gylling et al. [29] performed a study comparing cholesterol homeostasis surrogates among
individuals with and without metabolic syndrome. Subjects with metabolic syndrome had
higher plasma concentrations of cholesterol synthesis surrogates and lower concentration of
absorption markers than controls. Notably, differences in the absorption markers, but not in
the synthesis markers, disappeared when adjusted for differences in waist circumference
between groups. Among cholesterol homeostasis surrogates, increased plasma squalene
concentration (marker of synthesis) was the best predictor of the presence of metabolic
syndrome. The evidence for higher cholesterol synthesis and lower cholesterol absorption in
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patients with metabolic syndrome has been supported by other studies as well [41-43].
Cofán et al. [44] took these observations further. In a multivariate analysis of 674
dyslipidemic patients and 361 healthy subjects, they showed that a 1-SD increase in the
sitosterol-to-cholesterol ratio (reflecting increased cholesterol absorption) was associated
with reduced risk of all features of metabolic syndrome as well as with a reduction in the risk
of having metabolic syndrome as a whole. Individual associations were stronger with visceral
obesity and weaker with high blood pressure. These observations are concordant with the
finding that patients with low plasma HDL-C concentrations vs. those with high HDL-C are
characterized by relatively higher endogenous cholesterol synthesis and lower cholesterol
absorption [45].
Proposed mechanisms underlying the perturbed cholesterol homeostasis in metabolic
syndrome vary. Some investigators suggested that abdominal obesity may be the primary
factor responsible for the perturbed cholesterol homeostasis in metabolic syndrome [46],
while others have suggested insulin resistance per se may be responsible for these
metabolic changes [47]. In order to shed some light on this discussion, both viewpoints will
be discussed.
2.4. Abdominal obesity and cholesterol homeostasis
Abdominal obesity is one of the key etiological features of metabolic syndrome. Waist
circumference is the key variable used to characterize abdominal obesity in metabolic
syndrome [48, 49]. It is well known that excess abdominal fat and predominantly visceral fat
is associated with cardiometabolic features similar to the ones present in metabolic
syndrome, including high plasma concentrations of triglycerides [19]. High levels of
triglycerides are the result of an increased secretion of triglyceride-rich VLDL particles from
the liver and the small intestine, which in turn favours the accumulation of small dense LDL
13
particles [50]. Together, abdominal obesity and high triglycerides predict the presence of a
highly atherogenic metabolic triad comprising increased insulin and apoB concentrations
and small, dense LDL particles [51]. High apoB and small dense LDL are features not always
specifically associated with plasma LDL cholesterol concentrations [9, 13] and thus may
reflect perturbed whole-body LDL homeostasis.
Adipose tissue is no longer recognized simply as an energy storage organ, with now wellestablished
endocrine functions contributing to the release of free fatty acids and a wide
range of pro- and anti-inflammatory cytokines [52]. Free fatty acids released by visceral fat
cells enter the blood stream to be directed into the liver, thereby interfering there with lipid
metabolism and stimulating the synthesis of cholesterol [17]. Peltola et al. [53]
demonstrated that the degree of visceral fat (VAT) determined by computerized
tomography in 109 normoglycemic subjects predicted a higher estimated cholesterol
synthesis (as measured by plasma squalene concentrations). This association between VAT
and cholesterol synthesis was independent of variations in subcutaneous fat, insulin
sensitivity and plasma triglycerides. Estimates of cholesterol absorption correlated
negatively with various indices of obesity including levels of visceral fat and positively with
insulin sensitivity. Interestingly, none of the cholesterol absorption or synthesis markers was
associated significantly with the amount of subcutaneous fat or with insulin secretion. Based
on this, they have suggested that visceral obesity may be more important to cholesterol
homeostasis than subcutaneous fat [53]. They have also suggested that squalene synthesis
in itself in fat cells may contribute to the detrimental effects of abdominal obesity on
cholesterol homeostasis. The strong association with the degree of visceral abdominal
obesity may explain why cholesterol synthesis is increased in metabolic syndrome. The
reduced cholesterol absorption in abdominally obese subjects may simply be counter
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regulating the increase in cholesterol synthesis seen in these individuals to maintain whole
body cholesterol homeostasis.
These observations are challenged by data having shown that increased synthesis and
decreased absorption of cholesterol was dependent on liver fat content rather than on body
weight [54]. Indeed, plasma surrogate markers of cholesterol synthesis in patients with nonalcoholic
fatty liver disease (NAFLD) were shown to be significantly higher while markers for
cholesterol absorption were significantly lower than in non-NAFLD control subjects. These
differences remained highly significant after adjustment for sex and body mass index.
Patients with NAFLD also had higher visceral adipose tissue levels measured by computed
tomography than controls [54]. However, and surprisingly, authors have not controlled for
this important difference between patients when assessing the impact of NAFLD on
surrogates of cholesterol homeostasis. Although it is tempting to conclude based on these
data that liver fat, rather than obesity per se, is a key determinant of whole cholesterol
balance, the specific role of visceral fat in this process through its impact on free fatty acids,
triglyceride and apoB metabolism remains to be more definitely established.
2.5. Insulin resistance and cholesterol homeostasis
The data associating abdominal obesity and insulin resistance and the molecular as well as
physiological mechanisms underlying this association are undisputable. It is beyond the
scope of this paper to review this evidence (see Bergman et al. [17], Scaglione et al. [46] and
Hajer et al. [55] for reviews). Researchers have suggested that insulin resistance per se may
play a key role in the regulation of whole-body cholesterol homeostasis, independent of
obesity. Simonen et al. [56] have shown that directly measured cholesterol absorption was
lower in obese patients with type 2 diabetes than in body-weight matched controls, while
cholesterol synthesis was higher. Plasma blood glucose concentrations were positively
15
correlated to cholesterol synthetic rate in both groups. These results suggested that
cholesterol homeostasis is perturbed in diabetes, and thus in insulin resistance states,
independent of obesity alone since the two groups were matched for body weight. As
indicated above, body weight and body mass index are not specific markers of intraabdominal
visceral fat, which was not measured in this study by Simonen et al. [56]. The
extent to which insulin resistance state and type 2 diabetes would have predicted a
perturbed cholesterol homeostasis independent of variations in visceral fat levels was not
addressed.
Hoenig et al. [57] showed that the quantitative insulin sensitivity check index (QUICKI)
correlated negatively with percent LDL-C reduction in 66 high-risk vascular patients treated
with atorvastatin 80 mg for 6 weeks. Insulin-resistant patients had higher levels of
cholesterol synthesis markers and lower levels of absorption markers and the correlation
between QUICKI and percent LDL-C response to statin was no longer significant when
adjusted for variations in markers of cholesterol homeostasis. It was suggested that insulinresistant
patients might have superior LDL-C responses to statin therapy, partly due to their
high baseline cholesterol synthesis.
These observations are to some extent supported by a series of data from cross-sectional
studies. In their study of NAFLD patients, Simonen et al. [54] have found positive
associations between serum fasting insulin and cholesterol synthesis markers and negative
associations with cholesterol absorption markers. However, these associations were not
independent of liver fat accretion in these patients. Peltola et al. [53] reported a negative
correlation between cholesterol synthesis markers and whole-body glucose uptake, hence
suggesting that a higher degree of insulin sensitivity is associated with lower endogenous
cholesterol synthesis. However, as indicated above, the association between visceral fat and
16
estimated cholesterol synthesis in this study was independent of concurrent variations in
insulin sensitivity [53]. Pihlajamaki et al. [58] showed that the degree of insulin resistance
measured by hyperinsulinemic-euglycemic clamps in 72 healthy normoglycemic men was
associated with increased cholesterol synthesis and to a lesser degree with decreased
cholesterol absorption. Associations were significant even after adjustment for the
confounding effect of BMI. However, there was a significant difference in waist
circumference between insulin-sensitive and insulin-resistant groups. Paramsothy et al. [59]
have shown that cholesterol absorption markers were highest in lean insulin-sensitive men
and women, whereas cholesterol synthesis markers were highest in lean insulin-resistant
and obese insulin-resistant patients. Although insulin-sensitive and insulin resistant lean
subjects were matched for body mass index, the latter group had high levels of intraabdominal
visceral fat. Authors did not discuss the extent to which this may have affected
the association between insulin resistance and cholesterol homeostasis. Therefore, it cannot
be concluded from these studies that insulin resistance affects cholesterol homeostasis
independent of abdominal visceral obesity. Gylling et al. [47] investigated the link between
insulin resistance and altered cholesterol homeostasis in 781 participants with various
degrees of insulin resistance (normoglycemia, impaired fasting glucose, impaired glucose
tolerance, and type 2 diabetes). The authors reported that peripheral insulin sensitivity
evaluated by the Matsuda index was inversely related to the lathosterol/sitosterol ratio in
the entire population independently of BMI, suggesting that peripheral insulin resistance
may up-regulate cholesterol synthesis independent of overall obesity. However, variations in
waist circumference were also an independent predictor of the plasma lathosterol/sitosterol
ratio, an integrated marker of whole body cholesterol homeostasis. Again, it cannot be ruled
out from these data that the association between insulin resistance and cholesterol
homeostasis is fully independent of obesity, particularly abdominal obesity. Nevertheless, it
has been proposed that hyperinsulinemia as seen in insulin resistance states may up17
regulate the expression of SREBP-1c, a transcription factor that stimulates the synthesis of
fatty acids and the production of VLDL particles [60]. On the other hand, SREBP-2, another
transcription factor up-regulating de novo cholesterol synthesis, does not appear to be
affected by hyperinsulinemia or hyperglycemia. Further research is therefore required to
shed more light on these potential mechanisms and on how each one relates to abdominal
obesity and insulin resistance respectively.
3. Conclusion
There is consistent data demonstrating that metabolic syndrome, in addition to its
numerous and well established cardiometabolic risk factors, is also associated with a
perturbed whole-body cholesterol homeostasis. Yet, this is not accompanied by increased
plasma LDL-cholesterol concentrations. In general, studies are pretty consistent in
demonstrating that metabolic syndrome is associated with increased endogenous
cholesterol synthesis and reduced intestinal cholesterol absorption. The impact of these
perturbations per se on CVD risk remains unclear and needs to be investigated more
extensively. Because insulin resistance and abdominal obesity are probably the most
important etiological features of metabolic syndrome, there is some debate as to which of
the two, in insolation or in combination, is mostly responsible for the dysregulated
cholesterol homeostasis in metabolic syndrome. Data have been relatively consistent in
demonstrating that abdominal obesity, and perhaps visceral adiposity even more so, predict
increased cholesterol synthesis and reduced cholesterol absorption, independent of insulin
resistance (Figure 1). It is possible that insulin resistance per se may affect whole-body
cholesterol homeostasis, independent of abdominal visceral obesity but no studies to date
have provided such evidence using large cohorts of subjects with various degrees of obesity
and insulin resistance. Thus, more research will be needed to fill the gaps of knowledge on
18
cholesterol homeostasis before we can conclude that insulin resistance and abdominal
obesity each contribute independently to cholesterol homeostasis in metabolic syndrome.

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