Reducing Low Density Lipoprotein Cholesterol Health Essay

Reducing Low Density Lipoprotein Cholesterol Health Essay

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. Reducing Low Density Lipoprotein Cholesterol Health Essay.


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]. Reducing Low Density Lipoprotein Cholesterol Health Essay.


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


VLDL and IDL, are a better predictor of CHD risk than plasma LDL-cholesterol concentrations


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].  Reducing Low Density Lipoprotein Cholesterol Health Essay.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. Reducing Low Density Lipoprotein Cholesterol Health Essay.


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].Reducing Low Density Lipoprotein Cholesterol Health Essay.  These observations underscore the inter-relationship between the various

pathways and mechanisms involved in the maintenance of whole-body cholesterol


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


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. Reducing Low Density Lipoprotein Cholesterol Health Essay.

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].


Intestinal cholesterol absorption and endogenous synthesis can also be estimated using

surrogate markers in plasma such as non-cholesterol sterols, stanols and phytosterols. Reducing Low Density Lipoprotein Cholesterol Health Essay.

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


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.Reducing Low Density Lipoprotein Cholesterol Health Essay. 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


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.Reducing Low Density Lipoprotein Cholesterol Health Essay.  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


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. Reducing Low Density Lipoprotein Cholesterol Health Essay. 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


markers campesterol (48% in cases vs. 51% in controls) and beta-sitosterol (25% in cases vs. Reducing Low Density Lipoprotein Cholesterol Health Essay.

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.Reducing Low Density Lipoprotein Cholesterol Health Essay.  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


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]. Reducing Low Density Lipoprotein Cholesterol Health Essay.

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


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]. Reducing Low Density Lipoprotein Cholesterol Health Essay. 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


regulating the increase in cholesterol synthesis seen in these individuals to maintain whole

body cholesterol homeostasis.Reducing Low Density Lipoprotein Cholesterol Health Essay.

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. Reducing Low Density Lipoprotein Cholesterol Health Essay. Plasma blood glucose concentrations were positively


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


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


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. Reducing Low Density Lipoprotein Cholesterol Health Essay. 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. Reducing Low Density Lipoprotein Cholesterol Health Essay.


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


cholesterol homeostasis before we can conclude that insulin resistance and abdominal

obesity each contribute independently to cholesterol homeostasis in metabolic syndrome.  Reducing Low Density Lipoprotein Cholesterol Health Essay.