John Steele Taylor
November 14, 2007
Pharmacology 201
Lifestyle Factors and Pharmacological Agents that Manage Hyperlipidemia
Through Activation of Peroxisome Proliferator Activated Receptors
Part 1: Introduction and Overview
This paper concerns a specific class of drugs used in the treatment of
hypertriglyceridemia and hypercholesterolemia that operate through activating a class of
transcriptional activators known as peroxisome proliferator activated receptors (PPARs).
PPARs are transcriptional activators distributed throughout a diversity of tissues that
operate through orchestrated mechanisms primarily to regulate carbohydrate and lipid
metabolism. Therefore, these transcriptional activators play a central role in treatment of
atherosclerotic diseases and general metabolic syndromes that are highly prevalent in
western populations. Clinical and epidemiological studies have thoroughly established a
definite correlation between atherosclerotic related events and certain serum lipid
profiles. These serum lipid profiles represent independent risk factors; however, they
often accompany insulin resistance and other features of metabolic syndrome.
Due to the complexity of factors and pathways involved in lipid metabolism and
the pathogenesis of atherosclerosis, an introductory section is included to summarize
these mechanisms for the lay-reader. Additionally, mechanisms through which diet and
exercise regiments can favorably influence serum lipid profile and prevent atherosclerosis
will be discussed at considerable length, both for the purpose of emphasizing their role as
a first line of treatment and for elucidating some of the mechanisms that are targeted by
the drugs discussed later in this paper. Once this has been accomplished, a second standalone section is devoted entirely to the discussion of PPAR activating drugs, including
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proposed mechanisms of action, pharmacokinetic considerations, and adverse
effects/toxicities.
Lipoprotein Metabolism: Normal and Dysfunctional
The transport of cholesterol and triglycerides through the bloodstream is
complicated by the fact that these are hydrophobic molecules that need to be moved
through a watery environment. Transport is therefore achieved through packaging lipids
into lipoproteins, which have the general characteristic of having a protein hydrophilic
outer layer and a lipid core (hence the name lipo-protein). Three important outer
proteins, or apoproteins, will be considered in this paper and include apoprotein-A1 (apoA1), apoprotein-B-100 (apo-B-100), and apoprotein C-3 (apo-C3). These apoproteins are
discretely associated with certain lipoproteins and are major determinants in the
characteristics and function of these lipoproteins. Regulation of apoprotein expression,
degradation, and exchange is an important drug target due to their influence on
mechanisms involved in the development of arterial diseases (1).
Two pathways of lipoprotein metabolism exist: an exogenous pathway where
dietary triglycerides and cholesterol are packaged into chylomicrons in the intestinal
mucosaand distributed throughout the circulation; and an endogenous pathway where
triglycerides and cholesterol are packaged in to lipoproteins in the liver for distribution
through the bloodstream. The endogenous pathway is our primary concern, especially
due to the fact that a major fate of chylomicrons in post-prandial (post-meal) metabolism
is hepatic conversion into very-low-density-lipoprotein (VLDL), which are the primary
endogenous triglyceride transporter, (2).
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Circulating VLDLs are hydrolyzed by lipoprotein lipase (LPL), an enzyme fixed
on the luminar surface of vascular endothelium, into free fatty acids (FFAs) for uptake
into muscle and adipose tissue. VLDL is converted to intermediate-density-lipoprotein
(IDL) as it releases FFAs. IDL has two fates: degradation in the liver and conversion to
low-density lipoprotein through donating apolipoprotein C-II (Apo-C2) to high density
lipoproteins (HDL). In this manner, increasing LPL activity causes a decrease in VLDL
and an associated increase in HDL. This pathway is a major drug target. (2).
Low density lipoprotein (LDL) is responsible for the transfer of cholesterol to
peripheral tissues for utilization in numerous functions including membrane synthesis and
steroid hormone production. Under normal conditions most of the circulating LDL is
cleared by the liver for synthesis of bile acids, which are important for emulsifying fats in
the digestive tract, and represent the only avenue for removal of cholesterol from the
body. Apoprotein-B (apo-B) is a major component of LDL, and cellular uptake of LDL
occurs through recognition of apo-B at the receptor binding sites (2).
Dysregulation of LDL function occurs when LDL suffers oxidative damage,
which alters its composition to the extent that it is poorly recognized by hepatocytes.
Conversely, uptake of oxidized LDL is greatly increased in scavenger cells in peripheral
tissues, most notably in macrophages that are situated in the vascular endothelium (2).
For this reason LDL is referred to as ‘bad-cholesterol’, and increased levels are a major
risk factor for cardiovascular disease. (3) However it is probably more appropriate to
refer to oxidized LDL as the bad cholesterol. Mechanisms involved in oxidation of LDL,
and the pathogenesis that ensues from macrophage uptake, are discussed below. Without
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further mention, this should highlight the role of antioxidants in foods as cardiovascular
protective agents.
HDL is synthesized in the liver and is primarily composed of apoprotein-a-1 (apoa1) (2). Synthesis of apo-a1 is largely regulated by PPARα, and thus exogenous
activators of PPARα can directly contribute to increases in apo-a1 levels and
consequently increased HDL levels (4). HDL is responsible for reverse transport of
cholesterol from the periphery to the liver for elimination. This process of reverse
transport is primarily mediated by apo-A1 stimulation of lecithin-cholesterol-acetyltransferase (LCAT), which esterifies free cholesterol in the periphery for removal by
HDL. It also follows that apo-A1 stimulates ATP-binding cassette transporter A-1
(ABCA1), which is a transporter protein that enables this exchange of lipids from foam
cells to HDL(2). Because of this mechanism, HDL is referred to as ‘good cholesterol’
and decreased levels represent a risk factor for cardiovascular disease. Increasing HDL
levels is an important drug target and often occurs through degradation of VLDL, as
mentioned above.
Atherosclerosis Pathogenesis
Atherosclerosis essentially involves the inappropriate deposition of soft lipidbased masses, or atheromas, into the walls of the arterial lumen. These lipids are
primarily derived from circulating LDL. Atheromas start as fatty streaks and then
progress to plaques, which are characterized by accumulation of foam cells (macrophages
that are filled with lipids), proliferation of smooth muscle cells, and increased deposition
of collagen and other debris that progressively narrow and ultimately occlude the artery
(1). Consequences of this narrowing include impaired capacity to respond to vasodilators
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such as nitric oxide, diminished nutrient supply to associated tissues; and the preparation
of an environment for circulating blood clots to lodge thus causing acute ischemic events.
Finally, destabilized plaque can rupture, which initiates a clotting cascade that can
suddenly and completely occlude the artery (3).
Chronic mild vascular inflammation is an independent risk factor for
cardiovascular events. Cytokines (immune signaling chemicals) activate proinflammatory genes and vascular cell adhesion molecules (VCAMs), which allow
neutrophils to adhere to vascular walls and exert their inflammatory activity thus
furthering the local atherogenesis (5). Cytokine release from macrophages may be
induced by transcriptional activators released by oxidized LDL (2), however in the obese
state adipose tissue also releases proinflammatory compounds (7). Mechanisms for
reducing inflammation via diet, exercise, and drug therapy will also be explored in later
sections and is a major feature of cardioprotective therapy mediated through non-lipid
pathways.
Atherosclerosis, particularly in the coronary and cerebral arteries, is a silent killer
because no pain or prior symptoms need be necessary for a lethal event to occur as a
result. Indeed, over 50% of sudden death from cardiovascular disease occurs in
individuals with no previously recognized symptoms, and an artery can be over 70%
obstructed before symptoms (such as angina) develop. Alarmingly, although most
cardiovascular events are suffered in adulthood, atherosclerosis starts in childhood and
progresses throughout life. Autopsies performed on children and adolescents reveal
formation of fatty streak as early as 3 years of age, and adolescents with arterial
obstruction so significant that they could have suffered myocardial infarction (3). Based
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on this information the importance of regular preventative measures achieved through
exercise and diet cannot be overemphasized.
Effects of Exercise
Regular physical activity can profoundly reduce cardiovascular risk through
altering the dynamics of lipoprotein metabolism. This is best explained by summarizing
the mechanisms through which type two diabetes and metabolic syndrome (a complex
characterized by insulin resistance, obesity, hypertension, and dyslipidemia) can
profoundly increase cardiovascular risks, because these conditions are associated with a
sedentary lifestyle. Not all people with cardiovascular disease have diabetes, however, it
is estimated by the American Heart Association that around 50 million people in the
United States have metabolic syndrome (6), while 65 million people in the US suffer
from some sort of cardiovascular disease (3). The discussion that follows will highlight
this close correlation.
Type 2 diabetes and metabolic syndrome are both characterized by insulin
resistance. Insulin is essential for the cellular uptake of dietary fat, protein, and glucose
following a meal (during the post-prandial state) (3). This is important not only for the
effective storage and utilization of nutrients for tissue synthesis and cellular energy, but
for the often overlooked protection against the pathogenic consequences of pronounced
and prolonged increases in blood glucose levels becomes toxic to tissues. The interaction
of glucose with tissues and circulating compounds leads to the formation of advanced
glycated end-product (AGE) complexes, which disrupt normal tissue function in a broad
variety of ways. For our purposes, the glycation of circulating LDL renders it far more
susceptible to oxidative damage, thus increasing its deposition into vascular endothelium.
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Additionally, gylcation of HDL may inhibit its ability for reverse transport of cholesterol
(2).
AGE complex formation is greatly accelerated in a hyperglycemic environment,
which is a hallmark of insulin resistance. Under normal responsiveness to insulin,
glucose uptake is dramatically increased in skeletal muscle and hepatic tissue, which
stabilizes blood glucose levels following a post-prandial spike. This occurs through the
translocation of GLUT-4 receptors to the surface of these cells, which facilitate the
diffusion of glucose into the cytoplasm. Regular exercise favorably enhances this
mechanism, resulting in increased sensitivity to insulin, increased number and
translocation of GLUT-4, and increased glycogen synthase activity (3). Therefore regular
exercise profoundly reduces post-prandial hyperglycemia and consequently reduces
excessive glycation of LDL and HDL. On the other side of the equation, a sedentary
lifestyle results in an insulin resistant state, in which post-prandial blood glucose levels
are slow to stabilize and remain high post-absorptively, and thus LDL and HDL are
excessively glycated.
Fat metabolism is heavily dictated by insulin activity as well as through
adaptations to exercise. LPL activity is regulated by insulin in order to rapidly clear postprandial triglycerides: insulin stimulates LPL to liberate free fatty acids (FFA’s) from
VLDL for uptake into adipose tissue for storage. As fat reserves increase, adipose tissue
releases factors that promote insulin resistance (7). In the insulin resistant state,
circulating triglycerides increase and glycogen reserves are diminished due to
insufficient uptake by in skeletal muscle and hepatic tissue. As a consequence highly
metabolically active tissues in the central nervous system and cardiac muscle must rely
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more on FFA’s and ketone bodies as a fuel (3). FFA flux to the liver signals the liver to
increase output of apo-B (and thus increased LDL formation). This combined with
reduced LPL activity leads to significant increases in VLDL and LDL (2).
These trends and vicious cycles are reversible through regular exercise. As
already mentioned, skeletal muscle increases its sensitivity to insulin thus improving
post-prandial glucose clearance. Trained muscle also increases its LPL activity thus
reducing VLDL levels. A major training response is improved utilization of FFA’s as an
energy source at higher levels of intensity. Recent studies suggest that this effect is likely
mediated via PPARδ activation in skeletal muscle. This results in increased LPL activity
and improved mitochondrial populations, which is accompanied by enhanced oxidation
of fatty acids as mediated by upregulation of carnitine palmitoyl transferase activity
(CPT1) – a protein responsible for the transport of fatty acids across mitochondrial
membranes. Because these mechanisms ultimately lead to increases HDL levels, PPARδ
agonist drugs mimic favorable exercise-induced alterations in lipid metabolism (8).
FFA utilization increases in proportion to exercise intensity as intensity
approaches 50% of Vo2 max, and then FFA utilization declines as higher intensities are
achieved (7). Thus exercise at this moderate intensity level is desirable. However higher
intensity resistance training-induced increases in muscle mass also confer benefits in
metabolic syndrome via separate mechanisms not discussed.
Reduction of fat stores in adipose tissue through negative energy balance
achieved through regular exercise leads to decreased output of proinflammatory
compounds such as resistin and interleukin-6. The level of secretion stands in direct
relationship to fat reserves such that decreased reserves also decrease proinflammatory
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output (7). This is crucially important because, as discussed above, inflammation is a
prominent risk factor for cardiovascular events.
Effects of Diet
The ultimate goal of lifestyle and pharmacological interventions is to increase
hepatic clearance of cholesterol from the general circulation. However, once this has
been accomplished, cholesterol must still be eliminated, which is problematic because
cholesterol cannot be degraded in the body. Elimination occurs through hepatic
conversion of cholesterol to bile acids, which are delivered to the gallbladder and
ultimately secreted into the small intestine to assist in the emulsification of fats.
However, most bile acids are reabsorbed at the ileum of the small intestine and returned
to the liver – a process known as enterohepatic cycling. In fact, bile acids may be
recycled up to 18 times before they are finally eliminated in the feces(1).
Bile-acid binding resins are a major class of lipid-lowering drugs that work well
in combination with other interventions because they bind with bile-acids in the small
intestine and increase their elimination in the feces. Consequently the liver must
upregulate LDL receptors in order to pull more cholesterol from the circulation in order
to maintain bile-acid levels (9). Clearance is enabled through upregulation of cholesterol
7 alpha-hydroxylase, which is the rate limiting enzyme in bile-acid synthesis, and this
mechanism is a prominent indirect effect of these drugs (10).
A similar mechanism has been demonstrated for dietary fiber, such that dietary
fiber (particularly soluble fibers – lignans, gums, pectins, etc.) can prevent the
reabsorption of bile-acids and therefore also result in increased LDL clearance and
cholesterol 7 alpha-hydroxylase activity. Additionally, the binding of nutrients such as
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starches and sugars in the small intestine by dietary fibers slows their absorption thus
mitigating post-prandial spikes in blood glucose levels (11).
Reductions in dietary cholesterol and saturated fat intake are generally recognized
preventative dietary strategies for reducing the risk of heart disease. However,
supplementation with certain omega-3 fatty acids may confer much more specific
benefits. Most clinical evidence suggests that these effects are specifically derived from
two omega-3 fatty acids found in fish oils – eicosapentanoic acid (EPA) and
docosahexanoic acid (DHA) - and not necessarily from vegetable sources of omega-3’s
(although more research is necessary regarding potential benefits of vegetable omega3’s). The primary mechanism of action involves gradual displacement of arachidonic
acid from phospholipid membranes by DHA and EPA. As a consequence, eicosanoids
become increasingly derived from these fatty acids instead of from arachidonic acid. A 3series of prostanoids and thromboxanes are derived from EPA and DHA as opposed to
the 2-series derived from arachidonic acid, and as a general trend these 3-series
derivatives tend to have a far less pronounced vasoconstricting and platelet-aggregating
effect of the 2-series derived from arachidonic acid because they are much less active at
receptor sites (12).
Inflammatory pathways are also altered as EPA/DHA yield a 5-series of
leukotrienes that competitively inhibit AA-derived 4-series leukotrienes at their binding
sites, thus producing an anti-inflammatory and anti-allergenic effect. EPA and DHA may
also operate as ligands for PPARα, thus promoting increased levels of apo-A1, decreased
levels of apo-B, and increasing LPL activity. Activation of PPARα may also inhibit
smooth muscle proliferation, which is a feature of the pathogenesis atherosclerotic
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plaques. Adverse effects of omega-3 fat supplementation include increased bleeding due
to an anti-aggregating effect and the potential for increased oxidation of LDL as they are
polyunsaturated fats and thus highly prone to oxidative damage (12).
Part 2: PPAR Active Drugs
Peroxisome proliferator activated receptors are transcriptional activators
distributed throughout a diversity of tissues that operate together to produce orchestrated
effects that regulate lipid and energy metabolism. Three major subunits have been
identified: alpha, gamma, and delta – the former two have been exploited by marketed
pharmaceuticals, while drugs that operate on PPARδ are still in the advanced phases of
development. PPARγ coactivator-1-alpha (PGC1-A) is also of interest as it is activated
by nitric oxide and mediates exercise-induced proliferation of mitochondria in skeletal
muscle(13).
PPARα and Fibric Acid Derivatives
The class of lipid lowering drugs known as fibric acid derivatives (FAD’s), or
fibrates, are activating ligands for PPARα. Activation results in increased expression of
LPL in multiple tissue and consequently decreases circulating VLDL. Accompanying this
mechanism is a moderate increase in circulating HDL, both through stabilization of HDL
by VLDL hydrolysis, and increased hepatic expression of apo-A1 which improves
reverse transport of cholesterol. Improved LPL activity with FAD’s may occur via
reduction in the levels of apoliprotein C-III (apo-CIII), which is a component of VLDL’s
and has been demonstrated to inhibit the activity of LPL (2).
Similar to the statin drugs, FAD’s have non-lipid benefits for prevention of
cardiovascular disease. PPARα expression in vascular endothelial cells regulates
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inflammatory processes through complex mechanisms that suppress proinflammatory
pathways, vasoconstriction, and platelet aggregation (5).
Gemfibrozil has two approved clinical uses in the US: 1) the treatment of patients
with high triglyceride levels who are at increased risk for developing pancreatitis and 2)
patients with high serum triglycerides and low HDL levels. FAD’s should not be the first
line of defense for patients with hypercholesterolemia but low serum triglycerides.
FAD’s are an excellent combination drug, either with statin drugs or bile-acid binding
resins (11)
PPARgamma and Thiazolidinediones
The class of lipid lowering and anti-diabetic drugs known as thiazolidinediones or
glitazones are activators of PPARγ. In adipose and muscle tissue, this effect appears to
increase the output of LPL and thus improves insulin sensitivity and post-prandial
clearance of glucose and triglycerides. GLUT-4 transporter activity in adipocytes is also
enhanced. Additionally, PPARγ activation may lead to favorable redistribution of fat
stores from visceral adipose tissue to subcutaneous adipose tissue (14).
Similar to FAD’s and statins, glitazones also provide non-lipid benefits through
suppression of proinflammatory signaling pathways, mediated through their activity at
PPARγ binding sites in vascular endothelial cells and macrophages. Specifically PPARγ
expression in macrophages and endothelial cells increases the efflux of cholesterol for
reverse transport via HDL (4). Major side effects primarily concern increased plasma
volume and consequently an increased risk for hospitalization due to congestive heart
failure (14).
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Currently in the developmental phases is a drug referred to as propionic acid
derivative 8 (compound 8). Compound 8 has both PPARα and PPARγ activity, and is
thus a promising drug for reducing atherosclerosis and dyslipidemia in patients with type
2 diabetes mellitus (4).
PPARδ and GW501516
In contrast to PPARα and PPARγ activators, PPARδ activating drugs are still in
the developmental stages. GlaxoSmithKline is developing a drug currently referred to as
GW501516, which is in phase II of development. GW501516 shows promise for treating
hyperlipidemia through a variety of mechanisms.
Dramatic increases in HDL levels have been observed in human and primate
studies with GW501516 (4, 8). This effect is primarily achieved through increased
hydrolysis of VLDL that ultimately occurs through upregulation in oxidative activity of
skeletal muscle mitochondria such that FFA utilization as a fuel is enhanced. Additional
lipid associated benefits include increased expression of apo-1A and ATP-binding
cassette transporter A-1 (ABCA1). ABCA1 is a protein that enables the exchange of
lipids from foam cells to HDL. Thus HDL levels and efficacy are increased by
GW501516 (8).
Activation of PPARδ may also provide important cardioprotection with specific
regard to reperfusion-induced oxidative stress. As blood flow is returned to ischemic
tissue, oxidative stress and inflammation can occur to the extent that they are more
damaging than the actual ischemia. PPARδ mediated protection occurs through
upregulation in antioxidant mechanisms and inhibition of cardiac myocyte apoptosis
triggered by oxidative stress (15). Additionally, GW501516 may inhibit cardiac fibrosis
13
through the inhibition of cardiac fibroblast collagen synthesis and fibroblast proliferation.
Thus, this drug has a potential role in the treatment and prevention of congestive heart
failure (16).
Possible adverse effect for GW501516 involves its role as an angiogenic agent.
Excessive angiogenesis is associated with increased inflammatory activity and tumor
growth. In contrast to PPARα and PPARγ, which appear to be anti-angionenic through
their impact on eicosanoid activity, PPARδ stimulates vascular endothelial growth factor
(VEGF), which suggests that patients at risk for angiogenesis be increasingly monitered
if taking PPARδ’s such as GW501516. However, GW501516 may also represent a novel
and inadvertent pharmacological agent for promoting wound healing and treating
ischemic heart disease precisely due to its angiogenic properties (17).
Conclusions
Exciting new lines of therapy are emerging for the treatment of dyslipidemia, and
appear to operate through similar mechanisms and receptor activity. It is likely that as
advances are made in exercise physiology to understand the role of these receptors in
favorable adaptations to physical activity, increasingly precise and effective
pharmacological agents can be developed. It has also been demonstrated that
combination of exercise and diet produces a broader range of benefit that are generally
more potent and without side-effect. This justifies the generally accepted protocol of diet
and exercise as the first line of treatment in hyperlipidemic individuals, and
pharmacological intervention only if lipid levels fail to respond to these lifestyle changes.
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