Talia Kostal

Student number: 1124891

CHEM 221 Ad-hoc Essay


Mechanisms of Action for Hyperlipidemia Treatment

Low Density Lipoproteins (LDLs) are a biological molecule responsible for
transporting cholesterol and other fat molecules from the liver to specific receptors
in the body. In general, lipoproteins are classified by density. LDLs are typically
considered the bad form of cholesterol, as excess LDLs deposit fat molecules in
unwanted areas of the body, causing disease and malfunction of organ systems. A
common result of high levels of LDLs in the body is atherosclerosis, which is
characterized by a hardening of the arteries, and resultant reduced blood flow and
oxygenation of the cardiac muscles (Finney). People with high LDL levels are at
greater risk for thrombosis and embolisms, as well as coronary artery disease
(Bilgen). Due to the growing epidemic of obesity in the United States, there are
many well-established drug regimens to treat high LDL levels. The three primary
classes of treatment include: statins (HMG-CoA reductase inhibitors), bile-acid-
binding resins, and cholesterol absorption inhibitors. This paper will seek to explore
the biochemical mechanisms of action within the body of each drug class.

A common symptom of high cholesterol (high LDL levels, or hyperlipidemia)
is atherosclerosis. Matrix metalloproteinases (MMPs) are known to be a major
contributor to the development of the hard fatty plaques indicative of
atherosclerosis. It is thought that MMPs cause remodeling of the extracellular matrix
of vascular smooth muscle cells (VSMCs), which leads to the degradation of
interstitial collagen causing the cells to loose their strength (Laun 769). As a result,
the stress of ventricle contraction makes it more likely that the fatty plaques in the
systemic circulatory system will break loose, leading to myocardial infarction and/
or acute angina (Luan 769). Statins are a drug often prescribed to treat
hyperlipidemia. Structurally, stantins are similar to hdroxymthyglutaryl coenzyme
A (HMG-CoA) reductase inhibitors (HMG-CoA reductase is the first enzyme needed
in the synthesis of cholesterol). Studies have suggested that an increased
concentration of macrophages result in an increased secretion of MMPs. As a result,
many researchers have postulated that stantins inhibit the mechanism of secretion
of MMPs by macrophages. A study performed by Laun (2003), published in the
Journal of the American Heart Association, sought to investigate the mechanism in
which stantins inhibited MMP -1, -2, -3, and -9 expression in cultured rabbit and
human VSMCs and foam cell macrophages elicited in cholesterol-fed rabbits (Luan
770).
Laun (2003) investigated the mechanism for the plaque stabilizing
properties of statins by first exploring the effects of bypassing the HMG-CoA
inhabitation created by the drug, in an attempt to better understand the mechanism
of MMP secretion via macrophages in the VSMCs. The researchers showed rescue
in the MMP -1. -3, -9 secretion by mevalonate metabolism, which is an integral step
in the synthesis of cholesterol, in the absence of HMG-CoA reductase inhibitors
(Luan 774). The squalene, which is an intermediate substance produced during the
synthesis of cholesterol following mevalonate metabolism, showed a significant
impact in the lipid modification step of cholesterol synthesis. When the HMG-CoA
reductases are inhibited, the researchers found that the covalent bonding of the
protein precursors of cholesterol were significantly altered, therefore changing the
3-D conformational shape, and ultimately their overall activity (Luan 774). This
modification is known as prenylation, and was shown to be invaluable in the
process of MMP secretion. As a result, the researchers suggest that such a
posttranslational process, meaning modifications made to a protein after
translation has been completed (such as during the process of cholesterol
synthesis), is the mechanism for statin inhibition (Luan 744).
Although stains are a widespread and commonly used drug to treat
hyperlipidemia, there are many other classes of drugs which target different
mechanisms in the cessation of high LDL levels in the body. Another class of drug
commonly prescribed is Bile Acid Binding Resins. The most basic purpose of a Bile
Acid Binding Resin is to bind to the cholesterol containing bile salts in the intestines
and cause them to be eliminated in the feces. At present, much research is being
preformed in order to better understand the precise point at which Bile Acid
Binding Resins act in cholesterol metabolism. It is hypothesized that cholesterol 7 -
hyroxylase (CYP7AI) is the primary enzyme which catalyzes the hydroxylation
(addition of OH group) of the cholesterol molecule in bile acid synthesis (Giladari
450). Researchers have suggested that the inhibition of CYP7AI reduces the
intestinal cholesterol absorption keeping it from being transferred to the liver, and
thus produces a net overall lowering of LDL levels in the body.
There are many different pathways which researchers have explored in an
attempt to pinpoint the role of CYP7AI inhibition in bile acid synthesis. In a study
preformed by Goodwin et al (2000) the researchers sought to investigate how the
FXR class II nuclear receptor impacted the transcription process in protein
synthesis of the CYP7AI enzyme (Giladari 456). The researchers found a negative
feedback loop in that
FRX indirectly
inhibited the
transcription of
CYP7AI. They found
that a factor -
fetoprotien, which is a
key plasma protein
(FTF), binds to the bile
acid response element
(BARE), which in turn
begins the transcription process (Gilidari 456). At the same time that transcription
begins, the FRX molecule also stimulates the production of a small heterodimer
partner (SHP). The SHP binds to the promoter of CYP7AI, inhibiting the completion
of transcription. When the products of bile acid synthesis are high, SHP inhibits the
promoter region, creating a negative feedback loop. Bile Acid Binding Resins imitate
this process which, via inhibition of the bile acid pathway, lowers LDL levels in the
blood (Gilidari 456). The image on the previous page provides a visual diagram of
the inhibition of CYP7AI during protein synthesis (Gilidari 456).
Another class of medication available to treat hyperlipidemia is known as
Cholesterol Absorption Inhibitors. Saponin is a naturally occurring chemical
compound which is a known to be a cholesterol absorption inhibitor. Although
saponin in its natural state can show LDL lowering properties, the naturally
occurring compound is not potent enough to produce the levels of reduction needed
to treat someone with hyperlipidemia (Morehouse et al. 464). However,
researchers have taken the chemical structure of saponins and modified them to
make more potent synthetic compounds which elicit the same LDL lowering effects
on a larger scale. The figure at
right shows the molecular make
up of the two most well known
synthetic saponins: Tiqueside and
Pamaqueside (Morehouse et al.
467). In a study preformed by
Morehouse et al. (1999) the effects
of saponins (as well as their
synthetic counterparts) and their
mechanism of action were explored. In this study the researchers postulate that
saponins cause a chemical separation in the lumen, which is the innermost layer of
the intestine, therefore causing the cholesterol molecules to be unable to be
absorbed into the blood stream (Morehouse et al 465). Although the molecular
mechanisms regarding the exact nature of saponin action are widely unknown, the
researchers postulate that possibilities include that saponins act to extract
cholesterol from membranes within the intestine, or they form complexes with
cholesterol present in the intestine that are impermeable to the lumen walls
(Morehouse et al. 473). The fact that saponins act on the cholesterol molecules at a
local level within the body suggest that cholesterol absorption inhibitors may be a
viable alternative to systemic treatments such as HMG-CoA reductase inhibitors
(Morehouse et al. 464).

There are a variety of treatments for hyperlipidemia, each with a mechanism
of action that acts on the body in a different way. Depending on each individual case,
the differing medications may be prescribed separately or in tandem. Although the
available LDL treatments clearly help to lower the negative impacts of
hyperlipidemia, the fact that the mechanisms for cholesterol absorption and
inhibition are so widely unknown leaves much room for further research. Perhaps
in the future, while the mechanisms of action are continued to be explored for HMG-
CoA reductase inhibitors, Bile Acid Binding Resins, and Cholesterol Absorption
Inhibitors, new pathways will be discovered and alternative, innovative treatments
will emerge.

Word Count: 1,342

Works Cited:

Finney, Erick. "Chapter 17." University of Washington. Bagley Hall, Seattle. March
2012. Lecture.

Gilidari, Federcia et al. "The pharmacological exploitation of cholesterol 7!-
hydroxylase, the key enzyme in bile acid synthesis: from binding resins to
chromatin remodelling to reduce plasma cholesterol." Pharmacology &
Theraputeics. 116. (2007): 449-472. Print.

Luan, Zhaoxia. "Statins Inhibit Secretion of Metalloproteinases-1, -2, -3, and -9 From
Vascular Smooth Muscle Cells and Macrophages." American Heart
Association. 23. (2003): 769-775. Print.

Morehouse, Lee et al. "Comparison of synthetic saponin cholesterol absorption
inhibitors in rabbits: evidence for a non-stoichiometric, intestinal mechanism
of action." Journal of Lipid Research. 40. (1999): 464-474. Web. 19 May. 2012.
<www.jlr.org>.

Bilgen, Tolga. "Cardio Vascular System." University of Washington. Kane Hall,
Seattle. April 2012. Lecture.