Processes 2018, 6, 134
for a large number of cardiac diseases, for example coronary artery disease (CAD), cardiovascular
disease (CVD) and coronary heart disease (CHD). The chance of developing CAD, CVD or CHD is
determined by risk factors, some of which are modifiable. Modifiable risk factors include body weight,
blood pressure and blood lipid levels, which are all influenced by exercise levels, smoking and diet.
Non-modifiable risk factors include genetic predisposition, age, gender and ethnicity [2]. Whilst we
may not be able to control these factors, the effects are sometimes modifiable with pharmaceutical
interventions such as statins.
Dietary or exogenous cholesterol however, accounts for merely 20% of the body’s cholesterol.
The other 80%, endogenous cholesterol, is produced mainly by hepatocytes, but also by cells in
the central nervous system and reproductive organs [3]. Each cell is subject to the cholesterol
biosynthesis cascade initiated by 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR).
This signalling pathway cues the change in rate of production or inhibition of cholesterol in response to
declining or increasing cellular cholesterol levels. In this case the transcription factor, sterol regulatory
element-binding protein 2 (SREBP-2), is blocked from upregulating mRNA transcription of the HMGCR
gene when cellular levels of cholesterol are high, but is free to upregulate transcription when levels are
low. This allows the cell to change the rate of cholesterol production according to its needs.
Fats and cholesterol from a normal diet enter the blood stream, through the stomach, having been
packed into carrier molecules known as a lipoproteins. Lipids are insoluble and must thus be
packed into particles in order to be transported around the body. Lipoproteins are surrounded
by phospholipids and apolipoproteins. As well as surrounding lipoprotein molecules, apolipoproteins
play a vital role in the binding of lipoproteins to receptors on cell surfaces for removal from circulation.
They also act as activators for lipolytic enzymes involved in metabolism.
There are five main classes of lipoprotein: chylomicrons, very low density lipoproteins (VLDL),
intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein
(HDL). They are classed due to their varying triglyceride, cholesterol and apolipoprotein contents.
Lipoproteins continuously exchange lipids and proteins with cells and other lipoproteins leading to a
reduction in lipid content as the particles vary from being chylomicrons, to chylomicron remnants,
VLDL, IDL and subsequently LDL particles.
Carrying fats as an energy source through the blood stream to cells in need, lipoproteins eventually
end up in the liver where they are removed from circulation by a process known as receptor mediated
endocytosis (RME). The rate of lipoprotein uptake is regulated by the number of available free receptors
on the cell surface. Receptors are synthesised by the cell. Newly synthesised receptors are placed on
the surface of the cell where they collect in clathrin coated pits. Apolipoproteins attach the lipoprotein
to the receptor, after which the clathrin pit encloses around the lipoprotein and pinches off forming
endocytotic vesicles which are internalised. Empty pits may also undergo this process. Following
internalisation, the clathrin coating is shed and vesicles merge together to form larger endosomes
within which the lipoprotein dissociates from the receptor. Some receptors are removed at this point
and recycled to the cell surface. The endosomes then combine with lysosomes within the cell and the
contents are degraded by lysosomal enzyme hydrolysis releasing amino acids and cholesterol for use
in cellular metabolism [4].
Receptors, once synthesised or recycled, insert randomly on the cell surface before diffusing into
clathrin coated pits. The concentration of receptors in the pits determine how many lipoproteins
can bind and be internalised at any one time. LDL receptor (LDLR) synthesis is governed by
SREBP-2. When intracellular cholesterol concentrations are low transcription of LDLR is upregulated,
increasing the uptake of lipoproteins. Similarly high levels of cholesterol lead to downregulation of
LDLR synthesis, decreasing lipoprotein endocytosis. In high cholesterol concentrations, receptor and
cholesterol synthesis is inhibited. RME is the target of drugs, used in cardiovascular therapy, known as
statins which inhibit cholesterol biosynthesis and up-regulate receptor synthesis, thus increasing the
amount of lipoproteins cleared from the circulation.
81
for a large number of cardiac diseases, for example coronary artery disease (CAD), cardiovascular
disease (CVD) and coronary heart disease (CHD). The chance of developing CAD, CVD or CHD is
determined by risk factors, some of which are modifiable. Modifiable risk factors include body weight,
blood pressure and blood lipid levels, which are all influenced by exercise levels, smoking and diet.
Non-modifiable risk factors include genetic predisposition, age, gender and ethnicity [2]. Whilst we
may not be able to control these factors, the effects are sometimes modifiable with pharmaceutical
interventions such as statins.
Dietary or exogenous cholesterol however, accounts for merely 20% of the body’s cholesterol.
The other 80%, endogenous cholesterol, is produced mainly by hepatocytes, but also by cells in
the central nervous system and reproductive organs [3]. Each cell is subject to the cholesterol
biosynthesis cascade initiated by 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR).
This signalling pathway cues the change in rate of production or inhibition of cholesterol in response to
declining or increasing cellular cholesterol levels. In this case the transcription factor, sterol regulatory
element-binding protein 2 (SREBP-2), is blocked from upregulating mRNA transcription of the HMGCR
gene when cellular levels of cholesterol are high, but is free to upregulate transcription when levels are
low. This allows the cell to change the rate of cholesterol production according to its needs.
Fats and cholesterol from a normal diet enter the blood stream, through the stomach, having been
packed into carrier molecules known as a lipoproteins. Lipids are insoluble and must thus be
packed into particles in order to be transported around the body. Lipoproteins are surrounded
by phospholipids and apolipoproteins. As well as surrounding lipoprotein molecules, apolipoproteins
play a vital role in the binding of lipoproteins to receptors on cell surfaces for removal from circulation.
They also act as activators for lipolytic enzymes involved in metabolism.
There are five main classes of lipoprotein: chylomicrons, very low density lipoproteins (VLDL),
intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein
(HDL). They are classed due to their varying triglyceride, cholesterol and apolipoprotein contents.
Lipoproteins continuously exchange lipids and proteins with cells and other lipoproteins leading to a
reduction in lipid content as the particles vary from being chylomicrons, to chylomicron remnants,
VLDL, IDL and subsequently LDL particles.
Carrying fats as an energy source through the blood stream to cells in need, lipoproteins eventually
end up in the liver where they are removed from circulation by a process known as receptor mediated
endocytosis (RME). The rate of lipoprotein uptake is regulated by the number of available free receptors
on the cell surface. Receptors are synthesised by the cell. Newly synthesised receptors are placed on
the surface of the cell where they collect in clathrin coated pits. Apolipoproteins attach the lipoprotein
to the receptor, after which the clathrin pit encloses around the lipoprotein and pinches off forming
endocytotic vesicles which are internalised. Empty pits may also undergo this process. Following
internalisation, the clathrin coating is shed and vesicles merge together to form larger endosomes
within which the lipoprotein dissociates from the receptor. Some receptors are removed at this point
and recycled to the cell surface. The endosomes then combine with lysosomes within the cell and the
contents are degraded by lysosomal enzyme hydrolysis releasing amino acids and cholesterol for use
in cellular metabolism [4].
Receptors, once synthesised or recycled, insert randomly on the cell surface before diffusing into
clathrin coated pits. The concentration of receptors in the pits determine how many lipoproteins
can bind and be internalised at any one time. LDL receptor (LDLR) synthesis is governed by
SREBP-2. When intracellular cholesterol concentrations are low transcription of LDLR is upregulated,
increasing the uptake of lipoproteins. Similarly high levels of cholesterol lead to downregulation of
LDLR synthesis, decreasing lipoprotein endocytosis. In high cholesterol concentrations, receptor and
cholesterol synthesis is inhibited. RME is the target of drugs, used in cardiovascular therapy, known as
statins which inhibit cholesterol biosynthesis and up-regulate receptor synthesis, thus increasing the
amount of lipoproteins cleared from the circulation.
81