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Discussion:
Biochemistry of Hypertension
Cholesterol is an amphipathic (both hydrophobic and hydrophilic parts) lipid and as such is an
essential structural component of membranes, where it is important for the maintenance of
the correct permeability and fluidity, and of the outer layer of plasma lipoproteins. It is
synthesized in many tissues from acetyl-CoA and is the precursor of all other steroids in the
body, including corticosteroids, sex hormones, bile acids, and vitamin D.
A little more than half the cholesterol of the body arises by synthesis (about 700 mg/d), and the
remainder is provided by the average diet.
Typical product of animal metabolism, cholesterol occurs in foods of animal origin such as egg
yolk, meat, liver, and brain.
Synthesis of Cholesterol
It is synthesized from acetyl- CoA by a pathway that may be divided into five steps:
(1) synthesis of mevalonate from acetyl-CoA: HMG-CoA (3-hydroxy- 3-
methylglutaryl-CoA) is formed by the reactions used in mitochondria to synthesize
ketone bodies. However, since cholesterol synthesis is extramitochondrial, the two
pathways are distinct. Initially, two molecules of acetyl-CoA condense to form
acetoacetyl-CoA catalyzed by cytosolic thiolase. Acetoacetyl-CoA condenses with a
further molecule of acetyl-CoA catalyzed by HMG-CoA synthase to form HMG-CoA,
which is reduced to mevalonate by NADPH in a reaction catalyzed by HMG-CoA
reductase. Next step is the principal regulatory step in the pathway of cholesterol
synthesis and is the site of action of the most effective class of cholesterol-lowering
drugs, the statins, which are HMG-CoA reductase inhibitors
(3) condensation of six isoprenoid units form squalene: Isopentenyl diphosphate is isomerized
by a shift of the double bond to form dimethylallyl diphosphate, and then condensed with
another molecule of isopentenyl diphosphate to form the 10-carbon intermediate geranyl
diphosphate (Figure 26–2). A further condensation with isopentenyl diphosphate forms farnesyl
diphosphate. Two molecules of farnesyl diphosphate condense at the diphosphate end to form
squalene. Initially, inorganic pyrophosphate is eliminated, forming presqualene diphosphate,
which is then reduced by NADPH with elimina- tion of a further inorganic pyrophosphate
molecule.
(4) cyclization of squalene give rise to the parent steroid, lanosterol: Squalene can fold into a
structure that closely resembles the steroid nucleus (Figure 26–3). Before ring closure occurs,
squalene is converted to squalene 2,3-epoxide by a mixed-function oxidase in the endoplasmic
reticulum, squalene epoxidase. The methyl group on C14 is transferred to C13 and that on C8 to
C14 as cyclization occurs, catalyzed by oxidosqualene-lanosterol cyclase.
(5) formation of cholesterol from lanosterol: The formation of cholesterol from lanosterol takes
place in the membranes of the endoplasmic reticulum and involves changes in the steroid nucleus
and the side chain (Figure 26–3). The methyl groups on C14 and C4 are removed to form 14-
desmethyl lanosterol and then zymosterol. The double bond at C8 ́C9 is subse- quently moved to
C5 ́C6 in two steps, forming desmosterol. Finally, the double bond of the side chain is reduced,
produc- ing cholesterol.
Plasma low-density lipoprotein (LDL) is the vehicle that supplies cholesterol and cholesteryl
ester to many tissues. Free cholesterol is removed from tissues by plasma high-density
lipoprotein (HDL) and transported to the liver, where it is eliminated from the body either
unchanged or after conversion to bile acids in the process known as reverse cholesterol
transport. Cholesterol is a major constituent of gallstones. However, its chief role in pathologic
processes is as a factor in the genesis of atherosclerosis of vital arteries, causing
cerebrovascular, coronary, and peripheral vascular disease.
Since the lipoprotein produced in the intestine is the chylomicron, the apoB 48 particles are
chylomicrons of intestinal origin. VLDLs containing apoB100 are produced in the liver. After
VLDLs are excreted and undergo lipolysis (hydrolysis or removal of TG and phospholipids) they
become IDLs and LDLs. Thus there is a single molecule of apoB 100 on each VLDL, IDL and LDL
and a single molecule of apoB48 on each chylomicron.
This has consequences because LDL receptors remove beta-lipoproteins from plasma by
recognizing and attaching to the surface charges on certain segments of the apoB 100
molecule. ApoB48 is a shortened apoB100 and hence has a different conformation (lacks the
segment recognized by LDL receptors) present on apoB100 and is therefore apoB48 is not
recognized by LDL receptors. However, chylomicrons have a high content of apolipoprotein E
and LDL receptors also recognize and internalize apoE-containing lipoproteins. Thus the liver
LDL- receptors internalize chylomicrons by attaching to apoE and they internalize VLDLs by
attaching to apoB100 or apoE and they internalize LDLs by attaching to apoB100.
In FH, a condition characterized by very high levels of cholesterol in the blood due to mutations
in the LDL Receptor gene. The hereditary forms of hypercholesterolemia is caused by mutations
in the:
APOB gene: provides instructions for making two versions of the apolipoprotein B protein, a
short version called apolipoprotein B-48 and a longer version known as apolipoprotein B-
100.
LDLRAP1 gene: provides instructions for making a protein that helps remove cholesterol
from the bloodstream. The function of the LDLRAP1 protein is particularly important in the
liver, which is the organ responsible for clearing most excess cholesterol from the body.
PCSK9 gene: provides instructions for making a protein that helps regulate the amount of
cholesterol in the bloodstream by controling the number of low-density lipoprotein
receptors. Studies suggest that the PCSK9 protein helps control blood cholesterol levels by
breaking down low-density lipoprotein receptors before they reach the cell surface.
However, most cases of high cholesterol are not caused by a single inherited condition, but
result from a combination of lifestyle choices and the effects of variations in many genes.
ApoB100 is found in lipoproteins originating from the liver (VLDL, IDL, LDL[13]). Importantly,
there is one ApoB100 molecule per hepatic-derived lipoprotein. Hence, using that fact, one can
quantify the number of lipoprotein particles by noting the total ApoB100 concentration in the
circulation. Since there is one and only one ApoB100 per particle, the number of particles is
reflected by the ApoB100 concentration. The same technique can be applied to individual
lipoprotein classes (e.g. LDL) and thereby enable one to count them as well.
It is well established that ApoB100 levels are associated with coronary heart disease, and are
even a better predictor of it than is LDL level.[citation needed] A naive way of explaining this
observation is to use the idea that ApoB100 reflects lipoprotein particle number (independent
of their cholesterol content). In this way, one can infer that the number of ApoB100-containing
lipoprotein particles is a determinant of atherosclerosis and heart disease.
One way to explain the above is to consider that large numbers of lipoprotein particles, and, in
particular large numbers of LDL particles, lead to competition at the LDL receptor of peripheral
cells. Since such a competition will prolong the residence time of LDL particles in the circulation,
it may lead to greater opportunity for them to undergo oxidation and/or other chemical
modifications. Such modifications may lessen the particles' ability to be cleared by the classic
LDL receptor and/or increase their ability to interact with so-called "scavenger" receptors. The
net result is shunting of LDL particles to these scavenger receptors. Scavenger receptors
typically are found on macrophages, with cholesterol laden macrophages being better known
as "foam cells". Foam cells characterize atherosclerotic lesions. In addition to this possible
mechanism of foam cell generation, an increase in the levels of chemically modified LDL
particles may also lead to an increase in endothelial damage. This occurs as a result of
modified-LDL's toxic effect on vascular endothelium as well its ability both to recruit immune
effector cells and to promote platelet activation.