Tenp DPT Biochemistry: DR Pius Kiptembur

TENP DPT BIOCHEMISTRY
DR PIUS KIPTEMBUR
Cholesterol Metabolism
: “Cartoon representation of the molecular structure of protein registered with 1ldl code.”
Cholesterol Structure & Function
Cholesterol is an amphiphilic molecule, consisting of four nonpolar hydrocarbon rings

(A-D), a branched nonpolar hydrocarbon tail attached to carbon 17, and a polar
alcohol group on carbon 3. Cholesterol’s polar structure allows it to fit inside the
phospholipid bilayer and serve as a membrane fluidity buffer.
Cholesteryl esters are cholesterol molecules that have a fatty acid group attached to
the alcohol group at position 3 in the “A-ring.” Esters are more hydrophobic than
unesterified cholesterol and appear in bile components. Molecules of this type are too
hydrophobic to serve as a membrane fluidity buffer; they are associated with
lipoproteins.
Cholesterol Biosynthesis
Cholesterol is primarily synthesized in
 liver
 Intestines
 Adrenal cortex
 Reproductive tissues
The carbon skeleton that makes up its structure comes from Acetyl-CoA, whether
derived from glucose or fatty acid oxidation. Synthesis takes place in the cytosol, and
because this is an anabolic metabolic pathway, NADPH serves as the provider of
reducing equivalents.
: “HMG-CoA reductase pathway”
Cholesterol biosynthesis begins with the formation of mevalonate, which takes place
in a sequence of three reactions: Thiolase (ACAT), HMG-CoA synthase (HMGCS),
and HMG-CoA reductase (HMGCR). In these reactions, CoA groups are cleaved
off, with only the reductase step using reducing equivalents, in the form of 2 NADPH
that is spent to produce mevalonate. HMG-CoA Reductase is the rate-limiting step in
the pathway, and also serves as the key regulatory enzyme to synthesize cholesterol.
Note: MG-CoA has an alternative metabolic fate. When blood glucose levels are low,
Acetyl-CoA, produced from β-Oxidation of fatty acids, generates HMG-CoA, which
can be converted to ketone bodies by the activity of HMG-CoA Lyase (HMGCL), β-
hydroxybutyrate dehydrogenase, and Acetoacetate decarboxylase (AAD).
Mevalonate Kinase (MVK) converts mevalonate to mevalonate-5-phosphate by

hydrolyzing ATP. Then, Phosphomevalonate kinase
(PMVK) phosphorylates mevalonate-5-phosphate a second time,
producing mevalonate-5-pyrophosphate in a reaction that also uses ATP.
The ATP-dependent action of diphosphomevalonate decarboxylase (MVD) forms

the starter unit of cholesterol synthesis, Δ3-Isopentenyl-PP. Isopentenyl-P2 Δ-
isomerase (IDI-1) converts MVD to the repeating unit of cholesterol synthesis,
dimethylallyl pyrophosphate. Dimethylallyl transferase (DMAT) combines the
starter unit and repeat unit to form geranyl-pyrophosphate, which undergoes
conversion to farnesyl-pyrophosphate by geranyl transferase.
This linkage of start and repeat units occurs by “head-to-tail” nucleophilic

substitution, and the subsequently formed geranyl-pyrophosphate serves as the primer
for an analogous condensation yielding farnesyl-pyrophosphate.
Squalene is formed from the “head-to-head” condensation of two farnesyl-

pyrophosphate molecules by Squalene synthase (SQS), in a reaction that requires
NADPH as a cofactor. Eukaryotic cells and prokaryotes differ in their sterol synthesis
at this juncture. Our cells require oxygen (and NADPH) to fuel the reaction (squalene
monooxygenase) that forms squalene-2, 3-epoxide. Prokaryotes anaerobically
produce a compound called hopanoids, which is similar to cholesterol.
Lanosterol synthase produces lanosterol, which is the first compound on the way to
cholesterol that has four closed defined rings. From this point, a sequence of 19
reactions removes three methyl groups to form zymosterol. Zymosterol’s double
bonds are rearranged; eventually, one is removed, depending on the tissue in which
the synthesis takes place. The conversion of lanosterol to zymosterol takes place by
enzymes that require eleven NADPH. Cholesterol’s synthesis from zymosterol
requires an additional two NADPH to rearrange/remove double bonds.
An important conversion of cholesterol that takes place is esterification with long-

chain fatty acids (e.g., palmitic acid) in the endoplasmic reticulum, which blocks
cholesterol’s polar head group and, thus, its inclusion as a membrane fluidity buffer.
Cholesterol degradation leads to bile acids, which occur in the liver and excrete bile
into the small intestine. Bile acid amides form conjugates with taurine or glycine,
which dissociate completely at physiological pH levels due to their low pKa values.
Therefore, bile serves as a good anionic detergent for the body and forms cylindrical
micelles. It emulsifies lipids in the intestine so the intestinal mucosa can resorb them.
Regulation of Cholesterol Synthesis
The formation of mevalonate by HMG-CoA Reductase is strictly regulated because

it is the key reaction in the pathway leading to cholesterol. Glucagon (and thus cAMP)
induces HMG-CoA Reductase Kinase to phosphorylate HMG-CoA, thereby
inhibiting the enzyme. HMG-CoA will be shuttled to the mitochondria to produce
ketone bodies instead. When there is adequate glucose intake, insulin induces HMG-
CoA Reductase Phosphatase to dephosphorylate the enzyme, which allows for the
production of mevalonate and, eventually, cholesterol.
The transcription of HMG-CoA reductase is also under tight regulation so that the
synthesis of cholesterol only takes place when the cell has adequate precursors to do
so. When the cell needs to produce cholesterol, and there are plenty of
precursors, sterol regulatory element-binding protein (SREBP) is released from the
ER and translocates to the nucleus, where it binds the sterol regulatory
element (SRE). This increases the rate of HMG-CoA reductase transcription.
Conversely, when there are high levels of cholesterol, or the cell needs to use
precursors to produce other metabolites, SREBP is prevented from translocating to the
nucleus and binding to SRE, attenuating the production of HMG-CoA reductase.
HMG-CoA reductase is regulated at additional levels: Glucocorticoids (metabolites of

cholesterol) and other compounds accelerate HMGCR mRNA breakdown. Also,
HMG-CoA reductase is regulated by sterol-accelerated ubiquitination and
degradation. However, no total blockade of the enzyme occurs since sufficient
intermediates must be supplied to synthesize non-sterols. Similar regulation is exerted
with HMG-CoA synthase and mevalonate kinase.
Transport of Cholesterol
Lipoproteins are spherical complexes of lipid and protein, which

include chylomicrons, very-low-density lipoproteins (VLDL), low-density
lipoproteins (LDL), and high-density lipoproteins (HDL). They differ in their lipid
and protein compositions, sizes, densities, and biosynthesis sites. Lipoproteins
function in the transport of lipids between tissues. Cholesterol is one of the lipids that
is transported. As a result of their less than perfect transport, cholesterol is deposited
in tissues gradually. This could lead to a potentially life-threatening condition when
plaques form in blood vessels.
Metabolism of HDL
Lipoproteins are composed of endogenous or exogenous triacylglycerol or cholesteryl

esters, forming a core surrounded by a shell composed of apolipoproteins,
phospholipids, or free cholesterol. The polar portions of the lipids are oriented so that
they are on the surface of the lipoprotein, and this makes them soluble.
“Chylomikron-Struktur”
Structure of LDL
Chylomicrons are lipoprotein particles with the lowest density and largest size; in
other words, they contain the highest percentage of lipid and the lowest percentage of
protein. VLDLs and LDLs are successively denser, having higher ratios of protein to
lipid. HDL particles are the densest.
Degradation of Lipoproteins
Chylomicrons and VLDL

In under an hour, chylomicrons and VLDL can easily be eliminated from the
bloodstream. This is made possible with the help of lipoprotein lipase or LPL. This
enzyme is found in various locations in the body, including the walls of the blood
capillaries, the heart, liver sinusoids, lungs, and spleen, among many others. However,
the most active of these are the ones found in the endothelium of capillaries. LPL in
the liver is also responsible for the degradation of chylomicron remnants and HDL.
Hydrolysis is the main feature or LPL. It hydrolyzes lipoproteins in the presence of
cofactors, such as phospholipids and apo C-II. Once triglycerides are liberated from
this process, it is further hydrolyzed into free fatty acids and glycerols which can
either go to storage in adipose cells or for use in tissues that require ketone for energy,
such as the heart. The location of the LPL also dictates the predisposition of fatty
acids to metabolism or storage. For example, LPL found in the heart has a high
affinity for triglycerides which explains why fatty acids from triglyceride metabolism,
during starvation, are redirected to the heart.
LDL
LDL, on the other hand, is metabolized in cells containing an LDL receptor. This
receptor is specific for LDL as it detects apo B-100, an apoprotein unique to this
lipoprotein. The majority of this degradation occurs in the liver, while a certain degree
occurs in extrahepatic tissues.
LDL receptors, however, do not exist indefinitely. After functioning for some time,
they are eventually degraded by proteins. One of these includes the enzyme proprotein
convertase subtilisin/kexin type-9 or PCSK9. PCSK9 works by binding to the LDL
receptor, causing the receptor to undergo a series of changes leading to an eventual
degradation. Without these receptors, cells capable of metabolizing LDL would not be
able to do such.
After LDL enters the liver, cholesterol esters are hydrolyzed lysosomal cholesterol
esterase. The excess cholesterol produced in this way activates acetyl-CoA
cholesterol acyl-transferase (ACAT), which re-esterifies cholesterol into cholesterol
esters that can be deposited as lipid droplets or mobilized again to where it is
needed.
HDL
HDL is metabolized by the help of class B receptor B1 (SR-B1) in the liver and other
extrahepatic tissues that might use the cholesterol contained in the lipoproteins for
hormone synthesis. SR-B1 receptors have high affinity to apo A-I, the distinct
apoprotein found in HDL. Once SR-B1 bind to HDL, these empty the lipoprotein of
its contained cholesterol and use it for steroidogenesis, or excrete it as bile salts
The apolipoprotein portion associated with lipoprotein particles has several diverse
functions, such as providing recognition sites for cell-surface receptors and activating
lipoprotein metabolism. They are divided by structure and function into five major
classes, A through E. Most of the classes have subclasses, for example, apolipoprotein
(or apo) A-I and apo C-II.
Hypercholesterolemia
Disturbances in cholesterol metabolism cause various diseases. In familial

hypercholesterolemia, the uptake of cholesterol into the cells by LDL receptors is
diminished. Therefore, despite high plasma cholesterol concentration (intracellularly
regulated), cholesterol synthesis still proceeds at high speed
Disorders Affecting Lipid Metabolism
Dyslipidemias
This group of disorders could be categorized into either primary or secondary.

Primary dyslipidemia is the ones that are usually not associated with external causes
and may be brought about by single-gene mutations that could alter lipoprotein
synthesis or degradation. Examples are listed on the table below:
Genetic disorder
Gene defect
Elevated lipoproteins
Transmission
Hypertriglyceridemia
Lipoprotein lipase deficiency
LPL
Chylomicrons, VLDL
Autosomal recessive
Familial apoC-II deficiency
APOC2
Chylomicrons, VLDL
Autosomal recessive
ApoA-V deficiency
APOA5
Chylomicrons, VLDL
Autosomal recessive
GPIHBP1 deficiency
GPIHBP1
Chylomicrons
Autosomal recessive
Combined Hyperlipidemia
Familial hepatic lipase deficiency
LIPC
VLDL remnants, HDL
Autosomal recessive
Familial dysbetalipoproteinemia
APOE
Chylomicron remnants, VLDL remnants
Autosomal recessive
Hypercholesterolemia
Familial hypercholesterolemia
LDLR
LDL
Autosomal dominant
Familial defective apoB-100
APOB
LDL
Autosomal dominant
Autosomal dominant hypercholesterolemia, type 3

PCSK9
LDL
Autosomal dominant
Autosomal recessive hypercholesterolemia
LDLRAP
LDL
Autosomal recessive
Sitosterolemia
ABCG5 or ABCG8
LDL
Autosomal recessive
Secondary dyslipidemias, on the other hand, are manifested as imbalances in the

plasma levels of triglycerides and lipoproteins as a result of poor diet, co-existing
diseases or concurrent intake of other medications. Other more specific examples of
causes may include:
1. High-carbohydrate diet
2. Excessive alcohol intake
3. Obesity and insulin resistance
4. Excessive glucocorticoid levels
Treatment
The goal of treatment for patients having dyslipidemia is usually directed towards the
prevention of more serious diseases such as cardiovascular events and pancreatitis. In
order to reach and maintain this, lifestyle modifications and thorough meal planning
are instituted early in the diagnosis. More often than not, patients are also prescribed
with pharmacologic modalities that are designed to suit the type of dyslipidemia and
the concurrent risks that they have.
Statins:
HMG-CoA reductase converts HMG-CoA to mevalonate (a precursor to cholesterol) in
the liver.This is a rate-limiting step in cholesterol synthesis.
 Competitively inhibit the enzyme HMG-CoA reductase in hepatic cells
 Occupy a portion of the binding site of HMG CoA → block access of this
substrate to the active site on the enzyme
 ↓ Synthesis of cholesterol and isoprenoid intermediates (lipid compounds with
downstream inflammatory pathways)
 ↓ Cholesterol levels in hepatocytes → up-regulation of LDL receptors→ ↑ uptake of
LDL from the circulation
 They include Atorvastatin: 10–20 mg, Rosuvastatin: 5–10 mg, Simvastatin: 20–40 mg,
Pravastatin: 40–80 mg, Lovastatin: 40 mg, Fluvastatin: 40 mg twice daily, Pitavastatin: 2–4
mg
PSCK9 Inhibitors:
 Alirocumab
 Evolucumab
 Bococizumab

Tenp DPT Biochemistry: DR Pius Kiptembur

Uploaded by

Copyright:

Available Formats

Tenp DPT Biochemistry: DR Pius Kiptembur

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Tenp DPT Biochemistry: DR Pius Kiptembur

Uploaded by

Copyright:

Available Formats

TENP DPT BIOCHEMISTRY

Cholesterol Structure & Function

Cholesterol is an amphiphilic molecule, consisting of four nonpolar hydrocarbon rings

Cholesterol is primarily synthesized in

Mevalonate Kinase (MVK) converts mevalonate to mevalonate-5-phosphate by

The ATP-dependent action of diphosphomevalonate decarboxylase (MVD) forms

This linkage of start and repeat units occurs by “head-to-tail” nucleophilic

Squalene is formed from the “head-to-head” condensation of two farnesyl-

An important conversion of cholesterol that takes place is esterification with long-

Regulation of Cholesterol Synthesis

The formation of mevalonate by HMG-CoA Reductase is strictly regulated because

HMG-CoA reductase is regulated at additional levels: Glucocorticoids (metabolites of

Lipoproteins are spherical complexes of lipid and protein, which

Lipoproteins are composed of endogenous or exogenous triacylglycerol or cholesteryl

Chylomicrons and VLDL

Disturbances in cholesterol metabolism cause various diseases. In familial

Disorders Affecting Lipid Metabolism

This group of disorders could be categorized into either primary or secondary.

Lipoprotein lipase deficiency

Familial apoC-II deficiency

Familial hepatic lipase deficiency

VLDL remnants, HDL

Chylomicron remnants, VLDL remnants

Familial defective apoB-100

Autosomal dominant hypercholesterolemia, type 3

Autosomal recessive hypercholesterolemia

Secondary dyslipidemias, on the other hand, are manifested as imbalances in the

You might also like