Biosynthesis
and biotransformation of cholesterol. Metabolism of ketonå bodies. Regulation and disorders of
lipid metabolism
Biological
role of cholesterol.
Cholesterol is a lipidic, waxy alcohol found in the cell
membranes and transported in the blood plasma
of all animals.
It is an essential component of mammalian cell membranes where it is required
to establish proper membrane permeability and fluidity.
Cholesterol is the principal sterol synthesized by animals, but small
quantities are synthesized in other eukaryotes,
such as plants
and fungi.
It is almost completely absent among prokaryotes,
which include bacteria. Cholesterol is classified as a sterol (a
contraction of steroid and alcohol).
Cholesterol is an extremely important
biological molecule that has roles in membrane structure as well as being a
precursor for the synthesis of the steroid
hormones and bile acids.
Both dietary cholesterol and that synthesized de novo are transported
through the circulation in lipoprotein
particles. The same is true of cholesteryl esters, the form in which
cholesterol is stored in cells.
The synthesis and utilization of cholesterol must be tightly
regulated in order to prevent over-accumulation and abnormal deposition within
the body. Of particular importance clinically is the abnormal deposition of
cholesterol and cholesterol-rich lipoproteins in the coronary arteries. Such
deposition, eventually leading to atherosclerosis, is the leading contributory
factor in diseases of the coronary arteries. Although
cholesterol is essential for life, high levels in circulation are associated
with atherosclerosis. Cholesterol is synthesized in
virtually all cells, and significant amounts of it can be absorbed from the
diet.
The name cholesterol originates from the Greek
chole- (bile)
and stereos (solid), and the chemical
suffix
-ol for an alcohol, as François Poulletier de
Functions
Biological role of cholesterol:
-
building
blocks of membranes;
-
synthesis
of steroid hormones;
-
synthesis
of bile acids;
-
synthesis
of vitamin D;
-
cholesterol
is often deposited on the inner walls of blood vessels, together with other
lipids, a condition known as atherosclerosis,
which often leads to occlusion of blood vessels in the heart and the brain, resulting
in heart attacks and strokes, respectively.
The
liver produces about
and the hydrocarbon
chain is embedded in the membrane, alongside the nonpolar fatty acid
chains of the other lipids. Some research indicates that cholesterol
may act as an antioxidant. Bile, which is stored in
the gallbladder
and helps digest fats,
is important for the absorption
of the fat soluble vitamins, vitamins A,
D,
E,
and K.
It is the main precursor of vitamin D and of the steroid
hormones, which include cortisol
and aldosterone
(in the adrenal glands) and progesterone,
estrogens,
and testosterone
(the sex hormones), and their derivatives.
It provides the basic structure of all the
steroids. In myelin, it envelopes and insulates nerves, helping greatly to
conduct nerve impulses.
Recently, cholesterol has also
been implicated in cell signaling processes, assisting in the formation of lipid rafts
in the plasma membrane. It also reduces the
permeability of the plasma membrane to protons (positive hydrogen
ions) and sodium ions.
Cholesterol is essential for the structure and
function of invaginated caveolae and clathrin-coated pits, including caveola-dependent
and clathrin-dependent endocytosis. The role of cholesterol in such
endocytosis can be investigated by using methyl beta cyclodextrin (MβCD) to
remove cholesterol from the plasma membrane LDL are formed in liver and
transport cholesterol from liver to peripheral tissue. LDL is taken up by
various tissues and provides cholesterol, which the tissue utilize.
.
Contents
of cholesterol in a blood, transport forms of cholesterol
HDL picks up cholesterol from cell membranes or
from other lipoproteins. Cholesterol is converted to cholesterol esters by the
lecithin:cholesterol acyltransferase (LCAT) reaction. The cholesterol esters
may be transferred to other lipoproteins or carried by HDL to the liver, where
they are hydrolyzed to free cholesterol, which is used for synthesis of VLDL or
converted to bile salts.
The content of cholesterol in blood plasma – 3-8
mmol/l.
The plasma lipoproteins are
complexes in which the lipids and proteins occur in a relatively fixed ratio.
They carry water-insoluble lipids between various organs via the blood, in a
form with a relatively small and constant particle diameter and weight. Human
plasma lipoproteins occur in four major classes that differ in density as well
as particle size. They are physically distinguished by their relative rates of
flotation in high gravitational fields in the ultracentrifuge.
http://www.youtube.com/watch?v=x-4ZQaiZry8
Since cholesterol is
insoluble in blood, it is transported in the circulatory system within lipoproteins
complex spherical particles which have an exterior composed of amphiphilic
proteins and lipids whose outward-facing surface is water-soluble and
inward-facing surfaces are lipid-soluble; fats and cholesterol
esters are carried internally. There is a large range of lipoproteins within
blood, generally called, from larger to smaller size: chylomicrons VLDL is converted to intermediate
density lipoproteins (IDL), which is degraded by the liver or
converted in blood capillaries to low density lipoproteins LDL by further digestion of
triacylglycerols.
very low density lipoprotein (VLDL)
LDL is taken up by various tissues
and provides cholesterol, which the tissue utilize intermediate density lipoprotein
(IDL), low density lipoprotein (LDL) and high density lipoprotein (HDL).
High density
lipoproteins (HDL) which is synthesized by the
liver, transfers apoproteins to ehylomicrons and VLDL.
HDL
picks up cholesterol from cell membranes or from other lipoproteins.
Cholesterol is converted to cholesterol esters by the lecithin:cholesterol
acyltransferase (LCAT) reaction. The cholesterol esters may be transferred to
other lipoproteins or carried by HDL to the liver, where they are hydrolyzed to
free cholesterol, which is used for synthesis of VLDL or converted to bile
salts.
Composition of the blood lipoproteins
The major components of
lipoproteins are triacylglycerols, cholesterol, cholesterol esters,
phospholipids, and proteins. Purified proteins (apoproteins) are designated A,
B, C, and E.
Component Chylomicrons VLDL IDL LDL HDL
Triacylglycerol 85% 55% 26% 10% 8%
Protein 2% 9% 11% 20% 45%
Type B,C,E B,C,E B,E B A,C,E
Cholesterol 1% 7% 8% 10% 5%
Cholesterol ester 2% 10% 30% 35% 15%
Phospholipid 8% 20% 23% 20% 25%
The
cholesterol within all the various lipoproteins is identical although some
cholesterol is carried as the "free" alcohol and some is carried as
fatty acyl esters referred to as cholesterol esters.
Cholesterol is minimally soluble in water; it can dissolve and
travel in the water-based bloodstream only at exceedingly small concentrations.
In order to carry large quantities of cholesterol it is transported in the
bloodstream by lipoproteins—protein
"molecular-suitcases" that are water-dispersible and carry
cholesterol and triglycerides as well as phospholipids and
cholesterol esters. Phospholipids and cholesterol, being amphipathic, are
transported in the surface monolayer of the lipoprotein particle while neutral lipids
including triglycerides and cholesterol esters are carried in the core of the
lipoprotein particle. By serving as ligands for specific receptors on cell
membranes, the apolipoproteins that reside on the surface of a
given lipoprotein particle are thought to determine from what cells cholesterol
will be removed and to where it will be delivered.
Cholesterol is transported towards peripheral tissues by
the lipoproteins chylomicrons, very low density lipoproteins (VLDL) and low-density lipoproteins (LDL). Large
numbers of small dense LDL (sdLDL) particles are strongly associated with the
presence of atheromatous
disease within the arteries. For this reason, LDL is referred to as "bad
cholesterol".
On the other hand, high-density lipoprotein (HDL) particles
are thought to transport cholesterol back to the liver for excretion in a
process known as reverse cholesterol transport (RCT). Having large numbers of
large HDL particles correlates with better health outcomes. In contrast, having
small numbers of large HDL particles is independently associated with atheromatous
disease progression within the arteries.
Metabolism
of Chylomicrons
Chylomicrons are synthesized in intestinal
epithelial cells. Their triacylglycerols are derived from dietary lipid, and
their major apoprotein is apo B-48.Chylomicrons travel through the lymph into
the blood. In peripheral tissues,
particularly adipose and muscle, the triacylglyerols are digested by lipoprotein
lipase.The chylomicron remnants interact with receptors on liver cells and
are taken+ up by endocytosis. The contents are degraded by lysosomal enzymes, and the products (amino
acids, fatty acids, glycerol, and cholesterol) are released into the cytosol
and reutilized.
Metabolism of VLDL
VLDL is
synthesized in the liver, particularly after a
high-carbohydrate meal. It is formed from triacylglycerols that are package
with cholesterol, apoproteins (particularly apo B-100), and phospholipids and
it is released into the blood.
In peripheral tissues, particularly
adipose and muscle, VLDL triacylglycerols are digested by lipoprotein lipase,
and VLDL is converted to IDL.
IDL returns to the liver, is
taken up by endocytosis, and is degraded by lysosomal enzymes.
IDL may
also be further degraded by lipoprotein lipase, forming LDL.
LDL reacts with receptors on various cells, is
taken up by endocytosis and is digested by
lysosomal enzymes.
Cholesterol,
released from cholesterol esters by a lysosomal esterase, can be used for the
synthesis of cell memmbranes or bile salts in the liver or steroid hormones in
endocrine tissue.
http://www.youtube.com/watch?v=XPguYN7dcbE
Metabolism of HDL
HDL is synthesized by the liver and released into the blood as
disk-shaped particles. The major protein of HDL is apo A.
HDL cholesterol, obtained from cell membranes or from other
lipoproteins, is converted to cholesterol esters. As cholesterol esters
accumulate in the core of the lipoprotein, HDL particles become spheroids.
HDL particles are taken up by the liver by endocytosis and hydrolyzed by
lysosomal enzymes. Cholesterol, released from cholesterol esters may be
packaged by the liver in VLDL and released into the blood or converted to bile
salts and secreted into the bile.
Stages of biosynthesis of cholesterol, localization of this process
Slightly less than half of the
cholesterol in the body derives from biosynthesis de novo.
Biosynthesis in the liver accounts for approximately 10%, and in the intestines
approximately 15%, of the amount produced each day. Cholesterol synthesis
occurs in the cytoplasm and microsomes (ER) from the two-carbon acetate group
of acetyl-CoA.
The acetyl-CoA utilized for cholesterol biosynthesis is
derived from an oxidation reaction (e.g., fatty acids or pyruvate) in the
mitochondria and is transported to the cytoplasm by the same process as that
described for fatty acid synthesis (see the Figure
below). Acetyl-CoA can also be synthesized from cytosolic acetate derived from
cytoplasmic oxidation of ethanol which is initiated by
cytoplasmic alcohol dehydrogenase (ADH3). All the reduction reactions of
cholesterol biosynthesis use NADPH as a cofactor. The isoprenoid intermediates
of cholesterol biosynthesis can be diverted to other synthesis reactions, such
as those for dolichol (used in the synthesis of N-linked
glycoproteins, coenzyme Q (of the oxidative
phosphorylation pathway) or the side chain of heme-a.
Additionally, these intermediates are used in the lipid modification
of some proteins.
Most of the cholesterol in the
body is synthesized therein; some is absorbed in the diet. Cholesterol is more
abundant in tissues which either synthesize more, or have more abundant,
densely-packed membranes, for example, the liver, spinal cord
and brain.
It plays a central role in many biochemical
processes, such as the building of cell membranes and the synthesis of steroid
hormones.
Cholesterol is required in the membranes of mammalian cells for normal
cellular function, and is either synthesized in the endoplasmic reticulum, or derived from the
diet, in which case it is transported by the bloodstream in low-density or high-density lipoproteins. Low-density
lipoproteins are taken into the cell by LDL receptor-mediated
endocytosis
in clathrin-coated pits,
and then hydrolysed in lysosomes.Cholesterol is an isoprenoid lipid of the
steroid group, esterol subclass, with an important rol in the structure of cell
membrane, as a precursor of hormones, Vitamin D and bile acids, and in the
pathology of vascular diseases.
Cholesterol biosynthesis
occurs in practically all the tissues, but it is more active in liver and in
steroid producing organs, like suprarrenal cortex and gonads.
In the Cholesterol synthesis
participates enzymes from the smooth endoplasmic
reticulum and the cytosol.
Pathway for the movement of acetyl-CoA units from within
the mitochondrion to the cytoplasm for use in lipid and cholesterol
biosynthesis. Note that the cytoplasmic malic enzyme catalyzed reaction
generates NADPH which can be used for reductive biosynthetic reactions such as
those of fatty acid and cholesterol synthesis.
The
process of cholesterol synthesis has five major steps:
1.
Acetyl-CoAs are converted to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)
2. HMG-CoA
is converted to mevalonate
3.
Mevalonate is converted to the isoprene based molecule, isopentenyl
pyrophosphate (IPP), with the concomitant loss of CO2
4. IPP is
converted to squalene
5.
Squalene is converted to cholesterol.
Pathway of cholesterol biosynthesis.
Synthesis begins with the transport of
acetyl-CoA from the mitochondrion to the cytosol. The rate limiting step occurs
at the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reducatase, HMGR catalyzed
step. The phosphorylation reactions are required to solubilize the isoprenoid
intermediates in the pathway. Intermediates in the pathway are used for the
synthesis of prenylated proteins, dolichol, coenzyme Q and the side chain of
heme a. The abbreviation "PP" (e.g. isopentenyl-PP) stands
for pyrophosphate. Place mouse over intermediate names to see structure.
Acetyl-CoA units are converted to mevalonate by a series
of reactions that begins with the formation of HMG-CoA. Unlike
the HMG-CoA formed during ketone body
synthesis in the mitochondria, this form is synthesized in the
cytoplasm. However, the pathway and the necessary enzymes are similar to those
in the mitochondria. Two moles of acetyl-CoA are condensed in a reversal of the
thiolase reaction, forming acetoacetyl-CoA. The cytoplasmic thiolase enzyme
involved in cholesterol biosynthesis is acetoacetyl-CoA thiolase encoded by the
ACAT2 gene. Although the bulk of acetoacetyl-CoA is derived via this process,
it is possible for some acetoacetate, generated during ketogenesis, to diffuse out of the
mitochondria and be converted to acetoacetyl-CoA in the cytosol via the action
of acetoacetyl-CoA synthetase (AACS). Acetoacetyl-CoA and a third mole of
acetyl-CoA are converted to HMG-CoA by the action of HMG-CoA synthase.
HMG-CoA is converted to mevalonate by HMG-CoA reductase,
HMGR (this enzyme is bound in the endoplasmic reticulum, ER). HMGR absolutely
requires NADPH as a cofactor and two moles of NADPH are consumed during the
conversion of HMG-CoA to mevalonate. The reaction catalyzed by HMGR is the rate
limiting step of cholesterol biosynthesis, and this enzyme is subject to
complex regulatory controls as discussed below.
Mevalonate is then activated by two
successive phosphorylations (catalyzed by mevalonate kinase, and
phosphomevalonate kinase), yielding 5-pyrophosphomevalonate. In humans, mevalonate
kinase resides in the cytosol indicating that not all the reactions of
cholesterol synthesis are catalyzed by membrane-associated enzymes as
originally described. After phosphorylation, an ATP-dependent decarboxylation
yields isopentenyl pyrophosphate, IPP, an activated isoprenoid molecule.
Isopentenyl pyrophosphate is in equilibrium with its isomer, dimethylallyl
pyrophosphate, DMPP. One molecule of IPP condenses with one molecule of DMPP to
generate geranyl pyrophosphate, GPP. GPP further condenses with another IPP
molecule to yield farnesyl pyrophosphate, FPP. Finally, the NADPH-requiring
enzyme, squalene synthase catalyzes the head-to-tail condensation of two
molecules of FPP, yielding squalene. Like HMGR, squalene synthase is tightly
associated with the ER. Squalene undergoes a two step cyclization to yield
lanosterol. The first reaction is catalyzed by squalene monooxygenase. This
enzyme uses NADPH as a cofactor to introduce molecular oxygen as an epoxide at
the 2,3 position of squalene. Through a series of 19 additional reactions,
lanosterol is converted to cholesterol.
The terminal reaction in cholesterol biosynthesis is
catalyzed by the enzyme 7-dehydrocholesterol reductase encoded by the DHCR7
gene. Functional DHCR7 protein is a 55.5 kDa NADPH-requiring integral membrane
protein localized to the microsomal membrane. Deficiency in DHCR7 (due to gene
mutations) results in the disorder called Smith-Lemli-Opitz
syndrome, SLOS. SLOS is characterized by increased levels of
7-dehydrocholesterol and reduced levels (15% to 27% of normal) of cholesterol
resulting in multiple developmental malformations and behavioral problems.
The main “materials” required for the synthesis of cholesterol are:
a) Acetyl CoA, whose acetyl groups provide all the
carbons of cholesterol.
b) ATP, as an energy source.
c) NADPH.H+ as provider of the
reduction equivalents required for the synthesis.
There are three stage in cholesterol
synthesis. (1) acetic acid is converted to mevalonic acid, (2) mevalonic acid
is converted into squalene, and (3) squalene is converted into cholesterol.
http://www.youtube.com/watch?v=hRx_i9npTDU&feature=related
I.-
Mevalonate synthesis
Mevalonic acid is formed by condensation of three molecules
of acetyl-CoA. The key intermediate in this process is b-hydroxy-b-methylglutaryl-CoA (HMG-CoA), which is formed
as follows:
Acetyl-CoA Acetyl-CoA Acetoacetyl-CoA
b-hydroxy-b-methylglutaryl-CoA
The enzyme is called b-hydroxy-b-methylglutaryl-CoA
synthase.
The b-hydroxy-b-methylglutaryl-CoA undergoes an irreversible two-step
reduction of one of its carboxyl groups to an alcohol group, with concomitant
loss of CoA, by the action of hydroxymethylglutaryl-CoA
reductase, to yield mevalonate:
Mevalonate is phosphorylated by ATP, first to the 5-monophosphate
ester and then to the 5-pyrophosphomevalonic acid:
5-pyrophosphomevalonic acid
A third phosphorylation, at carbon atom 3, yields a
very unstable intermediate which loses phosphoric acid and decarboxylates to
form 3-isopentenyl pyrophosphate,
which isomerizes to 3,3-dimethylallyl
pyrophosphate.
3,3-dimethylallyl pyrophosphate
In the next several reactions 3,3-dimethylallyl pyrophosphate
is converted to squalene. In the last
stage of cholesterol biosynthesis, squalene undergoes attack by molecular
oxygen, undergoes cyclization and lanosterol is formed. Lanosterol is transformed to cholesterol.
Regulating
Cholesterol Synthesis
Normal healthy adults synthesize cholesterol at a rate of
approximately 1g/day and consume approximately 0.3g/day. A relatively constant
level of cholesterol in the blood (150–200 mg/dL) is maintained primarily by
controlling the level of de novo synthesis. The level of cholesterol
synthesis is regulated in part by the dietary intake of cholesterol.
Cholesterol from both diet and synthesis is utilized in the formation of
membranes and in the synthesis of the steroid hormones and bile acids. The greatest proportion of
cholesterol is used in bile acid synthesis.
The cellular supply of cholesterol is maintained at a
steady level by three distinct mechanisms:
1. Regulation of
HMGR activity and levels
2. Regulation of excess
intracellular free cholesterol through the activity of acyl-CoA:cholesterol
acyltransferase, ACAT
3. Regulation of
plasma cholesterol levels via LDL receptor-mediated uptake and HDL-mediated
reverse transport.
Regulation of HMGR activity is the primary means for
controlling the level of cholesterol biosynthesis. The enzyme is controlled by
four distinct mechanisms: feed-back inhibition, control of gene expression,
rate of enzyme degradation and phosphorylation-dephosphorylation.
The first three control mechanisms are exerted by
cholesterol itself. Cholesterol acts as a feed-back inhibitor of pre-existing
HMGR as well as inducing rapid degradation of the enzyme. The latter is the
result of cholesterol-induced polyubiquitination of HMGR and its degradation in
the proteosome (see proteolytic degradation below). This
ability of cholesterol is a consequence of the sterol sensing domain,
SSD of HMGR. In addition, when cholesterol is in excess the amount of
mRNA for HMGR is reduced as a result of decreased expression of the gene. The
mechanism by which cholesterol (and other sterols) affect the transcription of
the HMGR gene is described below under regulation of sterol content.
Regulation of HMGR through covalent modification occurs
as a result of phosphorylation and dephosphorylation. The enzyme is most active
in its unmodified form. Phosphorylation of the enzyme decreases its activity.
HMGR is phosphorylated by AMP-activated protein kinase, AMPK
(this is not the same as cAMP-dependent protein kinase, PKA). AMPK itself is
activated via phosphorylation. Phosphorylation of AMPK is catalyzed by at least
2 enzymes. The primary kinase sensitive to rising AMP levels is LKB1. LKB1 was
first identified as a gene in humans carrying an autosomal dominant mutation in
Peutz-Jeghers syndrome, PJS. LKB1 is also found mutated in lung adenocarcinomas.
The second AMPK phosphorylating enzyme is calmodulin-dependent protein kinase
kinase-beta (CaMKKβ). CaMKKβ induces phosphorylation of AMPK in
response to increases in intracellular Ca2+ as a result of muscle
contraction. Visit AMPK: The Master Metabolic Regulator for
more detailed information on the role of AMPK in regulating metabolism.
Regulation of HMGR by covalent
modification. HMGR is most active in the dephosphorylated state. Phosphorylation
is catalyzed by AMP-activated protein kinase, AMPK, (used to be termed HMGR
kinase), an enzyme whose activity is also regulated by phosphorylation.
Phosphorylation of AMPK is catalyzed by at least 2 enzymes: LKB1 and
CaMKKβ. Hormones such as glucagon and epinephrine negatively affect
cholesterol biosynthesis by increasing the activity of the inhibitor of
phosphoprotein phosphatase inhibitor-1, PPI-1. Conversely, insulin stimulates
the removal of phosphates and, thereby, activates HMGR activity. Additional
regulation of HMGR occurs through an inhibition of its' activity as well as of
its' synthesis by elevation in intracellular cholesterol levels. This latter
phenomenon involves the transcription factor SREBP described below.
The activity of HMGR is additionally controlled by the
cAMP signaling pathway. Increases in cAMP lead to activation of cAMP-dependent
protein kinase, PKA. In the context of HMGR regulation, PKA phosphorylates
phosphoprotein phosphatase inhibitor-1 (PPI-1) leading to an increase in its'
activity. PPI-1 can inhibit the activity of numerous phosphatases including
protein phosphatase
Since the intracellular level of cAMP is
regulated by hormonal stimuli, regulation of cholesterol biosynthesis is
hormonally controlled. Insulin leads to a decrease in cAMP, which in turn
activates cholesterol synthesis. Alternatively, glucagon and epinephrine, which
increase the level of cAMP, inhibit cholesterol synthesis.
The ability of insulin to stimulate, and
glucagon to inhibit, HMGR activity is consistent with the effects of these
hormones on other metabolic pathways. The basic function of these two hormones
is to control the availability and delivery of energy to all cells of the body.
Long-term control of HMGR activity is
exerted primarily through control over the synthesis and degradation of the
enzyme. When levels of cholesterol are high, the level of expression of the
HMGR gene is reduced. Conversely, reduced levels of cholesterol activate
expression of the gene. Insulin also brings about long-term regulation of
cholesterol metabolism by increasing the level of HMGR synthesis.
Proteolytic Regulation of HMG-CoA Reductase
The stability of HMGR is regulated as
the rate of flux through the mevalonate synthesis pathway changes. When the
flux is high the rate of HMGR degradation is also high. When the flux is low,
degradation of HMGR decreases. This phenomenon can easily be observed in the
presence of the statin drugs as discussed below.
HMGR is localized to the ER and like SREBP (see below)
contains a sterol-sensing domain, SSD. When sterol levels increase in cells
there is a concomitant increase in the rate of HMGR degradation. The
degradation of HMGR occurs within the proteosome, a multiprotein complex
dedicated to protein degradation. The primary signal directing proteins to the
proteosome is ubiquitination. Ubiquitin is a 7.6kDa protein that is covalently
attached to proteins targeted for degradation by ubiquitin ligases. These
enzymes attach multiple copies of ubiquitin allowing for recognition by the
proteosome. HMGR has been shown to be ubiquitinated prior to its degradation.
The primary sterol regulating HMGR degradation is cholesterol itself. As the
levels of free cholesterol increase in cells, the rate of HMGR degradation
increases.
Metabolism and excretion
Cholesterol is transported in the plasma
predominantly as cholesteryl esters associated with lipoproteins.
Dietary cholesterol is transported from the small intestine to the liver within
chylomicrons. Cholesterol synthesized by the liver, as well as any dietary
cholesterol in the liver that exceeds hepatic needs, is transported in the
serum within LDLs. The liver synthesizes VLDLs and these are converted to LDLs
through the action of endothelial cell-associated lipoprotein lipase.
Cholesterol found in plasma membranes can be extracted by HDLs and esterified
by the HDL-associated enzyme LCAT. The cholesterol acquired from peripheral
tissues by HDLs can then be transferred to VLDLs and LDLs via the action of
cholesteryl ester transfer protein (apo-D) which is associated with HDLs. Reverse
cholesterol transport allows peripheral cholesterol to be returned to
the liver in LDLs. Ultimately, cholesterol is excreted in the bile as free
cholesterol or as bile salts following conversion to bile acids in the liver.
Cholesterol is oxidized by the liver into a variety of bile acids.
These in turn are conjugated with glycine,
taurine,
glucuronic
acid, or sulfate. A mixture of conjugated and non-conjugated bile acids
along with cholesterol itself is excreted from the liver into the bile. Approximately 95% of
the bile acids are reabsorbed from the intestines and the remainder lost in the
feces.[12] The excretion and reabsorption of bile acids forms
the basis of the enterohepatic circulation which is
essential for the digestion and absorption of dietary fats. Under certain
circumstances, when more concentrated, as in the gallbladder,
cholesterol crystallises and is the major constituent of most gallstones,
although lecithin
and bilirubin
gallstones also occur less frequently.
Cytochrome P450 Enzymes in Cholesterol
Metabolism
Cytochrome P450 enzymes are involved in a diverse array
of biological processes that includes lipid, cholesterol, and steroid
metabolism as well as the metabolism of xenobiotics. The now common
nomenclature used to designate P450 enzymes is CYP. There are at least 57 CYP
enzymes in human tissues with eight being involved in cholesterol biosynthesis
and metabolism, which includes conversion of cholesterol to bile acids. CYP
metabolism of cholesterol yields several oxysterols that function as
biologically active molecules such as in the activation of the liver
X receptors (LXRs) and SREBP (see the next section).
CYP3A4: CYP3A4
is also known as glucocorticoid-inducible P450 and nifedipine oxidase.
Nifedipine is a member of the calcium channel blocker drugs used to treat
hypertension. CYP3A4 is a major hepatic P450 enzyme and is responsible for the
biotransformation of nearly 60% of all commercially available drugs. With
respect to cholesterol metabolism, CYP3A4 catabolizes cholesterol to
4β-hydroxycholesterol. This cholesterol derivative is one of the major
circulating oxysterols and is seen at elevated levels in patients treated with
anti-seizure medications such as carbamazepine, phenobarbitol, and phenytoin.
The nuclear receptor, pregnane X receptor (PXR), is known to be an inducer of
the CYP3A4 gene.
CYP7A1: CYP7A1
is also known as cholesterol 7α-hydroxylase and is the rate limiting
enzyme in the primary pathway of bile acid synthesis referred to as the
classic pathway. This reaction of bile acid synthesis plays a major role in
hepatic regulation of overall cholesterol balance. Deficiency in CYP7A1
manifests with markedly elevated total cholesterol as well as LDL, premature
gallstones, premature coronary and peripheral vascular disease. Treatment of
this disorder with members of the statin drug family do not alleviated the
elevated serum cholesterol due to the defect in hepatic diversion of
cholesterol into bile acids.
CYP7B1: CYP7B1
is also known as oxysterol 7α-hydroxylase and is involved in the synthesis
of bile acids via the less active secondary pathway referred to as the acidic
pathway. A small percentage (1%) of individuals suffering from autosomal
recessive hereditary spastic paraplegia 5A (SPG5A) have been shown to harbor mutations
in the CYP7B1 gene.
CYP8B1: CYP8B1
is also known as sterol 12a-hydroxylase and is involved in the conversion of
7-hydroxycholesterol (CYP7A1 product) to cholic acid which is one of two
primary bile acids and is derived from the classic pathway of bile acid
synthesis. The activity of CYP8B1 controls the ratio of cholic acid over
chenodeoxycholic acid in the bile.
CYP27A1: CYP27A1
is also known as sterol 27-hydroxylase and is localized to the mitochondria.
CYP27A1 functions with two cofactor proteins called adrenodoxin and adrenodoxin
reductase to hydroxylate a variety of sterols at the 27 position. CYP27A1 is
also involved in the diversion of cholesterol into bile acids via the less
active secondary pathway referred to as the acidic pathway. Deficiencies in
CYP27A1 result in progressive neurological dysfunction, neonatal cholestasis,
bilateral cataracts, and chronic diarrhea.
CYP39A1: CYP39A1
is also known as oxysterol 7α-hydroxylase 2. This P450 enzyme was originally
identified in mice in which the CYP7B1 gene had been knocked out. The
preferential substrate for CYP39A1 is 24-hydroxycholesterol, which is a major
product of CYP46A1, which via CYP39A1 action is diverted into bile acid
synthesis.
CYP46A1: CYP46A1
is also known as cholesterol 24-hydroxylase. This enzyme is expressed primarily
in neurons of the central nervous system where it plays an important role in
metabolism of cholesterol in the brain. The product of CYP46A1 action if 24S-hydroxycholesterol
which can readily traverse the blood-brain-barrier to enter the systemic
circulation. This pathway of cholesterol metabolism in the brain is a part of
the reverse cholesterol transport process and serves as a major route of
cholesterol turnover in the brain. 24S-hydroxycholesterol is a known
potent activator of LXR and as such serves as an activator of
the expression of LXR target genes and thus, can effect regulation of overall
cholesterol metabolism not only in the brain but many other tissues as well.
CYP51A1: CYP51A1
is also referred to as lanosterol-14α-demethylase. This P450 enzyme is the
only one of the eight that is involved in de novo cholesterol
biosynthesis and it catalyzes the removal of the 14α-methyl group from
lanosterol resulting in the generation of at least two oxysterols that, in
mammalian tissues, are efficiently converted into cholesterol as well as more
polar sterols and steryl esters. The oxysterols derived through the action of
CYP51A1 inhibit HMGR and are also known to inhibit sterol synthesis. Knock-out
of the mouse CYP51A1 homolog results in a phenotype similar to that seen in the
human disorder known as Antley-Bixler syndrome (ABS). ABS represents a group of
heterogeneous disorders characterized by skeletal, cardiac, and urogenital
abnormalities that have frequently been associated with mutations in the
fibroblast growth factor receptor 2 (FGFR2) gene.
Nutrition and health
Lipids
play diverse and important roles in nutrition and health. Many lipids are absolutely essential for life, however, there is also considerable awareness that abnormal levels of
certain lipids, particularly cholesterol (in hypercholesterolemia) and, more recently, trans fatty acids, are risk factors for heart disease and other diseases. We need fats in our
bodies and in our diet. Animals in general use fat for energy storage because
fat stores 9 KCal/g of energy.
Plants, which don’t move
around, can afford to store food for energy in a less compact but more easily
accessible form, so they use starch (a carbohydrate, NOT A LIPID) for energy
storage. Carbohydrates and proteins store only 4 KCal/g of energy, so fat
stores over twice as much energy/gram as other sources of energy.
We need fats in our bodies and in our diet. Animals in general use fat for energy storage
because fat stores 9 KCal/g of energy. Plants, which don’t move around, can
afford to store food for energy in a less compact but more easily accessible
form, so they use starch (a carbohydrate, NOT A LIPID) for energy storage. Carbohydrates
and proteins store only 4 KCal/g of energy, so fat stores over twice as much
energy/gram as fat. By the way, this is also related to the idea behind some of
the high-carbohydrate weight loss diets.
http://www.youtube.com/watch?v=-WhADd1GKtA&feature=relmfu
The human body burns carbohydrates and fats for
fuel in a given proportion to each other. The theory behind these diets is that
if they supply carbohydrates but not fats, then it is hoped that the fat needed
to balance with the sugar will be taken from
the dieter’s body stores. Fat is also is used in our bodies to a) cushion vital
organs like the kidneys and b) serve as insulation, especially just beneath the
skin.
http://www.youtube.com/watch?v=_TR8vUFP_O4&feature=related
Cholesterol levels
Able to control
What you eat.Certain foods have types of fat that raise
your cholesterol level.
·
Saturated fat raises your low-density lipoprotein (LDL) cholesterol level
more than anything else in your diet
·
Trans fatty
acids (transfats) are made when vegetable oil is hydrogenated to harden
it. Transfatty acids raise cholesterol levels
·
Cholesterol is found in foods that come from animal sources, for example,
egg yolks, meat, and cheese
Weight. Being overweight tends to increase your LDL
level, lower your high-density lipoprotein (HDL) level, and increase your total
cholesterol level.
Activity level.Lack of regular exercise can lead to weight
gain, which could raise your LDL cholesterol level. Regular exercise can help
you lose weight and lower your LDL level. It can also help you raise your HDL
level.
Unable to control.
Heredity.High blood cholesterol can run in families.
An inherited genetic condition (familial hypercholesterolemia) results in very
high LDL cholesterol levels. It begins at birth, and may result in a heart
attack at an early age.
Age. Starting at puberty, men have lower levels of HDL than women. As women
and men get older, their LDL cholesterol levels rise. Younger women have lower
LDL cholesterol levels than men, but after age 55, women have higher levels
than men.
A thorough examination of the state of the
live blood allows the doctor to consider various nutritional factors that often
prove to be the underlying causes of chronic ill-health. Furthermore, the
patient's physical response to a recommended course of treatment can be
monitored visually. Improvements in the condition of the blood can be seen,
sometimes within a few days and usually within weeks. This gives patients
tremendous encouragement to continue with their regimen of supplementation and
diet.
Treatment of Hypercholesterolemia
The importance of obesity, a sedentary lifestyle, very
high fat diet, and intake of large concentrations of refined carbohydrates
should not be underestimated as causes of severe hypertriglyceridemia.
Instituting a program of progressive aerobic and toning exercise, weight loss,
and dietary management can significantly lower triglyceride levels and, in some
cases, normalize them.
During pregnancy, severe hypertriglyceridemia is an
unusual complication and may cause pancreatitis.
·
Many
case reports have been published describing interventions to manage this
condition.
·
Most
commonly, a very low-fat diet was sufficient to control triglycerides and
prevent pancreatitis.
·
Intermittent
and, in persistent cases, continuous total parenteral nutrition has been
used—usually in the third trimester.
To treat hyperlipidemia, a
diet low in total fat, saturated fat, and cholesterol is recommended, along
with reducing or avoiding alcohol intake. The American Heart Association (AHA)
endorses the following dietary recommendations for people with high blood
cholesterol:
·
Total fat: 25% of total calories
·
Saturated fat: less than 7% total calories
·
Polyunsaturated fat: up to 10% total calories
·
Monounsaturated fat: up to 20% total calories
·
Carbohydrates: 50-60% total calories
·
Protein: ~15% total calories
·
Cholesterol: less than 200 mg/dL
·
Plant sterols:
·
Soluble fiber such as psyllium: 10- 25g
Categories of appropriate foods include:
·
Lean meat/fish: less than 5 oz/day
·
Eggs: less than 2 yolks per week (whites unlimited)
·
Low fat dairy products (<1% fat): 2-3 servings/day
·
Grains, especially whole grains: 6-8 tsp/day
·
Vegetables: less than 6 servings per day
·
Fruits: 2-5 servings per day
These recommendations translate into the following practical dietary
guidelines:
·
Select only the leanest meats, poultry, fish and shellfish. Choose chicken
and turkey without skin or remove skin before eating. Some fish, like cod, have
less saturated fat than either chicken or meat.
·
Limit goose and duck. They are high in saturated fat, even with the skin
removed.
·
Some chicken and turkey hot dogs are lower in saturated fat and total fat
than pork and beef hot dogs. There are also lean beef hot dogs and vegetarian
(tofu) franks that are low in fat and saturated fat.
·
Dry peas, beans and tofu can be used as meat substitutes that are low in
saturated fat and cholesterol. Dry peas and beans also have a lot of fiber,
which can help to lower blood cholesterol.
·
Egg yolks are high in dietary cholesterol. A yolk contains about 213 mg.
They should be limited to no more than 2 per week, including the egg yolks in baked
goods and processed foods. Egg whites have no cholesterol, and can be
substituted for whole eggs in recipes.
·
Like high fat meats, regular dairy foods that contain fat, such as whole
milk, cheese, and ice cream, are also high in saturated fat and cholesterol.
However, dairy products are an important source of nutrients and the diet
should include 2 to 3 servings per day of low-fat or nonfat dairy products.
·
When shopping for hard cheeses, select them fat-free, reduced fat, or part
skim.
·
Select frozen desserts that are lower in saturated fat, such as ice milk,
low-fat frozen yogurt, low-fat frozen dairy desserts, sorbets, and popsicles.
·
Saturated fats should be replaced with unsaturated fats. Select liquid
vegetable oils that are high in unsaturated fats, such as canola, corn, olive,
peanut, saf-flower, sesame, soybean, and sunflower oils.
·
Limit butter, lard, and solid shortenings. They are high in saturated fat
and cholesterol.
·
Select light or nonfat mayonnaise and salad dressings.
·
Fruits and vegetables are very low in saturated fat and total fat, and have
no cholesterol. Fruits and vegetables should be eaten as snacks, desserts,
salads, side dishes, and main dishes.
·
Breads, cereals, rice, pasta, grains, dry beans, and peas are high in
starch and fiber and low in saturated fat and calories. They also have no
dietary cholesterol, except for some bakery breads and sweet bread products
made with high fat, high cholesterol milk, butter and eggs.
·
Select whole grain breads and rolls whenever possible. They have more fiber
than white breads.
·
Most dry cereals are low in fat. Limit high-fat granola, muesli, and cereal
products made with coconut oil and nuts, which increases the saturated fat
content.
·
Limit sweet baked goods that are made with saturated fat from butter, eggs,
and whole milk such as croissants, pastries, muffins, biscuits, butter rolls,
and doughnuts.
·
Snacks such as cheese crackers, and some chips are often high in saturated
fat and cholesterol. Select rather low-fat ones such as bagels, bread sticks, cereals
without added sugar, frozen grapes or banana slices, dried fruit, non-oil baked
tortilla chips, popcorn or pretzels.
Reductions in circulating cholesterol levels can have
profound positive impacts on cardiovascular disease, particularly on atherosclerosis,
as well as other metabolic disruptions of the vasculature. Control of dietary
intake is one of the easiest and least cost intensive means to achieve
reductions in cholesterol. Recent studies in laboratory rats has demonstrated
an additional benefit of reductions in dietary cholesterol intake. In these
animals it was observed that reductions in dietary cholesterol not only
resulted in decreased serum VLDLs and LDLs, and increased HDLs but DNA
synthesis was also shown to be increased in the thymus and spleen. Upon
histological examination of the spleen, thymus and lymph nodes it was found
that there was an increased number of immature cells and enhanced mitotic
activity indicative of enhanced proliferation. These results suggest that a
marked reduction in serum LDLs, induced by reduced cholesterol intake,
stimulates enhanced DNA synthesis and cell proliferation.
Drug treatment to lower plasma
lipoproteins and/or cholesterol is primarily aimed at reducing the
risk of athersclerosis and subsequent coronary artery disease that exists in
patients with elevated circulating lipids. Drug therapy usually is considered
as an option only if non-pharmacologic interventions (altered diet and
exercise) have failed to lower plasma lipids.
Nicotinic acid: Nicotinic acid
reduces the plasma levels of both VLDLs and LDLs by inhibiting hepatic VLDL
secretion, as well as suppressing the flux of FFA release from adipose tissue by
inhibiting lipolysis. In addition, nicotinic administration strongly increases
the circulating levels of HDLs. Patient compliance with nicotinic acid
administration is sometimes compromised because of the unpleasant side-effect
of flushing (strong cutaneous vasodilation). Recent evidence has shown that
nicotinic acid binds to and activates the G-protein coupled receptor identified
as GPR109A (also called HM74A or PUMA-G). The identity of a receptor to which
nicotinic acid binds allows for the development of new drug therapies that
activate the same receptor but that may lack the negative side-effect of
flushing associated with nicotinic acid. Because of its ability to cause large
reductions in circulating levels of cholesterol, nicotinic acid is used to treat
Type II, III, IV and V hyperlipoproteinemias.
Representatives of ketone bodies, place and mechanism of ketogenesis.
KETONE BODIES
Fatty acids can be used as the major fuel for tissues such
as muscle, but they cannot cross the blood-brain barrier, and thus cannot be
used by the central nervous system (CNS). This becomes a major problem during
starvation (fasting), particularly for organisms such as ourselves in which CNS
metabolism constitute a major portion of the resting basal metabolic rate.
These organism must provide glucose to the CNS to provide for metabolic needs,
and thus during the initial fasting period must break down substantial amounts
of muscle tissue (protein) to provide the amino acid precursors of
gluconeogenesis. Obviously the organism could not survive long under such a
regime. What is needed is an alternate fuel source based on fat rather than
muscle. The
so-called ketone bodies serve this function:
Note that only two of the ketone bodies are in fact ketones, and that
acetone is an "unintentional" breakdown product resulting from the
instability of acetoacetate at body temperature. Acetone is not
available as fuel to any significant extent, and is thus a waste product.
CNS tissues can use ketone bodies any time, the
problem is the normally very low concentrations (<
The limiting factor in using ketone
bodies then becomes the ability of the liver to synthesis them, which requires
the induction of the enzymes required for acetoacetate biosynthesis. Normal
glucose concentrations inhibit ketone body synthesis, thus the ketone bodies
will only begin to be synthesized in high concentrations as serum glucose
concentrations fall. As an example, ketone bodies might start at about
Ketogenesis
Ketogenesis occurs in the mitochondrial matrix in
liver mitochondria. Fatty acids are first broken down to acetyl CoA via beta-oxidation
(providing energy for liver metabolism from the reducing equivalents
generated). The
acetyl CoA is then used in ketogenesis:
Mechanisms of the using
of ketone bodies in tissues with the purpose of energy obtsining (ketolysis).
Ketone Bodies as Fuel
The ketone bodies are water soluble and
are transported across the inner mitochondrial membrane as well as across the
blood-brain barrier and cell membranes. Thus they can be used as a fuel source
by a variety of tissues including the CNS. They are preferred substrates for
aerobic muscle and heart, thus sparing glucose when they are available.
In
the peripheral tissues the ketones must be reconverted to acetyl CoA in the
mitochondria:
- If we start with b-hydroxybutyrate,
then it is first oxidized to acetoacetate with the production of one NADH (1).
- Coenzyme A must now be added to the acetoacetate.
The thioester bond is a high energy bond, so ATP equivalents must be used.
In this case the energy comes from a transesterification of the CoAS from
succinyl CoA to acetoacetate by Coenzyme A transferase (2). The
succinyl CoA comes from the TCA cycle where a GTP is not made.
- The
acetoacetyl CoA is now cleaved to two acetyl CoA's with Thiolase (3).
The mechanism of
the increase of ketone bodies content in blood at diabetus mellitus and
starvation
When
the body is deprived of food whether by voluntary or involuntary fasting,
starvation is the net result. During starvation, glycogen reserves are rapidly depleted
and the body begins to metabolize reserves of fat and protein.
The
entry of acetyl CoA into the citric acid cycle depends on the availability of
oxaloacetic acid for the formation of citric acid. In starvation or
uncontrolled diabetes situations, oxaloacetic acid is used to synthesize
glucose and is then not available for use with acetyl CoA. Under these
conditions, acetyl CoA is diverted from the citric acid cycle to the formation
of acetoacetic and 3-hydroxybutanoic acids.
The odor of acetone may be detected on the breath of a person with
excess ketone bodies in the blood. The overall accumulation of ketone bodies in
blood and urine is known as ketosis. The acids also upset buffers in the
blood to cause acidosis.
Both
acetoacetic acid and 3-hydroxybutanoic acid can be used by the heart, kidneys,
and brain for metabolism to produce energy. The heart and kidneys actually
prefer these to glucose. In contrast, the brain prefers glucose, but will adapt
if necessary in starvation or diabetic conditions.
Ketonuria is a medical condition in which ketone bodies are present in the urine.
It is seen in conditions wherein the body produces excess ketones as an
alternative source of energy. It is seen during starvation or more commonly in
type I diabetes mellitus. Production of ketone bodies is a normal response to
a shortage of glucose, meant to provide an alternate source of fuel from fatty acids.
After 24 hrs fasting, ketone body levels increase in blood (called ketonemia or ketosis but all of it used up by the muscles no ketone bodies are left to be
excreted in urine.
Screening
Screening for ketonuria is done frequently for acutely ill patients,
presurgical patients, and pregnant women. Any diabetic patient who has elevated
levels of blood and urine glucose should be tested for urinary ketones. In
addition, when diabetic treatment is being switched from insulin to oral
hypoglycemic agents, the patient's urine should be monitored for ketonuria. The
development of ketonuria within 24 hours after insulin withdrawal usually
indicates a poor response to the oral hypoglycemic agents. Diabetic patients
who use oral hypoglycemic agents should have their urine tested regularly for
glucose and ketones because oral hypoglycemic agents, unlike insulin, do not
control diabetes when an acute infection or other illness develops.
In conditions associated with acidosis, urinary ketones are tested to assess
the severity of acidosis and to monitor treatment response. Urine ketones
appear before there is any significant increase in blood ketones; therefore,
urine ketone measurement is especially helpful in emergency situations. During
pregnancy, early detection of ketonuria is essential because ketoacidosis is a
factor associated with intrauterine death.
Causes of ketosis and ketonuria
- Metabolic abnormalities such as diabetes,
renal glycosuria, or glycogen storage disease
- Dietary conditions such as starvation,
fasting, high protein, or low carbohydrate diets, prolonged vomiting, and
anorexia
- Conditions in which metabolism is
increased, such as hyperthyroidism, fever, pregnancy or lactation
In nondiabetic persons, ketonuria may
occur during acute illness or severe stress. Approximately 15% of hospitalized
patients may have ketonuria, even though they do not have diabetes. In a
diabetic patient, ketone bodies in the urine suggest that the patient is not
adequately controlled and that adjustments of medication, diet, or both should
be made promptly. In the nondiabetic patient, ketonuria reflects a reduced
carbohydrate metabolism and excessive fat metabolism.
II.
Regulation and disorders of lipids metabolism.
Regulation
of lipid metabolism. Role of hormones and vitamins in lipolysis and
lipogenesis.
Lipolysis is the
breakdown of fat stored in fat cells. During this process, free fatty
acids are released into the bloodstream and circulate throughout the
body. Ketones
are produced, and are found in large quantities in ketosis
(a state in metabolism occurring when the liver converts fat into fatty acids
and ketone bodies which can be used by the body for energy.). Lipolysis testing strips
such as Ketostix
are used to recognize ketosis.
The following hormones induce lipolysis: epinephrine,
norepinephrine,
glucagon
and adrenocorticotropic hormone. These trigger
7TM receptors,
which activate adenylate cyclase. This results in increased
production of cAMP, which activates protein kinase A, which subsequently
activate lipases
found in adipose tissue.
Triglycerides undergo lipolysis (hydrolysis
by lipases)
and are broken down into glycerol and fatty acids. Once released into the blood, the
relatively hydrophobic free fatty acids bind to serum albumin
for transport to tissues that require energy. The glycerol also enters the
bloodstream and is absorbed by the liver or kidney where it is converted to glycerol 3-phosphate by the enzyme glycerol
kinase. Hepatic glycerol 3-phosphate is mostly converted into dihydroxyacetonephosphate (DHAP) and then glyceraldehyde 3-phosphate (G3P) to rejoin
the glycolysis
and gluconeogenesis pathway.
Pathologies
of lipids metabolism:
Obesity
Obesity is a condition in which the natural energy
reserve, stored in the fatty tissue of humans and other mammals, is increased to a point where it is a risk factor
for certain health conditions or increased mortality. Obesity develops from the
interaction of individual biology and the environment. Excessive body weight
has been shown to predispose to various diseases, particularly cardiovascular
diseases, diabetes mellitus type 2, sleep apnea, and osteoarthritis. Obesity is
both an individual clinical condition and is increasingly viewed as a serious
public health problem.
People that are
overweight can cause a lot of strain on the heart. The extra weight forces the
heart to work harder, making it less effective at pumping out blood to through
the arteries. In addition, too much weight can lead to an increase in blood
pressure and blood cholesterol, and create a higher risk of diabetes. A
carefully regulated diet with a limited amount of fat and alcohol intake along
with a regular exercise regimen can help with weight loss.
Fatty
degeneration of liver
It
is a recognized fact that all-seed diets, which are not only high in fat, but
deficient in many essential nutrients, predispose psittacine birds to fatty
liver degeneration. It would seem that the prevalence of this condition in all
companion birds, including cockatiels, would be decreasing since the advent of
pelleted diets, but this does not appear to be happening. Is this because we
cockatiel breeders do not recognize this condition when it appears and kills
our birds? Is it because we don’t know enough about what causes the disease? Is
it because we don’t generally recognize the benefits of pellets? Is it because,
in our pursuit of "substance" in show birds, we don’t differentiate
between a bird with a large frame and one that is fat?
The main symptom
that brought the problem to my attention was a substantial decline in weight,
although I did not notice a change in eating habits. As all my birds are kept
in large flights when not breeding, I did not notice this until I removed the
birds from the flight in order to set them up for breeding. (Foods present in
the flight cages are: pellets at all times, seed three times a week, and cooked
grain and vegetable "soft food" 3 times a week.) At that time, their
weight loss led me to take them to the doctor, where blood tests revealed liver
problems. Although I did medicate both birds, and tried very hard to get them
to eat a healthier diet in order to possibly reverse the course of this
disease, they both died within two months of diagnosis. Necropsy did confirm
the cause of death as fatty degeneration and failure of the liver.
Atherosclerosis
Hypercholesterolemia
According to the lipid
hypothesis, abnormally high cholesterol levels (hypercholesterolemia), or, more correctly,
higher concentrations of LDL and lower concentrations of functional HDL are
strongly associated with cardiovascular disease because these
promote atheroma
development in arteries (atherosclerosis). This disease process leads to
myocardial infarction (heart attack), stroke and peripheral vascular disease. Since higher
blood LDL, especially higher LDL particle concentrations and smaller LDL
particle size, contribute to this process more than the cholesterol content of the
LDL particles, LDL particles are often termed "bad cholesterol"
because they have been linked to atheroma formation. On the other hand, high
concentrations of functional HDL, which can remove cholesterol from cells and
atheroma, offer protection and are sometimes referred to colloquially as
"good cholesterol". These balances are mostly genetically determined
but can be changed by body build, medications,
food choices and other factors.
Conditions with elevated
concentrations of oxidized LDL particles, especially "small dense
LDL" (sdLDL) particles, are associated with atheroma
formation in the walls of arteries, a condition known as atherosclerosis,
which is the principal cause of coronary heart disease and other forms of cardiovascular disease.
In contrast, HDL particles (especially large HDL) have
been identified as a mechanism by which cholesterol and inflammatory mediators
can be removed from atheroma. Increased concentrations of HDL correlate with
lower rates of atheroma progressions and even regression. 
Elevated levels of the lipoprotein fractions, LDL, IDL
and VLDL are regarded as atherogenic (prone to cause atherosclerosis).
Levels of these fractions, rather than the total cholesterol level, correlate
with the extent and progress of atherosclerosis. Conversely, the total
cholesterol can be within normal limits, yet be made up primarily of small LDL
and small HDL particles, under which conditions atheroma growth rates would
still be high. In contrast, however, if LDL particle number is low (mostly
large particles) and a large percentage of the HDL particles are large, then
atheroma growth rates are usually low, even negative, for any given total
cholesterol concentration. Recently, a post-hoc analysis of the IDEAL and the
EPIC prospective studies found an association between high levels of HDL
cholesterol (adjusted for apolipoprotein A-I and apolipoprotein B) and
increased risk of cardiovascular disease, casting doubt on the cardioprotective
role of "good cholesterol".
Hypocholesterolemia
Abnormally low levels of
cholesterol are termed hypocholesterolemia. Research into the causes
of this state is relatively limited, but some studies suggest a link with depression,
cancer
and cerebral hemorrhage. Generally, the low
cholesterol levels seem to be a consequence of an underlying illness, rather
than a cause.
Cholesteric
liquid crystals
Some cholesterol derivatives,
(among other simple cholesteric lipids) are known to generate the liquid
crystalline cholesteric phase. The cholesteric phase is in
fact a chiral nematic phase,
and changes colour when its temperature changes. Therefore, cholesterol
derivatives are commonly used in liquid crystal thermometers
and temperature-sensitive paints.
Diabetes
When carbohydrates enter the body, they are broken
down into glucose (sugar), which is absorbed into the blood. Upon absorption,
the pancreas secretes the hormone insulin, which allows the glucose to be
absorbed into the body’s tissues and cells. Diabetes results when the body is
unable to produce sufficient amounts of insulin or does not respond to the
insulin produced.
As a result, there is a
glucose buildup in the body. This buildup can cause an increase in high blood
pressure, high levels of LDL cholesterol, and obesity, which all contribute to
cardiovascular disease. A controlled diet, regular exercise, and blood glucose
testing, as well as oral medication and insulin injections can help patients
with diabetes.
LIPID
PEROXIDATION
Free
radicals are molecular species which contain an unpaired electron (usually represented
as R·). Consequently, they are some of the most chemically reactive molecules
known. Because of the need to pair its single electron, a free radical must
abstract a second electron from a neighbouring molecule. This causes the
formation of yet another free radical and self-propagating chain reaction
ensues.
Free radicals in human body can arise from fatty food,
smoking, alcohol, environmental pollutants, hydrogen peroxide, pollutants,
ozone, toxins, carcinogen toxins, ionisation etc. The vast majority of free
radicals come from within the body, an unavoidable by-product of living system.
Free radical intermediates are produced in living systems under normal
conditions, the body handles free radicals formed by the breakdown of compounds
through the process of metabolism. The major sources of free radicals (such as
O2- and HO2·) are modest leakages from the
electron transport chains of mitochondria, chloroplasts and endoplasmic
reticulum.
The resulting free radicals, such as superoxide anion (O2-)
and hydroxyl radical (OH·), as well as the non-radical hydrogen peroxide, can
damage macromolecules, including DNA, proteins and lipids. Likewise, other
products of oxygen metabolism, such as hypochlorous acid, chloramines, and
oxidised lipids have all been related in such damages. The superoxide radical,
although it is unreactive in comparison with many other radicals, biological
systems can convert it into other more reactive species, such as peroxyl
(ROO·), alkoxyl (RO·) and hydroxyl (HO·) radicals.
There are four types of free radicals damages:
1.
Damage to fat compounds: The fatty membranes surrounding the cells being
the prime target to free radicals attacks. The damaged membranes then loose its
ability to transport oxygen, nutrients or water to the cells.
2.
Damage to protein molecules: Free radicals also attack the nucleic acid
which comprise the genetic code within each cell. The nucleic acids function is
to regulate the normal cell function, growth and also to repair the damaged
tissues.
3.
Cell damage: Damages done to the chromosoins and nucleic acids might
initiate the growth of abnormal cells, which is the first step in cancer
development.
4.
Lysosomes damages: Lysosomes are little sacs in the cell that contain
degenerative enzymes. The enzymes leak out when the membrane cell breaks and
they start digesting the cell itself, spreading to nearby cell causing a chain
reaction of destruction which, eventually, will lower the immune system
resistance.
And such production of reactive oxygen species and other free radicals
and theirs damages to various molecules and cells may result not only in the
toxicity of xenobiotics but also in the pathophysiology of ageing, and various
age-related diseases, including cataracts, arteriosclerosis, neoplastic
diseases, diabetes, chronic inflammatory diseases, cancer and etc.
Fortunately, the body also has several natural
chemical means or systems for neutralizing free radicals. There is agents that
counteract and minimize free radical damage and their function is to donate or
provide unpaired electrons to which free radicals can attach without causing
harm. Such "cell-savers" are called "Antioxidants."
Antioxidants get their name because they combat oxidation. Oxidation is a
reaction in which a molecule looses an electron. The two major sources of antioxidants are:
1.
Those that you get from food or food supplements
2.
Those produced within your own body.
And there are some types of antioxidants, like the
Flavonoids, found in the skin and seeds of fruits, possess the ability to
physically capture free radicals until these are actually removed from the
body. Others, like Sulphorophane, found in broccoli, tend to enhance the body’s
own free radical scavenging mechanism. And finally, the ones like L. Limonene,
phytochemical found in citrus fruit peels, can actually perform both actions.
Some popular antioxidants today include Vitamin E, Vitamin C, Vitamin A, which
can be taken under a health supplement form or through fruits, vegetables, fish
oil, green tea, sesame oil, and Genistein from soy bean shown to be cancer
preventive. Some antioxidants come from minerals, such as selenium, copper,
zinc (they are considered antioxidants because they work together in
conjunction with an antioxidant enzyme and are necessary for the enzyme to
function properly).. etc. The list of dietary antioxidants goes on and on, and
scientist are continually discovering more.
Mechanism of action of antioxidants, vitamin E
Free radicals, such as superoxide,
hydroxyl ions and nitric oxide all contain an unpaired electron. These radicals
can have a negative effect on cells causing oxidative damage that leads to cell
death.
Antioxidants,
such as vitamin E, prevent cell damage by binding to the free radical and
neutralising its unpaired electron. For example, vitamin E binds to OO· or
O2· they form an intermediate structure that is converted to a-tocopherylquinone.
A recent population based study of antioxidants concluded that a diet rich in
foods containing vitamin E might help protect some people against Alzheimer’s
disease (AD). Vitamin E in the form of supplements was not associated with a reduction
in the risk of AD.
