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summary of block 2 of medical biochemistry
- Instelling
- Vrije Universiteit Amsterdam (VU)
A summary of the second block of medical biochemistry
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Notes lectures block 2 medical biochemistryFat, cholesterol, and atherosclerosis
There is an increased mortality rate caused by obesity. Cardiovascular disease is still the number one
killer disease. People can get cloths in the artery which blocks the normal blood flow, and this will
lead to muscle damage in the heart. One can perform the dotter procedure where they insert a
balloon into the blood vessel and blow this balloon up. And the stent keeps the blood vessel open.
The stent can be compared to a spring that supports the blood vessel. Lipids and cholesterol are
transferred trough the blood by lipoproteins. Lipoproteins are classified based on size and their
density. Forward cholesterol transport is the delivery of the triglycerides to the tissue. This is done
by the bigger lipoproteins with a low density such as the LDL, VLDL and the Chylomicrons. There is a
strong correlation between the amount of serum cholesterol and the chance of getting
cardiovascular disease. Atherosclerosis is a normal process that occurs in everybody. But only in
people with obesity, high blood pressure, high cholesterol these plaques can become a problem.
These plaques develop in the intima layer. These plaques contain a lot of macrophages. LDL can
move between the endothelial cells and the intima. However, when there is a lot of cholesterol in
the blood and the LDL levels are high, there is a lot of LDL passing through. The LDL particles are
oxidized, and these particles are foreign to the body, so the macrophages take them up by the LOX-1
receptor and the CD36 receptor. The macrophages will develop into foam cells. These macrophages
will become activated and start to secrete proinflammatory cytokines and more reactive oxygen
species. This process aggravates oxidation of LDL. This proinflammatory environment promotes the
formation of plaques. These cells recruit mast cells and T-cells and all these cells together excrete
proteases (MMPs). These can cleave the connective tissue that has formed around these loaded
macrophages. The cap will then become instable and rupture. When this happens, you get leakage
of the blood vessel and blood clotting. The artery will clog up and this can lead to a heart attack or a
stroke. When the plaque is ruptured a small thrombus is formed and this can heal, or this can clog
the artery. HDL can pick up cholesterol from cellular membranes and transport it back to the liver.
The liver can turn it into other substances, e.g. bile salts. HDL are more or less protective. ApoAl
makes up the HDL particle. People with a mutation in ApoAL have less HDL and have a higher chance
of heart attacks. This is even true when LDL is low. The ratio between LDL/HDL should be low.
Physical activity and small alcohol consumption will increase HDL concentrations. Testosterone,
smoking, obesity, and steroid and epileptic drugs can lower the HDL. Women can have a heart attack
with having low cholesterol values. In these women the C-reactive protein is a better risk factor to
look at. The CRP is made by the liver and made when there is inflammation. The adipose tissue is
also an endocrine organ. It can release cytokines when you have high amount of fat tissue. These
cytokines induce the CPR in the liver. The metabolic syndrome is a combination of risk factors to
predict your chances of getting cardiovascular disease. Insulin resistance will increase the production
of cytokines. Non-alcoholic fatty liver disease is when the livers will get lipid loaded. The lipids will
not be transported to the adipose tissue.
Cholesterol is an essential precursor for all kinds of steroid hormones. Low cholesterol levels are
associated with aggressiveness and criminal behaviour. You can take cholesterol up from the food
and you can transport them as free or as cholesterol esters using the lipoproteins. The pancreas
produces enzymes that extract cholesterol form the diet. Chylomicrons can deliver the cholesterol to
the tissue. 80% of the plasma cholesterol is made by the liver. Acetyl CoA is the precursor for
cholesterol. From cholesterol the body can make membranes, bile salts and steroid hormones.
Acetyl CoA is first converted into Acetoacetyl CoA. Then HMG synthase will generate GHM-COA and
then HMG reductase will generate mevalonate. This is a committed step, so when you make
, mevalonate it will always end in cholesterol. The body tries to recycle the cholesterol as this takes
less energy. When cholesterol is synthesized, the VLDL transport it to the tissues where it can be
released and used. Chylomicrons and LDL have the same protein gene. The full-length protein is in
LDL and a shorter version due to RNA-editing is used in the Chylomicrons. Chylomicrons will take the
cholesterol from the tissue and bring it to the tissue. Hypercholesterolemia patients cannot take up
the lipoprotein particles. LDL particles are taken up with receptors via clathrin coated pits. The
patients have a deficiency in the receptors. ApoB-100 is the receptor and the whole lipoprotein LDL
is taken up. Then the LDL is divided using a lysosome and the cholesterol is deposited on the ER
membrane. The cholesterol can bind to the SREBP protein and keeps it in the ER. When there is no
cholesterol this whole complex then shifts to the Golgi. Then in the Golgi this complex is further
cleaved, and the regulatory element is going to the nucleus and this will activate target genes that
are involved in the synthesis of cholesterol. So, cholesterol itself regulates its synthesis. When insulin
is high, the HMG-CoA is activated as there is enough energy to make cholesterol. When glucagon
levels are high, the opposite happens. Becel proactive will prevent reabsorption of the bile salts.
However, this does not work. There is only one solution; inhibit the synthesis. This is done using
statins. The statin is a competitive inhibitor binding to the active site of HMG-CoA reductase.
Omega-3 and -6 are essential and can only be taken up with food. We need these as these are a
precursor of arachidonic acid. This acid is a precursor for eicosanoids. These are short lived local
signalling molecules for inflammation, pain, and thrombosis. Most of the prostaglandins have a 5
ring (that has been opened). They can have numerous functions. Eicosanoids (lipid mediators) act
trough specific receptors on the cells. Aspirins inhibit the pathway to produce the production of
prostaglandins and thromboxane’s. Aspirin binds to the active site, so there cannot be any
competition. It will bind to the cyclo-oxygenase and thereby inactivating the enzyme. Paracetamol
and Advil and all pain killers have the same ring. Taking too much aspirin may cause stomach ulcers
and intestinal bleedings. The enzyme has 2 compounds; COX 1 and 2. COX 2 is focused on the pain
and COX-1 is focused on the production of mucus. When you block COX-1, the production of mucus
will decrease, and this will make the stomach vulnerable and even cause injuries. So, we only want
to inhibit COX-2. COX-2 is induced by cytokines. A COX-2 specific inhibitor is called VIOXX. However,
this drug developed heart problems. There was a problem with platelet aggregation. COX-2 will
make PGI and this inhibits platelets aggregation. When you only block COX-2, you block the
inhibition of platelet aggregation. COX-1 will increase platelet aggregation. Thus, creating
thromboses.
Histology of blood vessels
Histology is the microscopic anatomy. The cardiovascular system is responsible of the transport of
blood and plasma. You have 2 systems: the pulmonary circuit (from the heart to the lungs and back)
and the systemic circuit. We have arteries (from the heart), veins (to the heart) and capillaries. All
the blood vessels have the same structure; tunica intima (inner layer), tunica media (middle layer)
and the tunica externa (outer layer). The tunica intima is mainly endothelium that seals of the blood
vessels. After the endothelium layer, there is a layer of loose connective tissue. The tunica media is
mainly smooth muscle cells. It may even contain blood vessels to supply the muscle cells. This is
called vasa vasorum which means vessels in vessels. The tunica externa is mainly connective tissue
with collagen. Again, here are vessels in vessels. We have 3 types of arteries: elastic, muscular and
arterioles. Arteries can change their diameter by elasticity and contraction. Contraction is the
innervation of smooth muscle cells via autonomic nervous system. You have vasoconstriction and
vasodilation (relaxation smooth muscle cells which will enlarge the lumen). The elastic arteries are
the largest arteries. They must withstand very large changes in blood pressure, so they have a large
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