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Medical Biochemistry exam 2 summary VU Amsterdam
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This summary covers all the chapters for the second exam of Medical Biochemistry at VU Amsterdam.
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MEDICAL-BIOCHEMISTRY-II
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Samenvatting Medische Biochemie deel 1
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Samenvatting Medische Biochemie deel 2
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Fat, chcolesterol and atherosclerosisThere is an increased mortality rate caused by obesity. Obesity is linked to cardiovascular diseases (myocardial infacrtion
+stroke), but also cancer (liver, kidney, uterus) and respiratory diseases. The number 1 killer are the cardiovascular diseases
(myocardial infarction and stroke). There is then a block in the artery thereby a part of the heart dies/muscle damage
occurs which can lead to death. What we can do is the dotter procedure: percutaneous coronary intervention. They put a
stick in the clogged artery and this stick extends and becomes a balloon, thereby extending the blood vessel and making the
passage open again.
The Framingham heart study shows that there is a relation between cardiovascular diseases and cholesterol. Lipids and
cholesterol are transported through the blood via lipoproteins. These lipoproteins suchs as LDL or VLDL carry cholesterol
and triglycerides and bring them to different organs when needed in times of energy lack. The lipoproteins are classified
based on their size and density. Especially the LDL lipoprotein contains a lot of cholesterol.
- Forward cholesterol transport = triglyceride delivery to tissues. The lipoproteins that are known to do this are the
chylomicrons, LDL and VLDL.
The atherosclerotic plaque is rich in cholesterol and macrophages, and often develop in the subintimal space. From the
inside to the outside of an artery:
1. Endothelial cells
2. Subintimal space (also called subintimal extracellular
matrix/subendothelial space)
3. Internal elastic lamina
4. Tunica media (also called vascular smooth muscle)
5. External elastic lamina
6. Adventitia
LDL lipoprotein (containing cholesterol and triglycerides) can move freely
between the endothelial cells in the arteries and veins. Then, it ends up in
the subintimal space. The subintimal space has an oxidative environment
because the endothelial cells in these arteries produce oxidative particles
that play a role in oxidation. These LDL lipoproteins become oxidised once it
enters the subintimal space. However, the macrophages that are present in
this subintimal space think that they need to get rid of these OxLDL’s so
they take these OxLDL’s up and develop into foam cells.
These macrophages take up these OxLDL’s via scavenger receptors called
Lox-1 and CD36 which mediate the uptake of OxLDL’s. When the
macrophages take up these OxLDL’s and develop into foam cells, they
become activated and secrete pro-inflammatory cytokines. We get a pro-
inflammatory environment. This pro-inflammatory environment promotes
the formation of these plaques in the arteries. These inflammatory cells
destabilize the fibrous cap (connective tissue) by MMP’s (matrix
metalloproteinases). In other words, the inflammatory environment
promotes the build-up of extracellular matrix, thereby creating plaques.
Also, these inflammatory cells (macrophages, T cells, B cells) can secrete
proteinases which can cleave the fibrous cap (layer of fibrous connective
tissue) so it then ruptures. When these fibrous caps rupture, you get
leakage in your blood vessel and you get blood clotting → atherosclerosis
leads to myocardial infarction and stroke.
Whereas LDL brings cholesterol to the tissues, HDL picks up the cholesterol
from the tissues (so HDL is the good guy in this case) and brings it back to
the liver. High HDL levels is protective. The ApoAL1.178P makes up this HDL
particle. When there is a mutation in this protein, these people produce
less HDL particles and experience heart attacks much earlier in life.
- Picking up cholesterol from tissues = reverse cholesterol
transport.
Low HDL concentration is an independent predictor for cardiac heart disease risk, even when LDL concentration is low
(According to the Framingham study). They determine the ratio LDL/HDL. The lower, the better! Your lifestyle factors
determine your HDL levels. Physical activity and a small alcohol consumption can increase your HDL level. Testosterone,
smoking, obesity, anabolic steroid and anti-epileptics decrease your HDL levels!
,Women can have a heart attack without even high levels of cholesterol. The C-reactive protein (CRP) is therefore a better
marker for cardiovascular diseases than cholesterol.. This CRP is produced by the liver and is secreted when there is an
inflammation.
Fat in adipose tissue is actually an endocrine organ, because it can release all sorts of factors including cytokines (IL-6, IL-8,
IL18) induce the production and release of this CRP by the liver
- Metabolic syndrome: cluster of conditions that occur together, increasing your risk of heart disease, stroke, and
type 2 diabetes. These conditions include high blood pressure, high blood sugar, excess body fat around the waist
and abnormal cholesterol and triglyceride levels.
Physiology of NFLD (non-alcoholic fatty liver disease): the cholesterol/triglycerides are
deposited in the liver (to much fat is stored in the liver). The fatty acid concentration
increases which leads to oxidative stress in the liver. This oxidative stress leads to
mitochondrial dysfunction (less energy is produced).
In the lab, we can detect that someone has NDLF from the aspartate/alanine ratio. A ratio >1
means that there is a progression of fibrosis/cirrhosis. On the images we can see that there is
a retention of lipids in hepatocytes and that there are aberrations.
Cholesterol is an important and
essential precursor metabolite. So
having cholesterol is actually necessary. Cholesterol is taken up
from food (eggs). Pancreas produces enzymes to extract
cholesterol from diet. After a meal, the cholesterol is incorporated
in lipoproteins called chylomicrons. These chylomicrons can
directly deliver the cholesterol to the tissues. 80% of the plasma
cholesterol is made by the liver!
From acetyl-CoA we can make cholesterol. Therefore, acetyl-CoA is
also the precursor metabolite for cholesterol synthesis. From
cholesterol, we can make membranes, Bile salts and steroid
hormones. Cholesterol synthesis:
Acetyl-CoA is converted into
Acetoacetyl CoA. Then there are 2
enzymes which can convert this
acetoacetyl CoA into:
1. HMG-CoA (enzyme: HGM-
CoA synthase)
2. Mevalonate (enzyme: HGM-
CoA reductase). This is a committed
step. Once you make mevalonate,
you cannot go back to acetyl-CoA.
HGM-CoA and HGM-CoA synthase
are also used in ketone body
synthesis!
Additional steps follow after we have made mevalonate (which is only used for cholesterol
synthesis). These steps require many ATP. At the end, we obtain cholesterol. Metabolism of
humans is set for having hunger! Making cholesterol takes a lot of energy.
, Between meals or when you have a fat-free diet, fatty acids and
cholesterol are made from carbohydrates and proteins, via the VLDL.
LDL and chylomicrons have the same protein (Apo-B) that encodes for
them, so they are both made from the same single gene which is the B-
apolipoprotein gene. the length of this protein decides whether LDL or
Chylomicrons will be produced. The full-length protein is incorporated in
the LDL lipoprotein and the shorter one is incorporated in the
chylomicrons.
You eat food and receive cholesterol. The cholesterol is
transported to your intestine where the chylomicrons transport
the cholesterol directly to the tissues that need it. The
chylomicron remnants go back to the liver where the liver can
bring more cholesterol back to the tissue via VLDL. When the
tissue has too much cholesterol, the excess cholesterol will be
taken away from the tissues via the HDL lipoproteins and go to
the liver. The liver can make from this cholesterol bile salts
which can be used to take up new cholesterol from food.
LDL receptor deficiency leads to a very high plasma cholesterol levels and accumulation of cholesterol in tissues → familial
hypercholesterolemia with xanthoma’s. These people cannot take up cholesterol due to a defect in these LDL receptors
which are used to transport cholesterol to tissues. This is a monogenetic disease. What happens is that these LDL particles
are taken up via clathrin coated pits.
Apo-B-100 receptor (LDL receptor) binds to cholesterol and takes it up. This LDL then undergoes receptor-mediated
endocytosis and enters the cell. Here, the LDL particle (which contains the cholesterol) is degraded and the cholesterol is
deposited on the ER membrane.
Regulation of cholesterol synthesis: when cholesterol is
present, it binds to the SCAP protein, which enables
the SCAP protein to keep the SREBP protein on the ER.
When cholesterol is gone and not bound to the SCAP
protein anymore, the SCAP+SREBP proteins are
unattached from the Insig protein. Together, the
SREBP+SCAP proteins are brought to the Golgi system
where they are further cleaved. This releases a
regulatory element which can go to the nucleus. Once
inside the nucleus, this regulatory element will activate
target genes that are involved in cholesterol synthesis.
→ it is cholesterol itself that regulates this synthesis.
- SREBP: sterol regulatory element-binding
protein
- SCAP: SREBP cleavage-activating protein
- Insig: insulin-induced gene
The liver is the cholesterol sensor: when plasma
cholesterol drops, the cholesterol production is
increased!
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