Lipoprotein Transport Flashcards
Describe the transport of free fatty acids in blood.
Free fatty acids are transported in blood complexed to albumin (noncovalent)
How are TAGs and cholesteryl esters transported in blood
TAGs and cholesteryl esters are transported inside of the lipoproteins
How are dietary lipid-soluble vitamins and dietary essential fatty acids in TAGs transported to the liver?
Dietary lipid-soluble vitamins and dietary essential fatty acids in TAGs reach the
liver via chylomicron remnants.
Dietary essential fatty acids are also stored after a meal in TAGs in fat cells and
can reach the liver during fasting as free fatty acids via transport by albumin
Which lipoprotein has the highest percentage of proteins?
HDL has the highest percentage of proteins due to apolipoproteins.
Which lipoprotein has the highest percentage of cholesterol plus cholesteryl esters?
LDL has the highest percentage of cholesterol plus cholesteryl esters
Which two lipoproteins are TAG-rich?
Chylomicrons and VLDL are TAG-rich lipoproteins
Which lipoprotein contains dietary lipids?
Chylomicrons are the lipoproteins that contain dietary lipids, mostly TAGs (~90%)
What is the role of Lipoprotein Lipase?
Cleaves TAGs in lipoproteins
What does Lipoprotein lipase need for activation?
Apo C-II
Where is Apo C-II found?
Membrane of TAG-rich lipoproteins, CMs, and VLDL
What functions as a storage for Apo C-II?
HDL
What is LCAT and what is its role?
Lecithin:Cholesterol acyltransferase;
An enzyme that cleaves a fatty acid out of phosphatidyl choline of the HDL membrane and esterifies it to free cholesterol and forms cholesteryl esters in the blood.
What does LCAT need for activation?
Apo A-1
From what does Lipoprotein lipase obtain apo C-II for activation?
HDL
What is Apo A-1? What is it needed for?
Apo A-1 is the main apolipoprotein in the membrane of HDL and is needed for
the reverse cholesterol transport performed by HDL.
Where in the human body is lipoprotein lipase (LPL) synthesized and which hormone favors synthesis and release from fat cells?
Lipoprotein lipase is mainly synthesized in myocardial cells, fat cells and skeletal muscle cells. Synthesis and release are favored by insulin in fat cells.
How is LPL anchored to the capillary walls?
LPL is anchored via a proteoglycan (heparan sulfate) to the endothelial surface of these cells. LPL does not travel within the blood stream.
What is the advantage of anchoring LPL to the walls of capillaries of specific tissues?
The fixed location of extracellular LPL ensures that the released fatty acids from
TAGs are directly available to the heart, skeletal muscle and fat cells.
The LPL isoform of the __________has a higher affinity for TAGs than the isozyme found in _________.
heart;
adipose tissue
Uptake of glucose into fat cells is performed by?
insulin-dependent GLUT-4
Where in the human body is LCAT synthesized and where is its site of action?
- LCAT is synthesized in liver; released as free enzyme into the blood.
- site of action: in blood close to cells that need to get rid of free cholesterol from their plasma membranes.
Which enzyme is needed to fill HDL with cholesteryl esters and needs apo A-1 for enzyme activation and for the recognition of HDL?
LCAT
Which apoprotein is needed for the release of chylomicrons from intestinal cells into the lymph?
The release of chylomicrons into the lymph needs apo B-48
Which two apoproteins are found in the membrane of chylomicron remnants before uptake into the liver?
Chylomicron remnants contain apo E and apo B-48
Which apoprotein is needed for the release of VLDL from the liver into the blood?
The release of VLDL into the blood from the liver needs apo B-100
Which two apoproteins are present in membranes of IDL ?
IDL contains apo E and apo B-100.
Which apoprotein is needed in general for recognition by remnant receptors?
Need apo E for recognition.
They can bind chylomicron remnants or IDLs, (which can be seen as the remnants
of VLDL. )
Which apoprotein is recognized in LDL for the uptake via the LDL-receptor?
LDL-receptors recognize apo B-100 in LDL.
-Uptake is via endocytosis of both, LDL and the LDL-receptor
How can LDL be modified?
LDL is modified by oxidants, especially when it is trapped in the blood with less
access to antioxidants, like vitamin E and vitamin C or uric acid and others.
How is LDL modification normally prevented to a tolerable amount?
The modification or oxidation often changes the structure of apo B-100 but can also change the phospholipids of LDLs.
Are oxLDL recognized by the LDL-receptor?
Ox LDL are not recognized by the LDL-receptor and cannot be taken up via the
LDL-receptor.
How are ox LDL taken up in macrophages?
OxLDL enter macrophages via an unspecific, uncontrolled scavenger receptor.
What is the name for the receptor that takes up oxLDL?
SR-A
How are macrophages changed to foam cells?
- Macrophages that take up excess of oxLDL become foam cells.
- oxLDL are mostly filled with cholesteryl esters which are now inside of Macrophages.
What is released by foam cells and stimulates the migration of smooth muscle cells?
Foam cells release growth factors and cytokines
Which is larger, LDL-A or LDL-B?
LDL-A
What are the risk factors for atherosclerosis?
LDL-B
Lp(a)
oxLDL
Lp(a) is an abnormal LDL with the protein apo (a) linked to apo B-100 via a ___________.
Disulfide bond
________is a risk factor as it is smaller and can be trapped in the ECM. It can also contribute to oxLDL.
LDL-B
What percentage of IDLs are taken up into the liver?
50%
Hepatic lipase, which is bound in the capillaries of the liver, does what?
Takes IDLs not taken up by liver and forms LDLs.
What percentage of LDLs are taken up into the liver?
70%
What happens to the remaining LDLs that are not taken into the liver?
Distributed via the blood to cells who have LDL-receptors and need cholesterol.
Under which conditions are liver LDL-receptors reduced?
Temporarily after a cholesterol-rich meal when the levels of free cholesterol increase in liver cytosol.
A hereditary, permanent deficiency of LDL-receptors is found in patients with?
Hyperlipidemia Type II
LDL receptors are ____________that are aligned in the coated pit. They recognize _________ in LDL which is __________charged.
Negatively charged glycoproteins;
Apo B-100;
Positively
cholesteryl esters are formed in
_________and are stored in the_______.
Liver cytosol;
liver
Apo(a) has the unusual structure of _______ and is _______ bound to ________.
kringles;
covalently;
Apo B-100
What is the role of ACAT?
At high freecholesterol levels, the cytosolic enzyme (fatty) acyl-CoA cholesterol acyl transferase(ACAT) is activated and a reservoir of cholesterylesters is formed.
[name: the acyl transferasetransfers an acyl-group to cholesterol and uses intracellular fatty acyl-CoA]
High free cholesterol levels lead to retention of the _____________complex in the
ER which prevents the initiation of transcription which needs _________in the
nucleus.
SCAP-SREBP;
SREBP
What is found in high concentration in blood in hyperlipidemia Type IIa?
High LDL
Hyperlipidemia Type IIb is characterized by what?
High LDL
High VLDL
Which cell type forms apo B-48, how is it generated and which cell type forms apo B-100?
Apo B-48 represents 48% of apo B-100 and is generated by mRNA editing.
Intestinal mucosal cells form apo B-48 and liver cells form apo B-100.
What is a discoidal nascent HDL?
The newly formed HDL that is not filled with cholesteryl esters has a discoidal shape. It consists mainly of its phospholipid monolayer and apoproteins. The main phospholipid found is phosphatidylcholine
HDL will provide _____and _______for chylomicrons and VLDLs, but the apoprotein_______ is kept for HDLs function of reverse cholesterol transport
Apo C-II;
Apo E:
Apo A-1
What is formed first from the discoidal HDL, is it HDL-2 or is it HDL- 3 in the so called reverse cholesterol transport?
Firstly, HDL-3 is formed from it after uptake of cholesteryl esters.
Once HDL-3 is filled with more cholesteryl esters and after uptake of phospholipids, then the larger HDL-2 is formed.
It is HDL-2 that delivers cholesteryl esters to the liver
How is LCAT (PCAT) able to form cholesteryl esters from free cholesterol in the blood?
LCAT uses a fatty acid from lecithin (phosphatidylcholine) of the monolayer of
HDL and links it to free cholesterol in order to form cholesteryl esters in blood.
This is a special process, as in the blood fatty acyl CoA is not available.
(Inside of cells, cholesteryl esters are formed using fatty acyl CoA catalyzed by ACAT)
What is the function of apo A-1?
Apo A-1 signals that the small lipoprotein is actually HDL and that HDL should
be filled with cholesteryl esters.
What is the location of LCAT?
-Extracellular and unbound in blood stream
Where is LCAT synthesized?
Liver
What is the location of ACAT?
Cytosol of cells
What are the substrates needed by LCAT?
Phosphatidyl Choline of the HDL monolayer and free cholesterol
What activates LCAT?
apo A-1
What are the substrates needed by ACAT?
Fatty acyl CoA and free cholesterol
What activates ACAT?
Free cholesterol (enzyme induction)
What is the function of the cholesteryl ester transfer protein (CETP)?
CETP allows the exchange of cholesteryl esters for TAGs between lipoproteins
Where is CETP found?
CETP is found in the blood
Which lipoproteins are mainly involved with CETP?
CETP allows the transfer of TAGs into HDL, and in return cholesteryl esters from HDL are transferred into VLDL.
How can some cholesteryl esters of HDL reach the liver via IDL and LDL?
The cholesteryl esters that were exchanged using CETP are now in VLDL and will be found in IDL and in LDL. Both, IDL and LDL can be taken up by the liver.
Using CETP, the HDLs have achieved that some of their cholesteryl esters are transported inside of IDL and LDL to the liver
Which three major apoproteins are found in the phospholipid monolayer of HDL? Which two are activating enzymes, which one is needed for other lipoproteins for their receptor recognition?
1) apo A-1 activates LCAT
2) . apo C-II activates lipoprotein lipase
3) . apo E is needed for remnant receptor recognition
(chylomicron remnants and IDL which are remnants of VLDL)
What is meant by reverse cholesterol transport?
The transport of cholesterol from extra hepatic cells to the liver is named reverse cholesterol transport
Why is reverse cholesterol transport different than the uptake of IDL or LDL into the liver?
these lipoproteins contain mainly the cholesteryl esters that were released in VLDL and put into VLDL by the liver itself.
What is needed to signal LCAT that the lipoprotein is HDL and that the
phosphatidyl choline of this lipoprotein should be used for formation of
cholesteryl esters in blood.
Apo A-1
Which membrane transporter is involved with the release of free cholesterol from plasma membranes into the blood?
Cholesterol ABC transporter
What is the role of Cholesterol ABC transporter?
- Found in the plasma membrane
- they transport free cholesterol to the outside of the plasma membrane.(the plasma membrane contains free cholesterol in both layers)
What happens to free cholesterol once it is released from plasma membranes into the blood by Cholesterol ABC transporter?
Can be “rubbed” into the phospholipid monolayer of HDL.
This can handle only limited amounts, and the free cholesterol is used by LCAT to
form cholesteryl esters in blood
Why do cholesterol esters move immediately from the blood into the core of HDL?
They are totally nonpolar
What is deficient in the rare Tangier disease?
cholesterol ABC transporter that
normally provides free cholesterol for LCAT
What is Tangier disease also known as and why?
Also known as hypoalphalipoproteinemia due to the very low levels of HDL
Why does Tangier disease lead to atherosclerosis?
apo A-1 is degraded when the nascent HDL cannot be filled with cholesteryl esters.
This leads to very low levels of HDL in these patients and the reverse cholesterol
transport is reduced which can lead to atherosclerosis.
What is characteristic in patients with Tangier Disease?
coronary disease,
orange-colored tonsils,
very low HDL
enlarged liver and spleen
What is abetalipoproteinemia?
A hypolipidemia which is characterized by very low amounts of serum VLDL, LDL and chylomicrons.
What is primarily reduced in abetalipoproteinemia?
levels of VLDL
Abetalipoproteinemia is due to…
a defect of the microsomal TAG transfer protein which is needed for the formation of VLDL and chylomicrons
What is characteristic for patients with abetalipoproteinemia?
- fat malabsorption
- TAG accumulation in liver and intestinal mucosal cells.
- Retinitis pigmentosa and peripheral neuropathy are also found.
Where is SR-B1 found?
Liver
What does SR-B1 bind to?
HDL-2
What is the role of SR-B1?
Binds to HDL-2 and acts very likely together with the phospholipase activity of hepatic lipase. The phospholipid monolayer of HDL-2 may be opened and cholesteryl esters are released into liver.
Where is SR-A found?
in macrophages
What is the role of SR-A?
It is a scavenger receptor for oxLDL found in macrophages. SR-A takes up total oxLDL. This uptake is not regulated and leads to foam cells
Lipoprotein Lipase is bound in capillaries around…
Heart
Adipose
Skeletal muscle
Hepatic lipase is bound in capillaries around…
Liver
Lipoprotein Lipase changes
VLDL to IDL
Chylomicrons to CM remnants
Hepatic Lipase changes
IDL to LDL (TAG-lipase activity)
What is special about hepatic lipase?
Hepatic lipase cleaves both, TAGs and phospholipids of lipoproteins which is
very unusual.
Hepatic lipase also contains a ligand-binding action with________ in liver.
SR-B1
Which enzyme is most likely deficient in Type I and in Type IV Hyperlipidemia?
lipoprotein lipase
High plasma levels of chylomicrons are found in which Hyperlipidemia?
rare Type I
High plasma levels of VLDL are found in which Hyperlipidemia?
common Type II
Which lipoproteins accumulate in Type V hyperlipidemia?
CM and VLDL
The hyperlipidemias Types I, IV and V are referred to as…
hypertriacylglycerolemias
Hyperlipidemia Type III is a rare disease that leads to…
Hypercholesterolemia
In hyperlipidemia Type III, which lipoprotein is increased in plasma and contains cholesteryl esters?
IDL (or CM remnants)
In hyperlipidemia Type III, which apoprotein is less functional?
The patients are homozygous for the isoform apo E-2 which binds poorly to
receptors. This is often described as apo E deficiency.
This leads to reduced uptake of lipoprotein remnants into the liver of these patients
Which Type of Hyperlipidemia is mostly related to defective LDL-receptors?
Hyperlipidemia Type IIa
Hyperlipidemia Type IIa leads to…
high blood levels of LDL as they are less taken up into cells.
In type IIB hyperlipidemia, what lipoproteins are elevated in the blood?
LDL
VLDL
Type IIB hyperlipidemia is different to type IIA in that
Type IIb is more complex and could be due to overproduction of apo B-100 and
of VLDL and in addition could also be due to defective LDL receptors
Which common diseases can lead to acquired (secondary) hypertriacylglycerolemia?
Untreated diabetes and hypertension and alcohol abuse can leads to acquired
hypertriacylglycerolemia.
Which diseases are often associated with acquired hypercholesterolemia?
Obstructive liver disease, nephrotic syndrome and hypothyroidism can lead to
acquired hypercholesterolemia
Why are statin drugs used to treat hypercholesterolemia?
Statins inhibit the regulated enzyme of cholesterol synthesis (HMG CoA reductase). When less free cholesterol is found in the liver, then more LDL-receptors are synthesized.
More LDL-receptors in the liver can take up more LDL from the blood and reduce hypercholesterolemia
Dietary cholesterol uptake into the liver leads to a temporary reduction of LDL-receptor synthesis. The synthesis is back to normal when the diet contains less cholesterol and when the cytosolic free cholesterol level is lower again
What is more harmful, is it dietary cholesterol or is dietary uptake of trans-fatty acids? Explain
The dietary uptake of trans-fatty acids is more harmful as these fatty acids can lead to smaller LDL of the LDL-B type. TAGs and cholesteryl esters with trans- fatty acids are stacked more closely inside of lipoproteins.
[unsaturated fatty acids have normally cis-configuration which bends the acyl-chains. When they are esterified in TAGs or cholesteryl esters, they need more space than esterified saturated fatty acids or trans-fatty acids]
What is the reasoning to use bile acid sequestering drugs for treatment of Type IIa hyperlipidemia?
Type IIa hyperlipidemia is a hereditary disease related to the deficiency of LDL-receptor synthesis. The treatment has the objective to optimize the reduced LDL-receptor synthesis as much as possible.
Bile acid sequestrants (resins) like cholestyramine, bind and trap bile acids/salts in the intestines and lead to excretion of bile salts via in feces. Less bile salts/acids are taken up into the liver again via the enterohepatic circulation. The liver has now to synthesize more primary bile acids using free cholesterol.
This reduces cytosolic free cholesterol levels in the liver and stimulates LDL-receptor synthesis. These patients have now more LDL-receptors than without the treatment.
The LDL-receptors take up LDLs into the liver and reduce to a certain degree the elevated amount of LDLs in the blood.
