Lipoprotein Metabolism Flashcards
sphingomyelin
Lipid with structure highly analogous to phospholipids
Instead of a glycerol backbone, there is a serine amino acid derrived nitrogen connected to a carbon tail
Fatty acid group can be linked to nitrogen to form a ceramide
Important signal transduction molecule
cholesterol
a sterol which serves critical functions in maintaining membrane fluidity and serving as a precursor molecule to steroid hormones
an important derivative is the cholesteryl ester
HMG-CoA reductase
an enzyme which leads to the synthesis of mevalonate, the basic building block of the sterol moiety
the rate limiting step of the cholesterol biosynthesis pathway
main classes of lipids
fatty acids
triglycerides
phospholipids
cholesterol
typical lipoprotein structure
apolipoproteins
amphipathic surface - mostly phospholipids and cholesterol
hydrophobic core - triglycerides and choleteryl ester
purpose of lipoproteins
deliver fats as fuel
cholesterol transport
phospholipid transport
roles of apolipoproteins
cofactors for enzymes and receptors, conferring specificity
structural scaffolds - acts as a belt to hide the hydrophobic tails of the phospholipids
acts as a cofactor for ABCA1, which is important for transferring cholesterol to apolipoproteins
major lipoprotein classes
chylomicrons
chylomicron remnants
very low density lipoproteins (VLDL)
intermediate density lipoproteins (IDL)
low density lipoproteins (LDL)
and high density lipoproteins (HDL)
key pathways of lipoprotein transport
exogenous pathway
endogenous pathway
reverse cholesterol transport
enterohepatic circulation
key enzymes of lipoprotein transport
lipoprotein lipase (LPL)
lecithin-cholesterol acyltransferase (LCAT)
cholesteryl ester transfer protein (CETP)
exogenous pathway
the process by which chylomicrons delivered from the gut via the thoracic duct mature, deliver tryglycerides to peripheral cells, and are then taken up by the liver
critical to converting triglycerides to free fatty acids is lipoprotein lipase, which is found on the endothelium
enterocyte package
triglycerides
cholesterol
phospholipids
ApoA
ApoB48
nascent chylomicron
a lot of triglycerides on the inside
two main apoproteins are ApoB48 and ApoA1
relatively big 100nm to 1um in diameter
How does a nascent chylomicron become a chylomicron?
ApoC and ApoE are added on with the help of HDL
How are chylomicrons turned into chylomicron remnants?
lipoprotein lipase converts triglycerides to free fatty acids with the help of lipoprotein lipase with the help of ApoC
the triglycerides can pass through the cell membrane
What happens to chylomicron remnants?
taken up by LRP in the liver and recycled
endogenous pathway
represents liver production of VLDL, which undergoes metabolism very similar to chylomicrons
LDL is a product of this pathway
it may be taken up by LDL receptors in the liver
an important derivative is oxidized LDL which may be taken up by macrophages through a variety of receptors and is critical to driving the foam cell phenotype and therefore atherosclerosis progression
What comprises a nascent VLDL?
ApoE, ApoB100, ApoC, cholesterol, and other lipids
How does nascent VLDL become VLDL?
it matures after interactions with HDL
How does VLDL become IDL?
VLDL acts as a cofactor for lipoprotein lipase due to the ApoC, which is lost during the reaction, giving rise to IDL
How does IDL become LDL?
IDL interacts with HDL and becomes LDL, which only has ApoB100
the LDL is then taken up by LDLR in the liver and peripheral cells
reverse cholesterol transport
the uptake f cholesterol by HDL from peripheral sites and delivery to the liver
an important pathway where excess cholesterol is disposed from the body
Describe the process of Apo-A1 becoming HDL3
Apo-A1 is produced by the liver or intestine, and it is lipidated to form a discoidal form of HDL called pre-beta-HDL
pre-beta-HDL is then matured into HDL3 by lecithin-cholesterol acyltranferase, which is an enzyme that transfers an acyl group to cholesterol, forming cholesteryl ester
Describe the fates of HDL3
matured into HDL2 through exchange with chylomicrons, VLDL
from there, it can be delivered directly to the liver
it can transfer cholesterol and cholesteryl ester to LDL, which is then delivered directly to the liver and taken up through the LDL receptor
enterohepatic circulation
the recirculation of bile salts in the gut
important metabolite of choesterol and serve to solubilize fats so that they can be taken up by enterocytes
genetic disorders of lipoprotein metabolism
familial hypercholesterolemia
PCSK9 deficiency
familial chylomicronemia syndrome (Fredickson Type I hyperlipoproteinemia)
Fredrickson Classification
systemt hat classifies hyperlipoproteinemias into six subtypes based on serum lipid values and clinical features
familial hypercholesterolemia
mutation in LDLR
autosomal dominant
1/500 are heterozygotes, who have cholesterol levels of around 300mg/dl
homozygotes have up to 1000 mg/dl
the hallmark of this disease is premature atherosclerosis
symptoms of familial hypercholesterolemia
arcus corneae (deposition of cholesterol in the cornea)
tendonous xanthomas (thickened tendons)
eyelid xanthomas
premature atherosclerosis
PCSK9 deficiency
a deficiency of the gene product of PCSK9 (proprotein convertase subtilisin/kexin type 9)
This protein binds to LDL Receptor and mediates its degradation
Patients who are deficient in PCSK9 therefore have elevated levels of LDL Receptor and—in turn—reduced levels of LDL-cholesterol
reduced risk of coronary artery disease
gain of function PCSK9 mutations exist, leading to increased LDL-C
Familial Chylomicronemia Syndrome (Fredrickson Type I Hyperlipoproteinemia)
a syndrome of very high levels of chylomicrons, which manifests on laboratory testing as very high triglyceride levels
The underlying genetic defects are either a deficiency of lipoprotein lipase or ApoC-II, both of which are essential for hydrolysis of triglycerides for delivery to peripheral tissues
How are lipoproteins measured clinically?
measurement of LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), and triglycerides
basic parts of the fasting lipid panel
LDL cholesterol is the amount of cholesterol and cholesteryl ester (found in IDL, LDL, and chylomicron remnants)
triglycerides is a measurment of VLDL and chylomicrons
Friedewald Equation
0.2*triglycerides (TG) + HDL-cholesterol (HDL-C) + LDL-cholesterol (LDL-C) = total cholesterol (TC)
