ICL 4.0: Lipoprotein Metabolism Flashcards
what are lipoproteins?
lipids are hydrophobic and have low solubility, need lipoprotein particles for transport in the blood for distribution to tissues
the major lipids are triglycerides and cholesterol
the amount and types of lipoprotein particles affects the risk for cardiovascular disease
what is the structure of lipoproteins?
- surface layer of amphipathic lipids = phospholipid and cholesterol
- core of nonpolar lipids = triacylglycerol and cholesterol ester
- apolipoproteins (peripheral and integral)
different types of lipoprotein particles contain specific proteins
what is the generalized function of apolipoproteins?
- part of structure of lipoprotein
- co-factors/activators for enzymes
- inhibitors for enzymes
- ligands for lipoprotein receptors
what are the major types of lipoproteins?
- chylomicrons
- very low density lipoproteins (VLDL)
- low density lipoproteins (LDL)
- high density lipoproteins (HDL)
what is the function of chylomicrons?
they are a type of lipoprotein that delivers dietary triacylglycerol from the intestine to adipose tissue
and, to a lesser extent, to liver and other tissues
they also deliver dietary cholesterol from intestine to liver
what is the function of VLDLs?
they are a type of lipoprotein that deliver hepatic triacylglycerol to adipose and other tissues
they are also the precursor of LDL!
what is the function of LDLs?
they are a type of lipoprotein that delivers cholesterol from liver to peripheral tissues
what is the function of HDLs?
they are a type of lipoprotein delivers cholesterol from peripheral tissues to liver
how are dietary triglycerides digested and transported?
triacylglycerides are digested into fatty acids and monoacylglycerols in the lumbar of the small intestines
then they’re transported into the cells and the triacylglycerides are re-synthesized in the cell
chylomicrons then transport the triacylglycerides to through the lymph system, to the blood, then finally to adipose cells –> they go through the lymph because they don’t want the fat to go to the liver
how are chylomicrons made?
intestinal endothelial cell absorb lipids from the lumen and packages them
RER makes apolipoprotein and then these proteins package the lipid components in the golgi and assemble the chylomicrons
they then get secreted into the lymph system which goes to the thoracic duct and gets delivered to the blood circulation
how are chylomicrons metabolized?
- intestinal mucosal cells secrete TAG-rich chylomicrons produced from dietary lipids
- apo C and apo E are transferred from HDL to the chylomicron
- in the circulation, extracellular lipoprotein lipase is activated by apo C which then degrades the TAG in the chylomicron into free fatty acids and glycerol –> free fatty acids go to tissues and glycerol goes to liver
- apo C is returned to HDL
- CE-rich chlymicron remnants bind through apoE to specific receptors on the liver and are endocytose
what is the importance of lipoprotein lipase?
normal fasting triglyceride levels is 100-150 mg/dL
if you have an LPL defieicency you have extremely high triglyceride levels because you can’t degrade them! there’s also a massive accumulation of chylomicrons because they’re just filled with TAGs that you can’t degrade
what is the main structural apolipoprotein in chylomicrons?
apoB48
apoCs
apoE
what is the main structural apolipoprotein in VLDLs?
apoB-100
apoCs
apoE
what is the main structural apolipoprotein in LDLs?
apoB-100
what is the main structural apolipoprotein in HDLs?
apoA-I
apoA-II
how are VLDLs made?
VLDLs transport triglycerides and cholesterol from the liver to extra hepatic tissues –> this is because the liver doesn’t store a lot of TG or cholesterol
VLDL formation in the liver is dependent on apoB100 –> the lipoprotein is assembled in the RER and put into secretory vesicles which are secreted directly into the blood
a fatty liver is abnormal and is a sign of chronic alcohol abuse or diabetes
what is the difference between chylomicrons and VLDLs?
CHYLOMICRONS
1. synthesized in intestine
- transport of dietary TG
- apolipoproteins = apoB48, apoA, apoC, apoE
- 90-1000 nm particle size
VLDLs
1. synthesized in liver
- transport of liver TG
- apolipoproteins = apoB100, apoC, apoE
- 30-90 nm particle size
how are apoB100 and apoB48 synthesized?
they’re both derived from the same gene, the apoB gene
in both the liver and the tissue, you have the same primary mRNA transcript
in the intestine though, there is RNA editing where one of the bases is converted from a C to a U and that change creates a stop codon! so when the mRNA is translated, you get a truncated protein which is apoB48 which is used in chylomicrons –> because of this, the chylomicron can’t bind to the LDL receptor since it’s missing that domain
in the liver, the full mRNA transcript is translated so you get apoB100 which is used in VLDLs
how are VLDLs and LDL metabolized?
- liver secretes TAG-rich VLDL particles containing primarily endogenously synthesized lipids
- apoC and apoE are transferred from HDL to the VLDL
- in the circulation, extracellular lipoprotein lipase is activated by apoC which then degrades the TAG in VLDLs into free fatty acids and glycerol –> the free fatty acids go to tissues and the glycerol goes to the liver
- apoC and apoE are returned to HDL –> loss of apoE and TAGs converts VLDL into LDL
- LDL binds to specific receptors on extraheptatic tissues and on the liver and are endocytose –> it primarily delivers cholesterol*
what is the structure of HDL?
apoA and apoE on the outside
inside is made of triglycerides and cholesterol
why is HDL cholesterol considered good cholesterol?
HDL transports cholesterol from the non hepatic tissues to the liver
it’s counteracts the function of LDL which takes cholesterol to tissues –> so it can transport cholesterol from plaques back to the liver
how is HDL metabolized?
- lipid-poor particles like apoA-I and phospholipid originate from the liver and intestine
- plasma apoA-I acquires phospholipids and cholesterol from cell membranes, resulting in pre-B HDL
- continued uptake of cholesterol and its esterification transforms pre-B HDL to spherical HDL
- LCAT catalyzes esterification of cholesterol; cholesterol ester is returned to the liver by HDL which reverses cholesterol transport
HDL also transfers apoCs and ApoE to chylomicrons and CLDL in plasma –> apoCs and apoE are synthesized in the liver and bind to HDL in the plasma which are then transferred to VLDL and chylomicrons
what is the cholesterol pathway?
acetyl CoA
acetoacetyl-CoA
HMG-CoA
Mevalonate
isopentenyl-PP
geranyl-PP
farnesyl-PP
squalene
cholesterol
what step of the cholesterol pathway do statins act on?
HMG-CoA –> mevalonate via HMG-CoA reductase
statins inhibit HMG-CoA reductase
however, this step is early on in the pathway so it shuts down production of some useful downstream products which can cause side effects
how do you regulate cholesterol levels?
SREBP = SRE binding protein SCAP = SREBP cleavage activating protein
low levels of cholesterol in ER activate SCAP which cleaves SREBP precursor
low levels of cholesterol result in the processing of SREBP which then translocates to the nucleus and activates transcription of genes = HMGCoA reductase and LDL receptors
HMGCoA reductase = increases cholesterol synthesis
LDL-R = increases uptake of cholesterol
which drug classes lower LDL-C levels?
decreasing intracellular cholesterol stimulates LDL-R synthesis, increasing LDL clearance
- statins inhibit cholesterol synthesis
- bile acid sequestrants stimulate the elimination of cholesterol by conversion into bile salts
- ezetimibe inhibits cholesterol uptake in the intestine
- monoclonal antibodies to PCSK9 inhibit LDL-R degradation
how does PCSK9 work?
PCSK9 binds to the LDL receptor and increases its proteolysis
this means that less LDL receptors will be recycled to the surface and then less LDL-C will be cleared
how do lipoproteins play a role in atherosclerosis?
LDL gets trapped in intima of arterial walls and oxidized
oxidized LDL is then taken up by macrophages and plaque forms (foam cells)
HDL tries to reverse this by transporting cholesterol back to the liver
how is dyslipidemia classified based on serum lipid levels?
- hypercholesterolemia = high LDL-C
- hypertriglyceridemia = high TG in VLDL
- low HDL
what is dyslipidemia in metabolic syndrome?
low HDL-C
high TG
elevated small dense LDL
what is the lipid hypothesis for CVD?
high LDL-C causes heart diseases
reducing the number of LDL particles is better than reducing cholesterol itself
what is the genetic link to hypercholesterolemia?
Homozygous Familial hypercholesterolemia (FH) is associated with a 20-fold increase in the incidence of heart attacks in middle age
FH is due to a deficit in the LDL receptor, causing very high levels of LDL particles in blood
PCSK9 mutations reduce LDL levels and incidence of heart attacks
both conditions affect LDL particle numbers
what is the Friedewald formula?
total cholesterol = LDL + HDL + VLDL
LDL = total - HDL - (triglycerides/5)
fast for 12-14 hours before and make sure TG <400 or else it’s not accurate
what are normal LDL, HDL and total cholesterol levels?
LDL < 100
HDL 40-60
Total = <200
which measurement from the lipid panel best predicts the risk of cardiovascular disease?
triglycerides:HDL ratio is the best predictor
low TG -high HDL is the a better prognosis and lower risk for CVD
high TG/HDL may not be causative but a marker for metabolic syndrome which can instigate CVD –> metabolic syndrome includes hyperglycemia, hyperinsulinemia, HTN, inflammation, low HDL, high TG
