Duan > Lipowhatthefuckever Flashcards
what are lipoproteins?
protein-lipid complexes responsible for transport of plasma lipids
what is on the surface of a lipoprotein?
phospholipids (duh)
unesterified cholesterol
apolipoproteins
what is in the core of a lipoprotein?
cholesterol esters
triglycerides
what are the 3 lipids?
triacylglycerol
phospholipids
cholesterol & cholesterol esters
what is the difference btwn triacylglycerol & phosopholipid?
triacylglycerol has 3 FAs w/ a glycerol backbone, phospholipids only have 2 FAs
where is Apo A-I?
liver & small intestine
what does Apo A-I do?
structural
activate LCAT
where is Apo A-II?
liver
what does Apo A-II do?
strucutral
inhibit hepatic lipase
component of ligand for HDL binding
where is Apo A-IV?
small intestine
what does Apo A-IV do?
activate LCAT
modulate LPL
where is Apo A-V?
liver
what does Apo A-V do?
direct fxnal role unk
regulates TG levels
where is Apo B-100?
liver
what does Apo B-100 do?
structural
synthesize VLDL
ligand for LDL-Receptor
what does Apo B-48 do?
structural
make chylomicrons
where is Apo B-48?
small intestine
what is Apo B-48 from?
from apo B-100 mRNA after specific mRNA editing
where is apo C-I?
liver
what does apo c-I do?
activate LCAT
inhibit hepatic TGRL uptake
what does apo C-II do?
activate LPL
inhibit hepatic TGRL uptake
where is apo C-II?
liver
where is apo C-III?
liver
what does Apo C-III do?
inhibit LPL
inhibit hepatic TGRL uptake
where is apo E?
liver
macrophages
brain
what does apo E do?
ligand for apoE receptor
mobilize cellular cholesterol
which lipoproteins are in the liver?
A-I A-II A-V B-100 C-I C-II C-III E
which lipoproteins are in the small intestine?
A-I
A-IV
B-48
which lipoproteins are in macrophages & the brain?
ONLY E!
what is the smallest lipoprotein?
HDL
how big is HDL?
9-15 nm
how big is LDL?
20-22 nm
how big are chylomicrons, VLDL, and their catabolic remnants?
> 30 nm
what are the biggest lipoproteins?
chylomicrons, VLDL, and their catabolic remnants
what is the density of HDL?
1.063-1.21 g/mL
what is the density of LDL?
1.019-1.063 g/mL
what is the density of chylomicrons, VLDL, & their catabolic remnants?
<1.006 g/mL
what affects the diameter & density of lipoproteins?
CE/TG/phospholipid/lipoprotein composition
what is the % total lipid & % total protein content of HDL?
50%
50%
what is the % total lipid & % total protein content of LDL?
80% total lipid
20% total protein
what is the % total lipid & % total protein content of IDL?
85% total lipid
15% total protein
what is the % total lipid & % total protein content of VLDL?
92% total lipid
8% total protein
what is the % total lipid & % total protein content of chylomicrons?
99% total lipid
1% total protein
what 3 things make up total lipid content?
CE
TG
phospholipids
what is the general trend as density of a particle decreases with total lipid and total protein?
lower density = larger diameter
higher lipid content
lower protein content
what are the 2 pathways for lipoprotein metabolism?
exogenous/chylomicron pathway
endogenous/VLDL pathway
what pathway does dietary fat use for lipoprotein metabolism?
exogenous/chylomicron
what happens to lipids synthesized by the liver (what lipoprotein metabolism pathway)?
endogenous/VLDL pathway
what are the 5 steps of the exogenous/chylomicrons pathway?
- bile salts solubilize dietary TG
- pancreatic lipases hydrolyze TGs
- diffuse into intestinal epithelial cells
- ER re-synthesizes TG
- packaged into chylomicrons
what is the half life of a chylomicron?
5-30 min
which apolipoproteins are in chylomicrons initially?
apo A
apo B-48
which apolipoproteins on chylomicrons are acquired in circulation?
apo E
apo Cs
what activates LPL?
apo C-II
where is LPL primarily?
on surface of capillaries of adipose & muscle tissue
what does LPL do?
hydrolyze TG to free FA + glycerol
what % of a chylomicron is TG?
> 90%
what % of a chylomicron is CE + cholesterol?
<5%
what % of a chylomicron is phospholipids?
5-10%
what % of a chylomicron is protein?
1-2%
what happens to the free FA from a chylomicron?
can be reused for energy or re-esterified
what happens to chylomicrons as they lose TG?
they shrink
what do apo E and apo C get transferred to (from a chylomicron)?
HDL
what is a chylomicron called when all the apo C is gone?
chylomicron remnants
what is the composition of a chylomicron remnant?
CE > TG
what happens to LPL after the chylomicron loses apo C-II?
no longer activated
what happens to chylomicron remnants?
taken up by liver
what is the half-life of a chylomicron remnant?
~5 min
what is the function of a chylomicron?
transport dietary lipids from the intestines to adipose, skeletal, & cardiac muscle tissue
where does a chylomicron get apo C II and apo E?
from HDL
what apolipoproteins does a chylomicron remnant have?
apo E
apo B-48
what is VLDL responsible for?
endogenous TG formation & transport
are VLDLs bigger or smaller than chylomicrons?
smaller
what is the surface monolayer of VLDL composed of?
12% phospholipids
14% free cholesterol
4% protein
what is the hydrophobic core of VLDL composed of?
65% TG
8% CE
C 8-10%, CE 12-15%
idk man this is weird
what lipoproteins does VLDL have?
apo Cs (C-II from HDL)
apo E
apo B-100
what is the half-life of VLDL?
~12 hours
what are TGs hydrolyzed by?
LPL
VLDLs decrease in size to become what?
IDL
what happens if you lose Apo C-II?
less activation of LPL
what is the composition of IDL?
TG about the same as CE
what lipoproteins are on IDL?
apo Cs
Apo E
Apo B-100
what is the half-life of IDL?
minutes to an hour
what takes up 50% of IDLs?
the liver
via apoE & Apo B-100
what happens to the IDLs that do not get taken up by the liver?
loses TG
becomes LDL
what is the primary carrier of cholesterol in the blood?
LDL
what lipoprotein has the highest cholesterol?
LDL
what is the composition of LDL?
5% TG
20% protein
70% C + CE
what removes LDL?
LDLR via apo B-100
what is the half life of LDL?
2.5-3 days
what lipoproteins have apo B-100?
VLDL, IDL, LDL
increased apo B-100 is correlated w/ what?
increased CVS disease
what is the genetic defect assoc w/ familial defective apo B?
glutamine substituted arginine at amino acid 3500 > missense mutation
what is familial defective apo B?
affects binding affinity of apo B-100 at its receptor (i.e. the LDL receptor)
where can you find the LDL receptor?
hepatic & extrahepatic tissues
what happens when an LDL particle binds to the receptor?
the receptor-LDL complex is endocytosed
what happens to the cholesterol in LDL after the LDL-receptor complex is endocytosed?
cholesterol is de-esterified & released as free cholesterol in cytoplasm > can be used in membranes
what re-esterifies XS cholesterol?
ACAT
acyl-CoA-cholesterol acyl transferase
what pathway occurs in the small intestine?
exogenous pathway
what pathway occurs in the liver?
endogenous pathway
what does ACAT do in the intestine/exogenous pathway?
regulates dietary cholesterol absorption
what does ACAT do in the liver/endogenous pathway?
esterifies cholesterol for production & release of VLDL
what does ACAT promote?
foam cell formation & atherogenesis
what does LDL come from?
VLDL
+ LPL
where is HDL synthesized?
liver & small intestine
what does HDL do?
transports cholesterol from peripheral tissues to liver
what is the composition of HDL?
CE & phospholipids (50/50)
what lipoproteins are present in HDL?
apo A-I
apo A-II
apo C-II
apo E
what is the cofactor for LCAT?
apo A-I
what is LCAT?
lecithin cholesterol acyl trasnferase
what does LCAT do?
esterifies cholesterol > moves into interior of particle to enlarge HDL
what happens to HDL particles as the circulate through the bloodstream?
they acquire cholesterol & phospholipids and grow
what does CETP do?
exchange VLDL TGs against HDL CEs
what are the 2 mechanisms of cholesterol regulation?
- rate of cholesterol synthesis
2. rate of LDL receptor transcription
what are the 4 primary lipoprotein disorders?
primary chylomicronemia
familial hypertriglyceridemia
familial combined hyperlipoproteinemia
familial dysbetalipoproteinemia
what is primary chylomicronemia?
LPL or cofactor deficiency
increased chylomicrons & VLDL
what is the result of hypertriglyceridemia?
increased VLDL
+/- chylomicrons
what is the result of familial combined hyperlipoproteinemia?
increased VLDL OR increased LDL OR both
what is the result of familial dysbetalipoproteinemia?
increased VLDL remnants & chylomicron remnants
what do mutations in the LDL receptor lead to?
familial hypercholesterolemia
what do most LDL receptor mutations result in?
impaired fxn
what do SOME LDL receptor mutations result in?
fewer receptors d/t impaired cell processing
what is the clinical result of heterozygous LDL receptor mutation?
serum cholesterol up to 2x normal
~5% have MI before 60yo
what is the clinical result of homozygous LDL receptor mutaiton?
high serum cholesterol
CVD signs at an early age
MI by 20yo
are hetero or homozygous mutations in the LDL receptor more common?
heterozygous (1 in 500)
homo is 1 in 1 million
what happens to TGs in alcoholism?
increase
what happens to TGs in liver disease?
increase
what happens to VLDL & chylomicrons in alcoholism & liver disease?
VLDL is low to normal
chylomicrons increase
T/F: only type 1 diabetes increases risk for CVD
FALSE
type 1 & 2
how does insulin affect LPL transcription?
increases it
increased removal of TGs
decreased VLDL
what happens to LPL transcription if insulin is low or if pt is insulin resistant?
decrease in LPL transcription
what happens to VLDL if insulin is low or if pt is insulin resistant?
increase VLDL
less effect of chylomicrons
what happens to proteins & lipids with high blood sugar?
can become glycated
increased risk of atherogenesis
what are the LDL mods in atherosclerosis?
oxidation of apo B-100
glycation
HDL has at least 2 antioxidant enzymes that can inhibit or reverse WHAT?
oxidation
what is a scavenger receptor?
binds to modified LDL (in atherosclerosis) & endocytosed the particles
what are foam cells?
cholesterol accumulates in macrophages > XS is deposited as droplets in cytoplasm
how does LDL impact atherosclerosis?
LDL moves out of arterial lumen & into arterial wall > modified & oxidized > inflammation > foam cells
what is the first step for therapy for atherogenic heart disease?
lowering plasma LDL thru diet & meds
how do statins work (GENERALLY)?
block cholesterol production
increase expression of LDL receptor by liver
what is another name for the statins?
HMG-CoA reductase inhibitors
what are the 6 statins you need to know?
lovastatin simvastatin pravastatin fluvastatin atorvastatin rosuvastatin
what are the 4 mechanisms of action of the statins?
inhibits HMG-CoA reductase
decrease in cholesterol synthesis
increased synthesis of hepatic LDL receptors
increased LDL uptake
how do statins impact TG, LDL, & HDL?
= or dec TG
dec LDL
= or inc HDL
what are the clinical uses of statins?
lowering LDL
heterozygous familial hypercholesterolemia
secondary hypercholesterolemia d/t diabetes
what can you combine statins w/ to achieve greater effects & 50% reduction in LDL?
bile acid-binding resins
or
ezetimibe
when does the majority of cholesterol synthesis occur?
at NIGHT
when are statins most effective (what time of day)?
at NIGHT bc that’s when cholesterol synthesis occurs
what are 2 other possible uses for statins?
osteoporosis
anti-inflammatory (modulate immune system AND decrease high sensitivity CRP)
what are the side effects of statins?
HA
photosensitivity
MYALGIA & MYOPATHY (grapefruit!)
rarely liver damage
how are statins cleared?
P450A (CYP3A4)
what can statins interact w/?
GRAPEFRUIT JUICE dihydropyridine CCBs St. John's wort fibrates niacin ketoconazole erythromycin
what is a possible consequence of statin therapy w/ other drugs?
increase levels of oral contraceptives, digoxin, & warfarin
what are the bile acid-binding resins?
cholestyramine
colestipol
colesevelam
what is the mechanism of action of bile acid binding resins?
anion exchange resin
binds bile acids in intestine > increased fecal excretion of bile acid
how do bile acid binding resins get absorbed?
they DON’T!
they’re hydrophobic & unaffected by digestive enzymes so they remain unchanged
what are the results of bile acid binding resins?
increased pdtion of LDL receptors
increased activity of HMG-CoA reductase
how are TGs, LDL, and HDL affected by bile acid binding resins?
inc or dec TGs
decreased LDL
= HDL
when do you use bile acid binding resins?
pts w/ high LDL
what do bile acid binding resins have an ADDITIVE effect in lowering LDL w/?
nicotinic acid & statins
what are the side effects of bile acid binding resins?
GI probs, nausea, indigestion
steatorrhea in high dose
impaired absorption of vitamins (A, D, E, K, folic acid)
may cause hyperchloremic acidosis
