Flashcards in L38 – Abnormal lipid metabolism; atherosclerosis Deck (66):
What are the 2 pathways for transportation of lipids by lipoproteins?
Exogenous and Endogenous pathways
What is first released in the exogenous pathway?
Mucosal cells in small intestine produce NASCENT CHYLOMICRONS from dietary lipids
Describe the nascent chylomicron secreted by small intestine mucosal cells at the start of exogenous pathway?
Contains apo B-48
TAG rich (TAG > CE, C)
What happens to nascent chylomicron in exogenous pathway?
HDL transfer apo C-II and apo E to n. chylomicron
n. chylomicron now has apo C-II, apo E and apo B48
What happens to chylomicron in capillaries of tissue in exogenous pathway?
After gaining apo E and apo C-II from HDL >
apo C-II activates lipoprotein lipase (LPL) >
TAG in chylomicron degraded into Fatty acid + glycerol
Fate of molecules released from chylomicron in exogenous pathway to tissue?
TAG in chylomicron broken down into FA and glycerol by LPL
FA enter into tissue
Glycerol to liver
After TAG break down in chylomicron at tissue in exogenous pathway, what happens to chylomicron?
Apo C-II is returned to HDL (previous given by HDL to activate LPL)
Becomes Chylomicron Remnant (CE-rich)
What apolipoproteins does chylomicron remnant contain?
Only apo E and apo B48
What happens to chylomicron remnant in exogenous pathway?
Chylomicron remnants bind through apo E to specific
receptors on liver > endocytosed
In the endogenous pathway , what is secreted to start the transport?
Liver secretes NASCENT VLDL (unlike exogenous where n. chylomicron is secreted)
Describe nascent VLDL in endogenous pathway.
contain primarily endogenously synthesized lipids, apo B-100
What happens to nascent VLDL to turn it into mature VLDL in endogenous pathway?
HDL transfers apo C-II, apo E to nascent VLDL via cholesteryl ester transfer protein (CETP)
Describe mature VLDL.
apo B-100, apo E, apo C-II
What happens to mature VLDL in exogenous pathway?
Extracellular LPL activated by apo C-II on mature VLDL at capillaries > degradation of TAG into FA and glycerol
Fate of TAG breakdown by LPL in endogenous pathway?
TAG > FA + glycerol
FA enter into tissue
glycerol to liver
What processes turns mature VLDL to LDL in endogenous pathway?
mature VLDL return apo C-II and apo- E to HDL
No longer TAG-rich
CE- rich, only apo B-100
What happens to LDL in endogenous pathway?
LDL binds through apo B-100 to receptors on liver OR extrahepatic tissue to be endocytosed
What is the difference in the ultimate fate of lipid transport between endogenous and exogenous pathways?
Endogenous > LDL to either liver or extrahepatic tissue
Exogenous > Chylomicron remnant to liver
Both use different apo. to enter cells (LDL= apo B100, CR= apo E)
What forms nascent HDL? *
Free apo A1 + excess cholesterol from peripheral cell via ABCA1 channel
How does nascent HDL pick up even more cholesterol? *
from peripheral cells via ABCG1 channel
What converts all the cholesterol HDL picks up into internalized Cholesterylester (CE) ? *
LCAT on HDL surface
What is the role of HDL?
Bring cholesterol from peripheral tissue to liver
What receptor is important in the uptake of HDL to liver and steroid hormone-producing tissue? *
What receptor is for transfer of cholesterol to VLDL, LDL, IDL to move into liver? *
What is the role of Apo B-100?
Found on VLDL, LDL (and IDL)
For LDL receptor binding upon returning to liver/ enter extrahepatic tissue in endogenous pathway
What is the role of apo B-48?
Found in n. chylomicron, chylomicron, chylomicron remnant
For secretion of chylomicron (and VLDL)
What is the role of apo E?
Found on chylomicrons, HDL, LDL, VLDL
For chylomicron remnant receptor binding to uptake to liver in exogenous pathway
What is the role of apo A1 (and A2)? *
for formation of HDL (and chylomicron)
Act as LCAT activator on HDL > turn TAG into internalized CE
Role of apo C-II?
Found in HDL, CHylomicron, VLDL (and IDL)
For activation of Lipoprotein lipase to break down TAG into FA and glycerol
What is used in the centrifuge of blood to separate blood into its components?
Centrifuge blood with jelly (lighter than red cells, heavier than serum) > separate blood into serum and RBCs
Which bit of centrifuged blood is used to assess lipid abnormalities?
What is the colour of serum in fasted vs lipemia ?
Fasted = clear
Lipemia = cloudy
What 2 tests can be done to test for cholesterol in blood? *
Standing plasma test
What is Type I phenotype in Frederickson classification? Rare or not? What is in the blood? *
Accumulation of chylomicron in blood, very high TAG, cholesterol normal or slightly high
What causes Type I phenotype? *
Defective apo C2 (main reason)
LPL not activated by defect apo C-II, chylomicron not converted to c. remnant, accumulate in blood
What is the appearance of serum in Type I phenotype? *
chylomicron form distinct opaque band
What is one Type IIa phenotype? *
What is defective to cause Type IIa ? Common or not? *
Deficient/ defective LDL receptor
in endogenous pathway LDL clearance into liver is hampered > accumulate of LDL
Appearance of serum of Type IIa?
Clear (LDL cant be seen)
What causes type IIb phenotype? *
Deficient/ defective LDL receptor AND Apo B-100
B-100 is found in LDL, VLDL, IDL
Defect leads to accumulation of all three
Appearance of serum in type IIb? *
Turbid to opaque
What is one type III phenotype?
What is defective in type III? Common or Rare?
present in chylomicron, chylomicron remnant, VLDL and IDL
IDL and Chylomicron remnant accumulate
Appearance of serum in type III?
THIN cream layer (unlike type I thick cream)
Name one type IV phenotype? Common?
Cause of type IV?
Very high VLDL levels
Could be eating habits, diabetes, metabolic defects
Appearance of serum?
Turbid to opaque
Name one type of Type V phenotype?
What causes type V?
very high Chylomicrons and VLDL
Appearance of type V serum?
What 2 genes are defective in Type IIa phenotype?
ARH and PCSK9
Which type of lipemia phenotype has no clinical findings/ subsequent diseases?
Type IV or V
Except for familial hypertriglyceridemia, what are the two common clinical findings for lipemia?
What is mixed hyperlipidemia?
Both hypercholesterolemia and hypertriglyceridemia
What is Hypertriglyceridemia associated with?
(e.g. type IV, V): elevated TAG is associated with increased insulin resistance
What is the remedy for Hypertriglyceridemia ?
What is Hypercholesterolemia associated with?
elevated serum LDL-cholesterol contribute to atherosclerosis / formation of atheroma
What is the remedy for Hypercholesterolemia ?
Which phenotype is associated with PCSK9 defect?
Which lipid is high in plasma in hypocholesterolemia?
Cholesterol rich, apo B
Explain action of PCSK9 on LDL regulation
LDL receptor expression is regulated by PCSK9
Normally, PCSK9 complexes with LDL receptor and degrades it
Type IIa defect: PCSK9 inhibited > prolong expression of LDL uptake > increase LDL uptake to cells
How come increased LDL uptake into cell in hypercholesterolemia (e.g. type IIa phenotype) is bad?
Increased plasma LDL >
LDL is small, infiltrate endothelium by passive diffusion > form atheroma/ lesion of fibrous plaque
What is the difference between activated and normal endothelial cells?
Activated endothelium = more permeable, more inflammatory cytokines and leukocyte adhesion molecules
Less antithrombotic molecules
What is the difference between activated and normal arterial smooth muscle cells?
Activated: more inflammatory cytokines, increase ECM synthesis and migration + proliferation into intima
What is the Ultimate complication of atherosclerosis?
Fibrous cap erupt > thrombosis > Stroke, Coronary artery disease, Myocardia infarction