T13 - Lipoprotein Metabolism Flashcards
Give an example of a hydrophilic amphipath. (2)
fatty acids
phospholipids
Give an example of a hydrophobic amphipath.
cholesterol
What is the composition of mixed micelles?
phospholipids
long chain fatty acids
MAGs
bile acids
Describe the relative orientations of the components of mixed micelles.
hydrophobic portions of PLs, fatty acids, and MAGs oriented toward center and surrounded by amphipathic bile acids
Describe the common, generic structure of all lipoproteins.
hydrophobic TG + CE core
trace quantities of fat-soluble vitamins
surface with amphipathic molecules (unCE + PLs) + amphipathic apolipoproteins
What are the two criteria by which lipoproteins are classified?
classification based on relative size and density
What is the density of plasma?
1.006 g/mL — slightly higher than water because of presence of proteins
List the relative densities of cholesterol, CE, PL, protein, and TG.
cholesterol/CE/PL = 1.000
TG = 0.900
protein = 1.200
What are the six major classes of lipoproteins?
HDL
LDL
VLDL
CM
IDL
CMr
Describe HDL.
small particles that are rich in protein + CE and poor in TG
Describe LDL.
less protein but mostly CE and slightly higher TG
Describe VLDL. (2)
large amounts of TG, some CE, and little protein
density below plasma density
Describe CM.
even more TG relative to CE (>10:1 ratio) and very little protein
Describe IDL.
have similar amounts of TG and CE
How are IDLs produced?
produced from metabolism of VLDL particles
Describe CMr.
remnants of chylomicrons rich in CE and TG
What is the alternative pathway for hepatic CM uptake if hepatic LDL receptors are nonfunctional?
LRP mechanism — CMr can still be cleared normally even in patients without functional LDLR (i.e. familial hypercholesterolemia)
What is the principal function of chylomicrons?
to deliver TG to peripheral tissues
What are the physical characteristics of VLDL? (3)
TG-rich but lower TG:cholesterol ratio (5:1) than that present in CMs (20:1)
VLDLs smaller than CMs (80 nm vs. 500 nm)
VLDL contains 1 copy of ApoB-100 but multiple copies of ApoAI, ApoCII, and ApoE
Where does VLDL synthesis occur?
ER of hepatocytes
Describe the steps of VLDL synthesis. (3)
made in ER → undergoes lipidation → secreted into blood → acquires multiple copies of ApoE + ApoCII from HDL
Which ApoB variant does VLDL contain?
ApoB-100 (remember, because VLDL is made in the liver, it can only have the B-100 variant)
What protein/enzyme does VLDL encounter as it circulates through the body?
encounters lipoprotein lipase (just like CMs do) and undergo breakdown such that most of the VLDL’s TGs are delivered to peripheral tissue
What does VLDL become after interaction with lipoprotein lipase?
becomes a VLDL remnant = intermediate density lipoprotein (IDL)
How are VLDL remnants cleared?
through two pathways:
1) 50% of the time, cleared by LDLR-mediated endocytosis in the liver
2) the other 50% of the time, VLDL remnant further metabolized into LDL, which contains a single ApoB-100
What enzyme is responsible for the conversion of IDL to LDL?
hepatic lipase
Hepatic lipase is responsible for what activity?
conversion of IDL into LDL
i.e. conversion of VLDL into LDL
Where does the formation of LDL from VLDL occur?
vascular space
How is LDL cleared from circulation?
in liver or peripheral tissue via LDLR-mediated endocytosis
What structure on LDL serves as the ligand for LDLR-mediated endocytosis?
ApoB-100
Differentiate between the rate of clearance of LDL and VLDLr.
VLDLr uses ApoE for uptake
LDL uses ApoB-100 for uptake
ApoB-100 has lower affinity than ApoE for LDLR
therefore, VLDLr cleared faster than LDL
(T/F) All LDL is cleared by the liver.
False. 20% of the LDL is taken up by extrahepatic tissues.
What are the values of VLDLr and LDL in a normal individual?
VLDLr = 10/20 mg/dl (cleared rapidly)
LDL = 90-100 mg/dl
What is the principal composition of HDL?
high amounts of ApoAI with smaller amounts of ApoCII and ApoE (basically, mostly protein)
Where is HDL synthesized?
in the liver and small intestines
How is HDL initially synthesized?
as disc-like particles w/ unesterified cholesterol, phospholipids, and ApoA-I
Describe the steps of HDL particle formation.
disc-like particle forms → unesterified cholesterol esterified to long-chain fatty acid via LCAT enzyme → esterified cholesterol forms HDL core
Which enzyme is responsible for HDL particle formation?
lecithin-cholesterol acyltransferase (LCAT)
(T/F) Cells in the body are capable of degrading sterols.
False. No cells in the body can degrade sterols.
What is the only cell type that does NOT continuously synthesize cholesterol from acetyl CoA?
RBCs
What are the two mechanisms by which HDL particles pick up cholesterol in peripheral tissue and deliver it back to the liver?
(1) CETP: cholesteryl esters in HDL transferred to CM/VLDL/LDL (all ApoB lipoproteins) via enzyme cholesterol ester transfer protein (CETP) and cleared by the liver via LDLR-mediated endocytosis
(2) SR-BI: ApoAI interacts with SR-BI (a.k.a. SCAR-B1) on hepatocyte which allows direct transfer of cholesterol esters from HDL to hepatocyte cytosol
How is cholesterol excreted by the liver and small intestines? (2)
some of the cholesterol that returns to the liver is converted to bile acid and secreted into bile
alternatively, cholesterol is secreted directly into bile by ABCG5/ABCG8
Describe the levels of CM, VLDL, HDL and LDL in fasting individuals.
in fasting individuals:
CM and VLDL low
HDL and LDL high
A mutation in CETP would have what effect on HDL levels?
mutation in CETP → high HDL levels
An increase in triglyceride levels has what effect on HDL levels?
increase in triglycerides → lower HDL levels
Why are levels of CM and VLDL so low in fasting blood samples?
CM and VLDL are low in fasting blood because they’ve been taken up/cleared by the liver
What is the effect of having a non-functional LDL receptor for the clearance of exogenously-derived lipoprotein particles?
No effect. LRP is a form of redundancy that can clear LDLs. LRP binds ApoE instead of ApoB. LRP, unlike LDL receptors, is not regulated and is constitutively on.
