Flashcards in Metabolism 9 Deck (32):
How are lipids transported in plasma?
Lipids Are Transported in Plasma as Lipoproteins That Are Composed of Apolipoproteins and Lipids.
For chylomicron (formed in intestines), What is the main lipid? Apopoproteins? Function?
Formed: in intestines
Main Lipid: TAG
Apoproteins: B-48 (A,C,E)
Function: transports dietary TAG to adipose and other tissues
For Chylomicron Remnant,
What is the main lipid? Apopoproteins? Function?
Main Lipid: TAG
Apoproteins: B-48 (A,C,E)
Function: delivers remaining dietary TAG to liver. Exchanges TAG for CE from HDL; delivers CE to the liver
For VLDL, where is it formed? What is the main lipid? Apopoproteins? Function?
Formed: in liver
Main Lipid: TAG
Apoproteins: B-100 (A,C,E)
Function: Transports endogenously synthesized TAG to adipose tissue and to skeletal and heart muscle. Exchanges TAG for CE from HDL
For IDL-VLDL remnant where is it formed? What is the main lipid? Apopoproteins? Function?
Formed: formed via processing of VLDL in the circulation
Main Lipid: TAG and cholesterol
Apoproteins: B-100, E
Function: Delivers remaining TAG and cholesterol to
Exchanges TAG for CE from HDL. Delivers
CE to the liver
For LDL, where is it formed? What is the main lipid? Apopoproteins? Function?
Formed: (formed via processing of IDL in the circulation)
Main Lipid: cholesterol
Function: Delivers cholesterol to the liver and other cells, including steroidogenic cells
For HDL, where is it formed? What is the main lipid? Apopoproteins? Function?
Formed: (formed in the liver;
some formed in intestines)
Main Lipid: cholesterol
Apoproteins: A's (C,E)
Function: Accepts cholesterol from peripheral cells,
esterifies it, and transports CE’s to liver
Exchanges CE for TAG in VLDL, IDL and chylomicron remnants.
Atheroprotective via enzymes such as paraoxonase that inhibit LDL oxidation
Serves as reservoir for circulating apoproteins (A,C,and E), which are
transported to other lipoprotein particles.
Describe the organs and pathways involved with lipoprotein metabolism.
What is the major LP for B-48? Function?
Function: chylomicron secretion
What are the major LPs for B-100? Function?
Binds LDL Receptor, VLDL secretion
What is the major LP for A-1? Function?
Activates LCAT (lecithin: cholesterol acyl transferase) and binds HDL receptor
What are the major LPs for C-II? Function
CyM, IDL, VLDL, HDL
cofactor that activates LP lipase
What is the major LP for Apoprotein E? Function?
CyM, VLDL, IDL
clearance via binding to LRP (LDL receptor associated protein)
Which aporoteins are cofactor for enyzmes?
Apo-CII: lipoprotein lipase
Apo-AI: lecithin: cholesterol acyltransferase (LCAT)
Which apoprotein are Apoliprotein ligands for extracellular receptors?
Apo E: Binds to LRP
Apo B-100: Binds to LDL receptor
Apo A-I: Binds to HDL receptor
Which apoproteins are in lipoprotein particles?
Apo B-48: Chylomicrons
Apo B-100: VLDL, IDL, LDL
Apo A-I: HDL
Describe chylomicron metabolism.
1. Chylomicrons transport dietary TA and cholesterol.
2. Nascent chylomicrons are synthesized in the intestines along with Apo A-1 and Apo B-48.
3. Chylomicrons transiently gain Apo-E and Apo C-II from HDL in the plasma.
4. Apo C-II activates lipoprotein lipase (LPL), located on capillary endothelia. LPL catalyzes
the conversion of TAGs to free fatty acids and glycerol. Fatty acids are taken up by tissues
5. Chylomicron remnants are removed by liver via receptor-mediated endocytosis. This
involves Apo E, which binds to the LDL receptor and LDL receptor related protein (LRP)
6. HDL serves as a repository for Apo C-II, A-I, and E.
p 6, slides 20-21
Draw a flow chart for Very Low Density Lipoproteins(VLDL) Transport Triacylglycerols (TAGs) and Cholesterol (C) That Are Synthesized Endogenously.
Slide 22 p 7
What do VLDL transport?
What is VLDL a precursor for?
Where are VLDL synthesized (with what else)?
What does VLDL pick up in the circulation?
What does C-II do?
1. VLDL transport TAGs and cholesterol that are synthesized endogenously. VLDL also serve as the precursor of IDL and of LDL.
2. VLDL are synthesized in the liver along with Apo B-100. VLDL picks up Apo E and Apo C-II from HDL in the
Apo C-II activates lipoprotein lipase (LPL), which catalyzes the conversion of TAGs to glycerol and FFA.
How to VLDL become IDL?
What happens in the conversion of VLDL to IDL?
What happens in the conversion of IDL to LDL?
What happens to remaining LDL?
As VLDL lose TAG and shrink, they are converted to IDL (intermediate density lipoproteins). IDL are also known as the VLDL remnant.
In the conversion of VLDL-> IDL-> LDL, Apo C-II activates lipoprotein lipase (LPL), which cleaves TAGs into
free fatty acids (FFA) and glycerol. FFA are taken up by tissues and metabolized.
In the conversion of IDL-> LDL, Apo C-II and Apo E are transferred to HDL. LDL retains Apo B-100.
Any remaining IDL can be removed from the circulation via receptor-mediated endocytosis, which involves the LDL receptor (via binding to Apo B-100 and to Apo E) and LRP (via binding to Apo E). LRP = LDL receptor related protein
What is the major pathway by which LDL is removed from the circulation?
The major pathway by which LDL is removed from the circulation involves the binding of Apo B-100 on LDL to the LDL receptor. LDL receptors are found on both hepatic and nonhepatic tissues.
The major mechanism for removal of LDL requires a functional LDL receptor
See diagram p 8
What happens when cholesterol levels are high to the LDL receptors?
When cholesterol levels are high, there is a down-regulation of the high affinity LDL
receptors that are involved with LDL receptor-mediated uptake of cholesterol. These
cellular adaptations occur when the cell has adequate cholesterol.
However, even in the presence of high cholesterol levels, the non-specific receptorindependent
pathway (pinocytosis) contributes to cellular uptake of LDL cholesterol. Although not a major pathway under conditions when cholesterol levels are normal, this pathway can assume greater importance when LDL cholesterol levels are high.
Describe the Uptake of Oxidized Cholesterol by Macrophages & Coronary Artery Disease:
What substances can oxidize LDL cholesterol? What can prevent oxidation?
How can oxidized LDL be taken up?
What happens next?/ with continued uptake of oxidized LDL?
1. LDL cholesterol can be oxidized by oxidants (superoxide, nitric oxide, hydrogen peroxide.
Vitamin E, ascorbic acid (vitamin C), B-carotene (vitamin A), and other antioxidants
can prevent such oxidation.
2. Oxidized LDL can be taken up by macrophages. It has been hypothesized that the
mechanism could involve a relatively minor pathway that utilizes oxidized LDL receptors
and/or the receptor-independent pathway (above). The cholesterol-laden macrophages
become foam cells.
3. Foam cells accumulate, release cytokines that stimulate the proliferation of smooth muscle cells and calcification of plaque.
4. Continued uptake of oxidized LDL leads to coronary artery disease and
Where are nascent HDL's synthesized? What shape are they secreted in? What do they contain?
Nascent HDLs are synthesized in the liver (and small intestines) and secreted with a discoidal shape. They contain Apo A-I, LCAT and phospholipids.
What is purpose of HDLs?
HDLs serve as a reservoir of apoproteins for chylomicrons and VLDL.
How do HDLs change as they accumulate cholesterol from peripheral tissues and other lipoproteins?
HDLs are rapidly converted to a spherical shape as they accumulate cholesterol from
peripheral tissues and other lipoproteins.
What happens to free (non-esterified) cholesterol?
When/how does it become esterified?
Free (nonesterified) cholesterol is transferred from plasma membranes to lipid poor
nascent HDL yielding HDL3; this is mediated by ABCA-1. HDL3 + additional free
cholesterol to HDL2.
Once free cholesterol is taken up by HDL, the enzyme PCAT (also called LCAT)
esterifies the cholesterol. This enzyme is activated by Apo A-1.
What does mature HDL do?
Mature HDL deliver cholesterol to the liver for excretion (reverse cholesterol
transport) by two mechanisms.
Mature HDL deliver cholesterol to the liver for excretion (reverse cholesterol transport) by two mechanisms.
a). CETP mediates the transfer of cholesterol esters from HDL’s to VLDL & IDL & chylomicron remnants in exchange for TAG. This produces a larger HDL2.
Cholesterol enriched IDL and chylomicron remnants are taken up by the liver via Apo E-dependent binding to the LDL receptor and LRP.
b). Spherical HDLs are taken up by liver by receptor-mediated endocytosis via Apo AI dependent binding to the scavenger receptor protein BI (SR-BI).
What happens to cholesterol that is delivered to the liver?
Cholesterol that is delivered to the liver is then either converted to bile acids or repackaged into lipoproteins.
Describe the additional atheroprotective effects of HDL.
a). HDL contains enzymes, i.e., paroxonase, that inhibit LDL oxidation in intima of blood vessels.
b). HDL increases NO synthesis by endothelial cells.